# Cellular Titanomachy: Viral Forces Clash with Mitochondrial Power

Théo Defresne, Rodolphe Suspène, Jean-Pierre Vartanian

► To cite this version:

Théo Defresne, Rodolphe Suspène, Jean-Pierre Vartanian. Cellular Titanomachy: Viral Forces Clash with Mitochondrial Power. Annual Review of Virology, 2025, 12 (1), pp.157-178. 10.1146/annurev-virology-092623-090901. hal-05395570

HAL Id: hal-05395570

https://hal.science/hal-05395570v1

Submitted on 3 Dec 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_2.png" /></figure>

*Annual Review of Virology*

*Cellular Titanomachy:
Viral Forces Clash with
Mitochondrial Power*

Théo Defresne,<fnref n="1" />,<fnref n="2" /> Rodolphe Suspène,<fnref n="1" /> and Jean-Pierre Vartanian<fnref n="1" />

Annu. Rev. Virol. 2025. 12:157–78

The *Annual Review of Virology* is online at
virology.annualreviews.org

https://doi.org/10.1146/annurev-virology-092623-090901

Copyright © 2025 by the author(s). This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

<figure><img src="image_3.png" /></figure>

ANNUAL
REVIEWS **CONNECT**

www.annualreviews.org

• Download figures

• Navigate cited references

• Keyword search

• Explore related articles

• Share via email or social media

**Keywords**

mitochondria, virus, mitochondrial dynamics, oxidative stress, antiviral immunity, metabolic pathways

**Abstract**

Mitochondria play a vital role in cellular metabolism, energy production, and immune signaling, making them key targets for viral manipulation. Viruses exploit mitochondrial functions to enhance replication and evade immune responses. They also disrupt mitochondrial dynamics by altering fission/fusion balance and modulating mitophagy, which is essential for mitochondrial quality control. Additionally, they reprogram mitochondrial metabolism, affecting pathways such as oxidative phosphorylation and glycolysis to support replication. Viruses regulate apoptosis, either inhibiting or activating mitochondria-mediated apoptosis to prolong host cell survival or facilitate viral spread. Viral infections also induce oxidative stress through reactive oxygen species generation, affecting cellular integrity. Furthermore, viruses manipulate mitochondrial antiviral immunity by degrading mitochondrial antiviral signaling protein and triggering the release of mitochondrial DNA, modulating immune responses. Understanding these interactions offers valuable insights into viral pathogenesis and presents therapeutic opportunities. Targeting mitochondrial dysfunction and enhancing antiviral immunity could provide new strategies to mitigate viral damage and enhance cellular resilience.

<footnote n="1">¹Virus and Cellular Stress Unit, Department of Virology, Université Paris Cité, Institut Pasteur, Paris, France; email: jean-pierre.vartanian@pasteur.fr</footnote>

<footnote n="2">²Complexité du Vivant, Sorbonne Université, Paris, France</footnote>
# 1. INTRODUCTION

The interaction between viruses and mitochondria is a critical feature of how viruses hijack host cells to promote replication and survival. Mitochondria, often referred to as the powerhouses of the cell, are involved in the production of energy, the regulation of cellular metabolism, apoptosis, and immune signaling, all processes that viruses can exploit. Viruses can alter the mitochondrial network, and this interaction plays an important role in the ability of viruses to replicate and evade the host immune system (Figure 1).

Mitochondria are dynamic organelles capable of changing shape through fission and fusion. Viruses can influence these processes by affecting the balance between them, which is essential for maintaining optimal mitochondrial function. Some viruses promote mitochondrial fragmentation (increased fission), which can impair energy production, dampen the innate immune response, and trigger apoptosis. In contrast, other viruses may favor mitochondrial fusion to meet the energy

<figure><img src="image_4.png" /><figcaption>Figure 1</figcaption></figure>

Viruses at the cross talk between mitochondria functions. Viruses affect mitochondria dynamics through perturbation of the fission/fusion balance and regulate mitophagy. They trigger and modulate mitochondria antiviral response by inducing or inhibiting apoptosis and triggering an innate immune and mtDNA release. Viruses also induce mitochondria-controlled metabolism reprogramming, ROS production, and calcium flow. Abbreviations: Cyt c, cytochrome c; mtDNA, mitochondrial DNA; ROS, reactive oxygen species. Figure adapted from images created in BioRender; DEFRESNE T. 2025. https://BioRender.com/rv4umik.
and metabolic demands of viral replication while modulating innate immunity. Many viruses re-
program host cell metabolic pathways to promote their replication. By modifying mitochondrial
metabolism pathways in this way, viruses can shift energy production for their own advantage.

Mitochondria play a role in the innate immune response, notably through the production of reactive oxygen species (ROS) and the activation of antiviral proteins such as the mitochondrial antiviral signaling protein (MAVS). Some viruses can interfere with these processes, attenuating the immune response and allowing the virus to persist in the host. However, during cellular stress or infection, disruption of the mitochondrial network also can lead to the release of mitochondrial DNA (mtDNA) into the cytoplasm, which can act as a danger signal, detected by the immune system.

Mitochondria also play a central role in the process of apoptosis, a mechanism used by cells for their self-destruction in response to viral infection. Viruses can inhibit the pathways leading to apoptosis in order to keep the host cell viable for extended periods, leaving more time for viral replication. Conversely, some viruses can induce apoptosis in order to spread into other cells.

In this review, we discuss the various points raised above by providing specific examples. We analyze how viruses interact with mitochondria and how they can target mitochondrial functions. By altering mitochondrial functions, dynamics, and signaling pathways, viruses can create a favorable environment for their replication and facilitate their evasion of host immune defenses. Understanding these interactions is essential for designing antiviral strategies and therapies.

2. MITOCHONDRIA: VULNERABLE TARGETS FOR VIRUSES

Mitochondria are essential for cellular energy production, signaling, and the regulation of apo-
ptosis, making them players in the maintenance of cellular homeostasis. However, due to their
pivotal role in the immune response and cell survival, mitochondria also are vulnerable targets
for viruses. By manipulating mitochondrial dynamics and metabolism, viruses can hijack host cell
machinery, evade immune surveillance, and optimize conditions for replication and persistence.

2.1. Structure of Mitochondria

Mitochondria are crucial organelles within cells characterized by intricately designed structures called cristae. Mitochondria are elliptical or cylinder shaped, ranging from 0.75 to 3 µm in length, and structured into four functional regions from the outside in: the smooth outer mitochondrial membrane (OMM), the inner intermembrane space (IMS), the inner mitochondrial membrane (IMM), and the matrix (1). Mitochondrial cristae are internal membrane invaginations that serve not only to enhance the surface area of the IMM but also to accommodate electron-carrying proteins and adenosine triphosphate (ATP) synthase. IMM proteins are involved in the assem- bly of the electron transport chain (ETC), which provides energy for oxidative phosphorylation (OXPHOS). The matrix contains mtDNA, enzymes, and ribosomes. In addition to supplying cells with energy, the mitochondrial matrix is the main site of several essential metabolic pathways, such as the tricarboxylic acid cycle (TCA cycle), fatty acid β-oxidation (FAO), and the unique carbon cycle (2). The number of mitochondria depends on the metabolic level of the cell; consequently, cells with increased metabolic activity exhibit more mitochondria (3).

Mitochondrial biogenesis is a complex process involving the coordination of nuclear and mi-
tochondrial genes to ensure the precise function of proteins in the mitochondrial ETC. mtDNA
present in the matrix is a double-stranded circular DNA molecule consisting of 16,569 base pairs.
The mitochondrial genome comprises 37 genes encoding 13 polypeptides (essential ETC genes),
2 ribosomal RNA (rRNA) genes (12S and 16S rRNA), and 22 transfer RNA (tRNA) genes re-
quired for mitochondrial protein synthesis (4). The remaining mitochondrial proteins are encoded
by nuclear genes, and around 1,500 nuclear-encoded proteins are involved in the regulation of mitochondrial functions in humans (5).

## 2.2. Function of Mitochondria

Mitochondria play a central role in cellular energy, metabolism, and signal transduction, mainly through the production of ATP and intermediate metabolites, such as glucose, fatty acids, and amino acids as energetic substrates (6–8). Glycolysis, which takes place in the cytoplasm, metabolizes glucose to pyruvate, which is converted into acetyl-coenzyme A (CoA). Glycolytic intermediates also are redirected to fatty acid and amino acid biosynthesis, and to the pentose phosphate pathway, which generates nicotinamide adenine dinucleotide phosphate (NADPH), which is essential for antioxidant protection. Acetyl-CoA, also generated by fatty acid oxidation, supplies the TCA cycle in the mitochondrial matrix, which produces the reducing intermediates nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2). Reductive intermediates transfer electrons to molecular oxygen through redox reactions, catalyzed by a series of electron-carrying complexes (complexes I to IV), known as the ETC, in a process called OXPHOS, which takes place in the IMM. Indeed, the ETC creates a membrane potential (ΔΨm) by generating a proton gradient across the IMM that fuels ATP production.

Mitochondria also are the main source of intracellular ROS production, with mitochondrial OXPHOS generating significant amounts of ROS as a biochemical by-product of the ETC (9). ROS include O₂⁻, H₂O₂, OH⁻, and LOOH, which can provide O₂⁻ free radicals in biochemical reactions and have potent biological activities (10). During viral infections, mitochondria play a crucial role in the innate immune response by generating ROS, facilitating interactions between their MAVS and viral genome sensors, and through the release of mtDNA, all of which contribute to an effective defense mechanism against viral invasion.

## 3. VIRAL INFECTION DISRUPTS MITOCHONDRIAL DYNAMICS

Mitochondria play a crucial role in maintaining cellular homeostasis, regulating energy production, apoptosis, and immune responses. By disrupting mitochondrial dynamics, viruses can manipulate these essential cellular processes to create a more favorable environment for their replication and survival. Altering mitochondrial function, particularly the balance between fission and fusion, can help viruses evade immune detection, modulate cellular metabolism, and promote host cell survival, all of which contribute to viral persistence and propagation. In this context, viral proteins can directly interact with key mitochondrial regulators to induce mitochondrial fragmentation, a strategy that optimizes replication and enhances the virus's ability to evade host defenses.

### 3.1. Viruses Alter Fission/Fusion Balance

Following different types of stress, such as genotoxic, oxidative, or viral stress, mitochondria may need to turn over some of their components to restore their original healthy metabolic state (11). This renewal is made possible by the high number of mitochondria present in each cell, varying from 100 to 1,000 mitochondria in most human cell types (12) and up to 100,000 mitochondria in the mature oocyte (13). Maintaining a healthy pool of mitochondria will enable effective innate immune and antiviral responses (14), but it also will ensure an adequate cellular metabolism. Mitochondria should not be considered as individual organelles but rather as a network of cooperating and dynamic organelles. This dynamic allows the mitochondrial network to be highly regulated spatially, quantitatively, and functionally in order to maintain cellular homeostasis.
<figure><img src="image_5.png" /><figcaption>Figure 2</figcaption></figure>

Viruses dysregulate mitochondria dynamics. Some viruses tend to influence fusion of mitochondria, promoting survival of the cells and helping meet their energy demands, while other viruses may induce mitochondria fission, preventing an effective innate immune response. Mitochondria synthesis and degradation are two processes driven by mitochondria biogenesis and mitophagy, respectively, allowing a tight regulation of cell metabolism and antiviral response. Some viruses may regulate the number of mitochondria by inducing or preventing mitophagy. The red and blue boxes represent inhibitor and inducer viruses, respectively. Light blue boxes represent viruses targeting both fission and fusion. Abbreviations: DENV, dengue virus; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IAV, influenza A virus; SARS-CoV, severe acute respiratory syndrome coronavirus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ZIKV, Zika virus. Figure adapted from images created in BioRender; DEFRESNE T. 2025. https://BioRender.com/9mrmde8.

In fact, this network is regulated by a dynamic balance between fission and fusion, allowing the biogenesis of new mitochondria and the rescue or clearance of damaged ones (Figure 2). Fission is the process by which a mitochondrion divides, using a structurally conserved molecular machinery similar to that regulated by the FtsZ (Filamenting temperature-sensitive mutant Z) that assembles into a ring at the future site of bacterial cell division (15), underlining the bacterial origin of mitochondria (16). This machinery relies on the recognition of Drp1 (Dyanmin-related protein 1), a cytosolic protein with a GTPase domain, by several OMM receptors (including MFF, MiD49, and MiD51) (17). This recognition leads to the formation of a contractile Drp1 oligomerized ring around the mitochondria, which ultimately enables membrane scission in a GTP-dependent manner (18).

Alternatively, fusion is the process by which two mitochondria fuse, resulting in the sharing of their compounds and the formation of one elongated mitochondrion. This process is closely
mediated by several dynamin-like GTPase interactions, including the homo- and heterotypic in-
teraction of two mitofusins (MFN1 and MFN2) anchored in the OMM (19), and by the different
isoforms of optic atrophy 1 (OPA1) anchored in the IMM (20). This regulated balance between
fission and fusion will participate in mitochondrial quality control, where damaged mitochondria
can be either rescued by fusion, thus restoring energy requirements, or cleared following fission
by the process known as mitophagy (Figure 2). It also has been documented that the fusion/fission
balance directly regulates RLR (retinoic acid-inducible gene I-like receptor) signaling, enhancing
or inhibiting it, respectively, and thus modulating the antiviral response (21). Viruses have devel-
oped different strategies to regulate the fission/fusion balance, thereby controlling the state of the
mitochondrial network to maintain an efficient infection (Figure 2).

**3.1.1. Viruses promote fusion.** Some viruses are able to induce mitochondrial fusion (Figure 2), allowing them to remodel and maintain the mitochondrial network functions to promote cell survival during viral replication. Severe acute respiratory syndrome coronavirus (SARS-CoV) induces mitochondrial fusion, with the anti-inflammatory viral protein orf9b targeting Drp1 for its ubiquitination and subsequent proteasomal degradation (22). Dengue virus (DENV) is reported to successfully replicate in replication factories termed convoluted membranes derived from the endoplasmic reticulum (ER) (23). Induction of the elongation mechanism appears to be conserved in other flaviviruses (FVs) such as Zika virus (ZIKV) (24). The viral protein NS4B promotes fusion by impairing the activation of the Drp1 fission factor (24). In turn, mitochondrial elongation promotes DENV replication and alleviates retinoic acid-inducible gene I (RIG-I)-dependent interferon (IFN) response. Interestingly, microscopic observations of DENV have revealed disruption of the ER, specifically at the mitochondria-associated membranes (MAMs) sites, potentially reducing the interaction between mitochondria and the ER and thus leading to an attenuated inflammatory response (24, 25). Consequently, DENV serves as a prime example of a virus that can regulate both the spatial localization and the dynamic balance of mitochondria to its benefit.

**3.1.2. Viruses promote fission.** Other viruses are capable of inducing mitochondrial fission (Figure 2), creating defective mitochondria with dysfunctional metabolism and anti-inflammatory responses. This includes Epstein-Barr virus (EBV), which is a known oncogenic virus. The viral oncogenic latent membrane protein 1 (LMP1) of EBV stimulates the active phosphorylation state of Drp1. This active form will then induce mitochondrial fission and promote glycolysis, thus participating in the process of tumorigenesis (26). Both hepatitis B virus (HBV) and hepatitis C virus (HCV) can induce mitochondrial fragmentation by targeting several key players in the fission/fusion balance. HBV-encoded oncogene X protein (HBx) is a key multifunctional regulatory protein that drives viral replication and interferes with several cellular signaling pathways. This protein has been described as promoting not only the expression/activation of Drp1 but also the degradation of MFN2, leading to a disrupted mitochondrial network with fragmented mitochondria (27). Similar modulation also has been observed during HCV infection, where the virus promotes Drp1 expression/activation as well as the expression of the Drp1 receptor, MFF. Notably, experimental inhibition of HCV-induced mitochondrial fission led to increased apoptosis, enhanced innate immune response, and infection failure (28). During infection, the state of the mitochondrial network can be critical, leading to excessive fission and accumulation of defective mitochondria, as described with HBV and HCV. In this case, defective mitochondria can be eliminated by asymmetric fission followed by mitophagy, another cellular process playing a major role in the fission/fusion balance.

Depending on the cellular model and the time of infection, some viruses appear to modulate
the fission/fusion balance in both directions during viral infection (Figure 2), underlining the
importance of viral control over the mitochondria dynamics. For instance, ZIKV induces mitochondrial fission in neurons by downregulating MFN2 protein levels (29), whereas DENV utilizes its NS2B3 protease to cleave MFN1 and MFN2 (30), thereby driving mitochondrial fission and inhibiting the MFN-mediated RLR response (31).

Viral proteins can actively regulate the mitochondrial fission/fusion balance, with some specifically interacting with Drp1 to promote or prevent mitochondrial fragmentation. This modulation of mitochondrial dynamics is not incidental but serves as a key viral strategy. By directly influencing the fission/fusion machinery, viruses optimize their replication processes, alter host cell energy metabolism, disrupt immune responses, and create a cellular environment that supports viral persistence. This sophisticated manipulation of mitochondrial function allows viruses to exploit host cell resources more efficiently and evade host defenses, thereby enhancing their survival and propagation within the host.

## 3.2. Viruses Modulate Mitophagy

Mitophagy is a specific form of autophagy (from the Greek *phagos*: to eat, to consume) aimed at clearing and recycling damaged and depolarized mitochondria. Indeed, when mitochondria are too severely damaged to be salvaged by fusion with healthier mitochondria, they undergo asymmetric fission, allowing the cell to discard damaged mitochondria containing defective compounds through a process known as mitophagy (32). This process plays a crucial role in fission/fusion balance and cellular homeostasis, promoting mitochondrial turnover to maintain a healthy energy state and prevent apoptosis.

At the mechanistic level of mitophagy, following dissipation of the mitochondrial membrane potential during cellular stress, the kinase PINK1 (phosphatase and tensin homolog-induced putative kinase 1) is stabilized on the OMM and autophosphorylated in order to recruit Parkin, an E3 ubiquitin ligase (33). The ubiquitination of OMM proteins by Parkin enables their recognition by several adapters that interact with autophagosomal light chain 3 (LC3) through their LC3-interacting region (LIR) motif, thereby triggering phagophore formation around defective mitochondria. Other players such as mitophagy receptors, which are activated under specific stimuli, such as hypoxia and differentiation signals, provide powerful control of autophagosome formation (34). Subsequently, autophagosomes are degraded by fusion with lysosomes.

### 3.2.1. Viruses promote mitophagy.
Viruses share the ability to capitalize on mitophagy and may exploit it to evade the mitochondria-dependent antiviral response (Figure 2). For example, HBV and HCV induce mitochondrial fission and the expression of the *PARK2* (Parkin) and *PINK1* genes, thereby promoting mitophagy and avoiding the onset of an apoptotic state in infected cells (28, 35). Influenza A virus (IAV) also is capable of inducing mitophagy by using IAV protein PB1-F2, which translocates to mitochondria via its interaction with TOM40 and induces mitochondrial fission via a Drp1-dependant pathway (36). Interestingly, PB1-F2 possesses an essential LIR motif that enables recruitment of the mitophagy machinery to those fragmented mitochondria, allowing the virus to escape the mitochondria-dependent innate immune response by mimicking signals that induce mitochondria degradation (37). More recently, it has been identified that the IAV nucleoprotein NP also is capable of triggering mitophagy by interacting with the mitochondrial MAVS and TOLLIP proteins (a cellular adaptor that recruits LC3 via its LIR motif) (38), indicating that IAV has developed several strategies for eliciting mitophagy. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, also has been described as inducing mitophagy and therefore escapes detection by mitochondrial MAVS. The viral protein orf10 interacts with both the mitophagy receptor Nip3-like protein (NIX) and LC3 to enable phagosome formation and mitochondria degradation (39).
**3.2.2. Viruses prevent mitophagy.** More rarely, viruses also can inhibit mitophagy (Figure 2). This appears to be the case for ZIKV with the NS5 protein, which prevents PINK autophosphorylation and consequently induces the cell into a state of sustained inflammation and chemokine expression (40). These released chemokines could play a role in monocyte recruitment, enabling their subsequent infection and thus promoting tissue invasion by the virus. Interestingly, exposure of human primary neurons to human immunodeficiency virus (HIV) gp120 and Tat proteins accelerates the shift in mitochondrial dynamics toward fission, resulting in fragmented mitochondria. This process induces perinuclear aggregation of mitochondria leading to neuronal mitochondrial fragmentation and incomplete mitophagy (41, 42). This phenomenon has been described as playing an important role in HIV-associated neurocognitive disorders (HANDs) (41).

Finally, it has been shown that mitochondrial dynamics are directly correlated with cellular
metabolism, with fusion promoting ATP production by mitochondria and fission decreasing mito-
chondrial respiration (43). Consequently, for an infection to succeed, viruses target mitochondria
to overcome the antiviral response and hijack cellular metabolism to their advantage.

4. VIRUS INFECTIONS INFLUENCE MITOCHONDRIAL METABOLISM AND HOMEOSTASIS

Most viruses are expected to have developed several ways of overcoming cellular energy
metabolism by modulating glycolysis, TCA, and mitochondrial OXPHOS because energy sup-
ply is a prerequisite for a successful replication (44). Some metabolic pathways can take place in
mitochondria, such as lipid metabolism, while others are strongly interconnected with mitochon-
dria through the metabolites synthesized during the TCA cycle, such as amino acid and nucleotide
synthesis (2). Therefore, mitochondria provide not only energy but also all the necessary compo-
nents for the biosynthesis of new virions, reinforcing the selective pressure exerted on viruses to
target mitochondria in order to maintain a complete and productive infection cycle.

**4.1. Virus-Induced Modulation of Mitochondrial Metabolism Processes**

Mitochondrial metabolism is highly regulated by the cell, depending on several endogenous and exogenous signals. Viruses are described as obligate intracellular parasites because their replication depends on the availability of cellular ATP to fulfill their intense energy requirements (44). During evolution, they developed several mechanisms to hijack mitochondrial metabolism and influence the glycolysis/OXPHOS balance (Figure 3).

**4.1.1. Viral inhibition of mitochondrial metabolic pathways.** It has been observed that EBV triggers OXPHOS inhibition to promote glycolysis and tumorigenesis. The viral protein LMP1 not only promotes mitochondrial fission (Figure 3, step 1a) but also upregulates DNMT1 (DNA methyltransferase 1) and enables its translocation to the mitochondrial membrane (45). DNMT1 simultaneously downregulates OXPHOS complex genes through mtDNA hypermethylations (Figure 3, step 2) and induces epigenetic activation of aerobic glycolysis (Figure 3, step 3). LMP1 has a broad-spectrum action that not only targets mitochondria but also stimulates glucose transport (Figure 3, step 4), activators of glycolysis and other related pathways, thus establishing a bona fide Warburg effect during EBV infection (46–48).

Another example is provided by Newcastle disease virus (NDV), an avian pathogen mainly studied for its oncolytic properties (49). This virus has recently been described as inducing mi-ochondrial stress, leading to mitochondrial damage (depolarization, ETC dysfunction, ROS production) by inducing mitochondrial fission (Figure 3, step 1a) and mitophagy (Figure 3, step 1b) (50). This triggers a hypoxic environment that stabilized Hypoxia inducible factor 1
<figure><img src="image_6.png" /><figcaption>Figure 3</figcaption></figure>

Viruses hijack mitochondria metabolism. Glucose is imported and used for glycolysis, which produces ATP for the cell and pyruvate to fuel the TCA cycle. The TCA cycle then allows the mitochondria respiratory chain to produce even more ATP through its ETC by using electron transporters and oxygen to create a proton (H⁺) gradient activating the cellular ATP synthase. Viruses may therefore directly influence glycolysis, TCA, or ETC to metabolically hijack the cell and produce the energy and substrates they need. For example, viro-induced mitochondrial fission (step 1a) or degradation (step 1b) result in reduced OXPHOS and enhanced glycolysis. Both mitochondria (step 2) and nuclear (step 3) transcriptomic levels are targeted by viruses, allowing either the activation or the inhibition of ETC and glycolytic genes. Different regulatory axes used by viruses include glucose uptake modulation (step 4), increased respiration through viral factories (step 5), cristae architecture modification (step 6), and viral homologs imitating ETC and glycolysis enzymes (step 7). OXPHOS also produces ROS as a bystander product, which may increase during viral infection and act as an antiviral mechanism through inflammasome activation. However, ROS production has been shown to sustain a favorable environment for certain virus replication (step 8). The red and blue boxes represent inhibitor and inducer viruses, respectively. Abbreviations: ATP, adenosine triphosphate; Cyt c, cytochrome c; EBV, Epstein-Barr virus; ETC, electron transport chain; e⁻ transport, electron transport, FV, flavivirus; GLUT, glucose transporter; HBV, hepatitis B virus; HCMV, human cytomegalovirus; HCV, hepatitis C virus; KSHV, Kaposi's sarcoma herpesvirus; mtDNA, mitochondrial DNA; NCLDV, nucleocytoplasmic DNA virus; NDV, Newcastle disease virus; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; RSV, respiratory syncytial virus; RuV, rubella virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TCA, tricarboxylic acid cycle. Figure adapted from images created in BioRender; DEFRESNE T. 2025. https://BioRender.com/k9bjpx2.

subunit alpha (HIF-1α), which in turn induces glycolytic gene production (Figure 3, step 3), enabling a cellular switch from OXPHOS to aerobic glycolysis in NDV-infected cells.

Different studies have highlighted that SARS-CoV-2 can downregulate TCA and ETC genes in host airway epithelial cells (Figure 3, step 3), with apoptosis and decreased ATP levels leading to
hypoxemia in patients (51). We also can report that human Kaposi's sarcoma herpesvirus (KSHV) suppresses aerobic glycolysis and OXPHOS by decreasing glucose uptake (Figure 3, step 4) to promote cell survival in nutrient stress condition and thus viral infection (52).

### 4.1.2. Viral enhancement of mitochondrial metabolic pathways.
In some cases, viral infection has been shown to elevate OXPHOS levels. Notably, rubella virus (RuV) forms a viral factory in cytopathic vacuoles surrounded by mitochondria (Figure 3, step 5) (53). In fact, during viral assembly, the viral nucleocapsid interacts with the mitochondrial p32 protein, which is functionally important in maintaining OXPHOS (54). A significant increase in ETC complex activity has been described in infected cells (55), suggesting the dependence of RuV on structurally and energetically viable mitochondria to facilitate its replication. Interestingly, HBV has a specific effect on OXPHOS in macrophages. It has been documented that macrophages undergo metabolic reprogramming in response to environmental cues, with M1 macrophages being proinflammatory and glycolysis dependent, while M2 macrophages are anti-inflammatory and OXPHOS dependent (56). During HBV infection, it appears that the virus is able to induce the expression of interleukin-1β (IL-1β), which upregulates mitochondria-encoded genes (Figure 3, step 2) and reprograms macrophages to display higher OXPHOS activity, thereby reducing their antiviral activity (57).

### 4.1.3. Viral enhancement of both glycolysis and OXPHOS.
To support its replication, human cytomegalovirus (HCMV), a well-known persistent herpesvirus, can induce both glycolysis and OXPHOS (58). Indeed, increased glucose uptake has been observed during infection, following viral activation of glucose transporter 4 (Figure 3, step 4) (59). The viral protein pUL13, which is required for productive HCMV replication, has been described to interact with mitochondrial cristae (Figure 3, step 6), modifying its architecture, thereby promoting ETC activity and increasing the bioenergetic state of the persistently infected cell (60). Following metabolomic profiling of norovirus-infected cells, it has been shown that glycolysis and OXPHOS increase during viral infection. This increase in overall metabolism disproportionately promotes the glycolysis pathway during norovirus infection (61). Finally, nucleocytoplasmic DNA viruses (NCLDVs), a diverse group that currently contains the largest known virions and genomes, also called giant viruses, mimic cellular protein by encoding viral homologs of glycolysis and the TCA enzyme (Figure 3, step 7), enabling a complete reprogramming of cellular metabolism (62).

## 4.2. Virus-Induced Oxidative Stress in Host Cells

Mitochondria are fundamental to the generation of oxidative stress, being the main source of ROS production. Viral targeting of mitochondria may therefore damage mitochondrial integrity and modulate overall cellular redox homeostasis. Although high levels of ROS have been described to enhance innate immunity through activation of the inflammasome (63), their increase also may be beneficial for viruses by regulating several cellular pathways (Figure 3).

The respiratory syncytial virus (RSV) is able to promote a dynein-dependent spatial redistribution of the mitochondrial network around the nucleus, inducing a decrease in mitochondrial membrane potential and respiration while increasing mitochondrial ROS generation and lung inflammation (Figure 3, step 8). Inhibition of mitochondrial redistribution and mitochondrial ROS generation was detrimental to viral infection and systemic inflammation (64), reinforcing the idea that the effect of redox balance is essential for replication of this virus (65). Specifically, the core protein of HCV interacts with heat shock protein 60 (HSP60), a chaperone protein of the mitochondrial matrix, damaging mitochondrial proteins and leading to the dysfunction of mitochondria and ROS production (66) (Figure 3, step 8). These mitochondrial perturbations have long been reported to induce ROS production in the context of HCV infection, promoting the
activation of STAT3 (67), which plays a key role during HCV-induced oncogenesis in hepatocytes (68). Most FVs appear to induce oxidative stress during the course of infection, creating a favorable environment for the NS5 guanylyl transferase activity (Figure 3, step 8), a viral cap protein that protects the viral RNA genome during replication (69).

The membrane contact sites (MCSs) between mitochondria and MAM, just like the ER, are being actively studied, as these organelles are involved in several common and interdependent cellular pathways, notably during innate immunity (70), ROS production (71), and calcium homeostasis (72, 73).

### 4.3. Virus-Induced Regulation of Ca²⁺ Homeostasis in Host Cells

Calcium homeostasis has long been described as being involved in a plethora of cellular signaling pathways, with Ca²⁺ playing the role of second messenger (74). Associated with the ER, mitochondria act as reservoirs and regulators of calcium flow within the cell. Indeed, cytosolic Ca²⁺ is first transported through the OMM by the voltage-dependent anion channel (VDAC) and through the IMM to the mitochondrial matrix using the mitochondrial calcium uniporter (MCU) complex (75). Consequently, targeting mitochondria to modulate their calcium permeability is a widespread mechanism among viruses, enabling them to use numerous cellular pathways such as autophagy and apoptosis.

Porcine reproductive and respiratory syndrome virus (PRRSV), first discovered in Europe in 1990, has recently been described as stimulating calcium influx from the ER to mitochondria, with the viral protein GP5 promoting the formation of MAMs. On the one hand, this Ca²⁺ influx into mitochondria in turn stimulates ROS release and triggers the activation of the NLRP3 inflammasome (76). On the other hand, this calcium-induced ROS release participates in autophagy activation, described to promote PRRSV viral replication (76, 77). Curiously, autophagy was shown to antagonize inflammasome during PRRSV infection activation and prevent antiviral response, consistent with previous reports on the interaction between the inflammasome and autophagy (76, 78). In addition to highlighting the importance of calcium homeostasis for several pathways during viral infection, this mechanism underscores the complex interplay between calcium homeostasis and ROS production (79).

In neuroblastoma cells, poliovirus (PV) infection has been shown to promote Ca²⁺ efflux from the ER and its subsequent entry into mitochondria via MCU and VDAC, where it triggers mitochondrial and apoptotic dysfunction (80). Under stress conditions, mitochondrial calcium overload and ROS overproduction act synergistically to trigger cell death via activation of the mitochondrial permeability transition pore (mPTP), a nonselective IMM channel that triggers dissipation of the mitochondrial membrane permeabilization (MMP). The mPTP then leads to mitochondrial outer membrane permeabilization and the release of cytochrome c (Cyt c) into the cytosol (81, 82). The precise composition of this mPTP in the IMM is still under investigation, but it has been speculated that VDAC and pro-apoptotic members of the blc-2 Bax/Bak family play a role in MOM permeabilization (MOMP) (83).

## 5. VIRUSES MODULATE MITOCHONDRIAL ANTIVIRAL RESPONSE

Mitochondria are key players in the host's antiviral defense, as they are involved in the detection and response to viral infections through the activation of innate immune pathways. To evade immune detection, many viruses have developed strategies to modulate the mitochondrial antiviral response. By interfering with mitochondrial signaling and regulating apoptotic and immune pathways, viruses can effectively reduce host defenses and enhance their replication within infected cells.
## 5.1. Viruses Regulate Apoptosis

Apoptosis is one of the most studied forms of regulated cell death, characterized by DNA fragmentation, nuclear envelope disassembly, cytoskeletal disorganization, formation of apoptotic bodies by budding, and externalization of phosphatidylserine (84). This process is triggered by cellular stress and aims to get rid of cells that have been damaged beyond repair, which will be eliminated by phagocytes that recognize the “eat me” signals exhibited by apoptotic cells (85). Apoptosis is composed of two pathways, the intrinsic and extrinsic pathways, both of which trigger the activation of a cascade of cellular endoprotease effectors referred to as caspases, which precipitate the cell into an apoptotic state (86). The extrinsic pathway is linked to the activation of plasma membrane death receptors [such as Fas and tumor necrosis factor (TNF) receptors] by death signals from the extracellular microenvironment, while the intrinsic pathway (also known as the mitochondrial pathway) is linked to activation by intracellular stress (87).

The intrinsic pathway is tightly regulated by the balance between pro-apoptotic and anti-apoptotic members of the B cell lymphoma 2 (Bcl-2) protein family [all of which contain at least one Bcl-2 homology (BH) domain] (88). Bcl-2, the first regulator of apoptosis identified in an organism, blocks programmed cell death (apoptosis), whereas other members of the Bcl-2 family can either inhibit or induce it. The BAX/BAK pore-forming proteins (both pro-apoptotic Bcl-2 family members) assemble during the switch from an anti-survival to a pro-apoptotic signal and induce the activation of MOMP and the release of Cyt c into the cytosol. Cytosolic Cyt c then activates the apoptosome, a platform that plays a key role in inducing the caspase cascade leading to apoptosis (89). The implications of apoptosis during viral infection constitute a vast and still very active field of research, due to its involvement in viral pathogenesis. Indeed, we have seen that viruses trigger a change in cellular homeostasis, directly affecting the apoptotic mitochondrial pathway. Viruses have developed a wide range of evolutionary strategies to alter or promote this phenomenon, depending on their replication requirements.

### 5.1.1. Viral inhibition of apoptosis.
Some viruses counteract apoptosis in order to promote their own replication, thereby delaying cell death and completely diverting the cellular biosynthesis compounds needed to synthesize new virions (Figure 4). HCMV encodes several viral proteins that aim to prevent apoptosis and allow the virus to progress through its replication cycle (90). For example, the viral protein vMIA induces BAX ubiquitination and proteasomal degradation at the MAM interface, thus preventing MOMP through the Bax/Bak pore (91) (Figure 4, step 1). Other viruses also are capable of inhibiting apoptosis by blocking caspases. KSHV encodes a viral homolog of cellular FLIP (vFLIP), an inhibitor of pro-apoptotic caspase 8 (Figure 4, step 2) and a modulator of nuclear factor-κB (NF-κB) signaling, which is involved in regulating mitochondrial release of Cyt c in the extrinsic apoptotic pathway (92). Several viruses, including members of the poxviruses (PXVs), adenoviruses (AdVs), and herpesviruses (HVs), encode viral homologs of the Bcl-2 family (known as vBcl-2) that mimic their anti-apoptotic properties (93) (Figure 4, step 3). The herpesvirus KSHV has been reported to encode Ks-Bcl-2, which binds to several pro-apoptotic BH3-only proteins (i.e., Bcl-2 proteins containing only a single BH domain), preventing Cyt c release from mitochondria (94). This underlines the complex coevolution of viruses with their host, showing the acquisition of viral proteins that mimic cellular anti-apoptotic proteins, allowing them to sustain the progression of the viral cycle and ensure the survival of the infected cell.

### 5.1.2. Viral activation of apoptosis.
Although apoptosis is an antiviral response of the infected cell designed to reduce the production of viral progeny, some viruses are known to encode pro-apoptotic proteins. Inducing apoptosis at a particular stage of viral infection may be a means of
<figure><img src="image_7.png" /><figcaption>Figure 4</figcaption></figure>

Viruses modulate cell antiviral response. On the left, cells are capable of inducing apoptosis, a programmed cell death that responds to signals such as uncontrolled viral replication. This mitochondrial pathway involves the release of Cyt c through mitochondrial pores and caspases activation, acting as the apoptotic cell death switch and apoptosis effectors, respectively. Various strategies have emerged among viruses to prevent cell death to maintain this replication-friendly environment. For example, some viruses directly inhibit Cyt c release (step 1) and caspase activation (step 2), while others code for viral homologs of anti-apoptotic proteins (step 3), indirectly preventing pore opening. Other viruses may benefit from the apoptotic response, allowing the spreading of their viral progeny. Different approaches such as the induction of pore opening (step 4) and the inhibition of anti-apoptotic proteins (step 5) are used by a wide variety of viruses to induce apoptosis. On the right, cells respond to viral infection by initiating innate immune responses following viral or mitochondrial genome detection and activation of mitochondrial MAVS signalization and endoplasmic reticulum STING signaling. However, different strategies have been selected to prevent mitochondria-dependent innate immune responses by targeting the MAVS (step 6), targeting RNA (step 7a) and DNA (step 7b) cytosolic sensors, protecting their genome (step 8), and disrupting the interaction between endoplasmic reticulum and mitochondria (step 9). Finally, many viruses have been shown to induce mtDNA release (step 10) through different mechanisms (pore opening, viroporin, morphology alternation), in turn acting as a danger signal in the cytosol. The red and blue boxes represent inhibitor and inducer viruses, respectively. Abbreviations: AdV, adenovirus; ASFV, African swine fever virus; cGAS, cyclic GMP-AMP synthase; CHIKV, chikungunya virus; Cyt c, cytochrome c; DENV, dengue virus; EBOV, Ebola virus; EV-A71, enterovirus A71; HBV, hepatitis B virus; HCMV, human cytomegalovirus; HCV, hepatitis C virus; HIV-1, human immunodeficiency virus 1; HSV-1, herpes simplex virus 1; HV, herpesvirus; IAV, influenza A virus; IFN, interferon; IRF, interferon regulatory factor; KSHV, Kaposi's sarcoma herpesvirus; MAM, mitochondria-associated membrane; MAVS, mitochondrial antiviral signaling protein; MDA5, melanoma differentiation-associated gene 5; mtDNA, mitochondrial DNA; MV, measles virus; NF-κB, nuclear factor-κB; Pol III, polymerase III; PXV, poxvirus; RIG-I, retinoic acid-inducible gene I; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; STING, stimulator of interferon genes; VDAC, voltage-dependent anion channel; ZIKV, Zika virus. Figure adapted from images created in BioRender; DEFRESNE T. 2025. https://BioRender.com/viskodj.
promoting the release of neo-synthesized virions, allowing them to successfully infect other cells (Figure 4).

The viral protein R (Vpr) of HIV-1 has been described as a pro-apoptotic viral protein (Figure 4, step 4). Vpr reduces the level of the OMM protein Mfn2 and promotes the opening of the mPTP, leading to mitochondrial fragmentation and apoptosis (95, 96). Modulating Bax/Bak pore formation seems to be a shared feature of several viruses that triggers apoptosis. For instance, ZIKV has been shown to infect neural progenitors and increase apoptotic cell death, leading to characteristic prenatal microcephaly (97). Viral NS4B protein-dependent activation of BAX accompanied by Cyt c release (Figure 4, step 4) has been proposed as one of the possible mechanisms responsible for ZIKV-induced apoptosis (98). African swine fever virus (ASFV) also encodes a pE199L protein that targets several anti-apoptotic members of Bcl-2 (Figure 4, step 5), enabling the formation of the Bax/Bak mitochondrial pore leading to apoptosis in the late phase of infection (99).

As previously mentioned, the disruption of homeostatic balances due to viral stress leads to an antiviral response, in which mitochondria induce apoptosis to limit viral production. However, apoptosis is an antiviral response of last resort, activated when the cell is irreparably damaged. Remarkably, mitochondria also play a key role in earlier steps of the infection by generating an innate immune response.

## 5.2. Viruses Modulate Mitochondrial Innate Immune Response

In the course of viral infection, cytoplasmic double-stranded RNA sensors of the RLRs family, such as RIG-I (100) and melanoma differentiation-associated gene 5 (MDA5) (101), can detect viral double-stranded RNA intermediates, while cytosolic DNA sensors, such as cyclic GMP-AMP synthase (cGAS) (102), can detect viral and mitochondrial double-stranded DNA. As a result, RIG-I/ MDA5 and cGAS can interact, respectively, with MAVS, which is a transmembrane protein of the OMM (103), and with the stimulator of interferon genes (STING), which is a transmembrane protein of the ER (104). RIG-I-MAVS and STING then create a complex at the MAMs interface, establishing a crossroads for the inflammatory response (70). In turn, STING and MAVS trigger the translocation into the nucleus of transcription factors NF-κB and interferon regulatory factor 3/7 (IRF3/7), stimulating the transcription of IFN-I genes (103, 104). Consequently, an innate immune response can be established, with the autocrine and paracrine effects of IFNs stimulating the expression of ISGs (interferon-stimulated genes), which play an essential role in the fight against viruses (105). Mitochondria-mediated innate immunity is a key element of the antiviral response, and viral evolution has led to the selection of viruses capable of counteracting such immunity (Figure 4).

Several viruses have been described as promoting MAVS cleavage and degradation, or blocking upstream and downstream signaling, due to their central role in the antiviral response (106). The HCV NS3/4A protein was the first viral protease to localize in mitochondria and cleave MAVS (Figure 4, step 6), thus interrupting the IFN-I response (107). HBV, on the other hand, encodes the HBx protein, which interacts directly with MAVS and promotes its ubiquitination and proteasomal degradation (108) (Figure 4, step 6). Numerous studies have reported the ability of viral proteins 3Cpro and 2Apro of enterovirus A71 (EV-A71) to cleave not only MAVS (Figure 4, step 6) but also MDA-5 and RIG-I (Figure 4, step 7a), blocking signaling upstream of MAVS (109–111). Modification or protection of the viral genome is another mechanism for evading RLR detection (112). The VP35 protein of the Ebola virus (EBOV) is a case in point. It interacts with the intermediate double-stranded RNA of the viral genome, concealing it from RIG-I detection (113) (Figure 4, step 8). Recently, SARS-CoV-2 has been the subject of
numerous studies demonstrating its ability to evade host antiviral defense, suppressing the IFN response through the encoding of several accessory proteins. For example, Orf3c colocalizes with mitochondria and induces MAVS cleavage (114), while Orf10 induces MAVS degradation by mistophagy (39) and Orf9b localizes in mitochondria to block IRF3 signaling downstream of MAVS by competing with HSP90 for binding to the OMM protein TOM70 (115, 116). These redundant mechanisms provide significant control of the type I IFN response by SARS-CoV-2 (Figure 4, step 6).

Some viruses also can antagonize cGAS-STING-mediated responses by targeting cGAS to prevent viral DNA or released mtDNA from being detected. Hence, different members of FVs have been characterized to counteract cGAS-STING detection (Figure 4, step 7b). ZIKV NS1 protein indirectly blocks cGAS by recruiting host ubiquitin-specific protease 8 (USP8), which cleaves K11-linked poly-ubiquitin chains, preventing proteasomal degradation of caspase-1. The resulting caspase-1 stabilization was shown to increase cGAS cleavage (117). NS2B protein of DENV interacts with cGAS, resulting in autophagosomal degradation of the innate immunity sensor (118). Loss of cGAS expression during infection by chikungunya virus (CHIKV) occurs via an autophagic mechanism, whereas CHIKV capsid protein is sufficient to cause cGAS degradation (119). Finally, HCMV has recently demonstrated an ability to mediate a spatiotemporal modulation of MAMs (Figure 4, step 9), first in the early stage of the infection by disrupting MCS between ER and mitochondria to reduce the STING-dependent anti-inflammatory response and then in the late stage of infection by enhancing MCS to promote viral production (120).

## 5.3. Viral Infections Induce the Release of Mitochondrial DNA

Viruses target mitochondria and reduce MAVS antiviral response, leading paradoxically to a mitochondrial stress response. Indeed, it has been reported that mtDNA contained in the mitochondrial matrix can be released under viral infection and trigger antiviral responses when recognized by intracellular cytosolic receptor pathways of innate immunity such as cGAS-STING (102) and RIG-I/polymerase III (121). The activation of an antiviral response through the release of mtDNA may represent an indirect outcome of the cellular defense mechanisms triggered by viral infection (Figure 4, step 10).

Some picornaviruses, such as EV-A71, which is responsible for hand, foot, and mouth disease in children, can trigger the release of mtDNA and its subsequent detection by the cytosolic DNA sensor cGAS-STING, thus triggering an IFN-dependent antiviral response (122). More precisely, the release of mtDNA is triggered by the 2B protein of picornavirus, which induces VDAC and/or Bax/Bak pore opening, depending on the virus. Protein 2B also may participate in the release of Cyt c from mitochondria to the cytosol by directly inducing conformational activation of Bax, thus participating in EV-A71-induced apoptosis (123) (Figure 4, step 4).

This also has been observed in IAV, which encodes an M2 viroporin, an ion channel involved in viral entry by endocytosis (124) and egress by budding (125). The M2 protein targets the mitochondria, where its viroporin activity creates a pore enabling mtDNA to be released into the cytosol and detected by cytosolic receptors such as cGAS (126). Additional infection models have revealed that mtDNA is a key player in triggering the IFN response. Indeed, a lung-on-a-chip model demonstrated that SARS-CoV-2 infection induces cGAS-STING signaling pathway in endothelial cells through the release of mtDNA, resulting in cell death and type I IFN production (127).

Recently, measles virus (MV) protein V was shown to sequester the mitochondrial enzyme ALAS1 (5-aminolevulinate synthase) in the cytosol, perturbing the mitochondrial network and
triggering the release of mtDNA into the cytosol. The mtDNA released into the cytosol can in
turn be translated into RNA by RNA polymerase III, thereby inducing an IFN-I response fol-
lowing its detection by the cytosolic RNA sensor RIG-I (128). A similar effect was described with
the herpes simplex virus 1 (HSV-1) viral protein UL12.5, inducing a decrease in mitochondrial
volume and fragmentation of mitochondria, leading to mtDNA release. This in turn triggered an
innate immune response through enhanced IFN-I expression (129).

Both DNA and RNA viruses can trigger the release of mtDNA, a potent danger signal that activates the host immune system. This creates a paradox: While viruses develop strategies to target mitochondria and suppress their antiviral responses, they inadvertently promote mtDNA release, which in turn activates the host immune response. This suggests that viruses may face selective pressure to evolve mechanisms that modulate both the cGAS-STING and RIG-I/RNA polymerase III pathways enabling them to evade immune detection of both mitochondrial and viral genomes. These dynamics illustrate an ongoing evolutionary arms race between the virus and the host immune system, where each side constantly adapts to outmaneuver the other.

6. CONCLUSION

Mitochondria are at the frontlines in the fight against viral infections, functioning both as regulators of cellular metabolism and as mediators of innate immune responses, making them a double-edged sword in the context of infections. Mitochondria are crucial to the energetic functioning of the cell, providing the ATP required for a wide range of viral activities, such as viral genome replication and viral protein production. Viruses exploit mitochondrial vulnerabilities through various mechanisms, from disrupting mitochondrial dynamics and metabolism to manipulating apoptosis and oxidative stress pathways. By hijacking these processes, viruses effectively create an environment that favors their survival and replication, ultimately compromising the innate antiviral defenses of the cell.

The viral regulation of mitochondrial antiviral immunity further complicates the ability of the host to mount an effective defense against infections. From a therapeutic standpoint, targeting mitochondrial dysfunction represents a promising avenue for antiviral treatment (130, 131). Modulating mitochondrial dynamics, safeguarding mitochondrial integrity, and restoring the balance of mitochondrial metabolism could help mitigate the damage caused by viral infections. Furthermore, therapies designed to enhance mitochondrial antiviral immunity or prevent viral degradation of key mitochondrial proteins, such as MAVS, could reinforce the natural defense mechanisms of the host.

Innovative approaches, such as the transfer of healthy mitochondria, offer a novel frontier in combating the detrimental effects of viral infections. Mitochondrial transfer has the potential to restore mitochondrial function in infected cells, counteracting virus-induced dysfunction and bolstering cellular resilience. This emerging therapy could provide an important tool in managing viral infections that specifically target mitochondrial health. Taken together, these insights not only deepen our understanding of viral pathogenesis but also pave the way for new therapeutic avenues that target the root causes of mitochondrial damage in viral infections, offering the prospect of more effective treatments in the future.

DISCLOSURE STATEMENT

The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
## ACKNOWLEDGMENTS

We would like to thank Béibhinn O’Hora for proofreading and editing this review. This work was supported by grants from the Institut Pasteur and the Ecole Doctorale “Complexité du Vivant” from Sorbonne Université.

## LITERATURE CITED

1. Frey TG, Mannella CA. 2000. The internal structure of mitochondria. *Trends Biochem. Sci.* 25(7):319-24

2. Spinelli JB, Haigis MC. 2018. The multifaceted contributions of mitochondria to cellular metabolism. *Nat. Cell Biol.* 20(7):745-54

3. Brown DA, Perry JB, Allen ME, Sabbah HN, Stauffer BL, et al. 2017. Mitochondrial function as a therapeutic target in heart failure. *Nat. Rev. Cardiol.* 14(4):238-50

4. Taanman JW. 1999. The mitochondrial genome: structure, transcription, translation and replication. *Biochim. Biophys. Acta* 1410(2):103-23

5. Sharma N, Pasala MS, Prakash A. 2019. Mitochondrial DNA: epigenetics and environment. *Environ. Mol. Mutagen.* 60(8):668-82

6. Pfanner N, Warscheid B, Wiedemann N. 2019. Mitochondrial proteins: from biogenesis to functional networks. *Nat. Rev. Mol. Cell Biol.* 20(5):267-84

7. Morgenstern M, Peikert CD, Lübbert P, Suppanz I, Klemm C, et al. 2021. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. *Cell Metab.* 33(12):2464-83.e18

8. Sung AY, Floyd BJ, Pagliarini DJ. 2020. Systems biochemistry approaches to defining mitochondrial protein function. *Cell Metab.* 31(4):669-78

9. Murphy MP. 2009. How mitochondria produce reactive oxygen species. *Biochem. J.* 417:1-13

10. Sies H, Jones DP. 2020. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. *Nat. Rev. Mol. Cell Biol.* 21(7):363-83

11. Youle RJ, van der Bliek AM. 2012. Mitochondrial fission, fusion, and stress. *Science* 337(6098):1062-65

12. Robin ED, Wong R. 1988. Mitochondrial DNA molecules and virtual number of mitochondria per cell in mammalian cells. *J. Cell. Physiol.* 136(3):507-13

13. Zhang D, Keilty D, Zhang Z, Chian R. 2017. Mitochondria in oocyte aging: current understanding. *Facts Views Vis. ObGyn* 9(1):29-38

14. Kim S-J, Ahn D-G, Syed GH, Siddiqui A. 2018. The essential role of mitochondrial dynamics in antiviral immunity. *Mitochondrion* 41:21-27

15. Boguszewska K, Szewczuk M, Kaźmierczak-Barańska J, Karwowski BT. 2020. The similarities between human mitochondria and bacteria in the context of structure, genome, and base excision repair system. *Molecules* 25(12):2857

16. Roger AJ, Muñoz-Gómez SA, Kamikawa R. 2017. The origin and diversification of mitochondria. *Curr. Biol.* 27(21):R1177-92

17. Ng MYW, Wai T, Simonsen A. 2021. Quality control of the mitochondrion. *Dev. Cell* 56(7):881-905

18. Mears JA, Lackner LL, Fang S, Ingerman E, Nunnari J, Hinshaw JE. 2011. Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission. *Nat. Struct. Mol. Biol.* 18(1):20-26

19. Ishihara N, Eura Y, Mihara K. 2004. Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. *J. Cell Sci.* 117(26):6535-46

20. Anand R, Wai T, Baker MJ, Kladt N, Schauss AC, et al. 2014. The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. *J. Cell Biol.* 204(6):919-29

21. Castanier C, Garcin D, Vazquez A, Arnoult D. 2010. Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway. *EMBO Rep.* 11(2):133-38

22. Shi C-S, Qi H-Y, Boularan C, Huang N-N, Abu-Asab M, et al. 2014. SARS-CoV ORF-9b suppresses innate immunity by targeting mitochondria and the MAVS/TRAF3/TRAF6 signalosome. *J. Immunol.* 193(6):3080-89

23. Welsch S, Miller S, Romero-Brey I, Merz A, Bleck CKE, et al. 2009. Composition and three-dimensional architecture of the dengue virus replication and assembly sites. *Cell Host Microbe* 5(4):365-75
24. Chatel-Chaix L, Cortese M, Romero-Brey I, Bender S, Neufeldt CJ, et al. 2016. Dengue virus perturbs mitochondrial morphodynamics to dampen innate immune responses. *Cell Host Microbe* 20(3):342–56

25. Barbier V, Lang D, Valois S, Rothman AL, Medin CL. 2017. Dengue virus induces mitochondrial elongation through impairment of Drp1-triggered mitochondrial fission. *Virology* 500:149–60

26. Xie L, Shi F, Li Y, Li W, Yu X, et al. 2020. Drp1-dependent remodeling of mitochondrial morphology triggered by EBV-LMP1 increases cisplatin resistance. *Signal Transduct. Target. Ther.* 5:56

27. Kim S-J, Khan M, Quan J, Till A, Subramani S, Siddiqui A. 2013. Hepatitis B virus disrupts mitochondrial dynamics: induces fission and mitophagy to attenuate apoptosis. *PLOS Pathog.* 9(12):e1003722

28. Kim S-J, Syed GH, Khan M, Chiu W-W, Sohail MA, et al. 2014. Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence. *PNAS* 111(17):6413–18

29. Yang S, Gorshkov K, Lee EM, Xu M, Cheng Y-S, et al. 2020. Zika virus-induced neuronal apoptosis via increased mitochondrial fragmentation. *Front. Microbiol.* 11:598203

30. Yu C-Y, Liang J-J, Li J-K, Lee Y-L, Chang B-L, et al. 2015. Dengue virus impairs mitochondrial fusion by cleaving mitofusins. *PLOS Pathog.* 11(12):e1005350

31. Kim IS, Silwal P, Jo E-K. 2021. Mitofusin 2, a key coordinator between mitochondrial dynamics and innate immunity. *Virulence* 12(1):2273–84

32. Shirihai O, Song M, Dorn GW. 2015. How mitochondrial dynamism orchestrates mitophagy. *Circ. Res.* 116(11):1835–49

33. Okatsu K, Oka T, Iguchi M, Imamura K, Kosako H, et al. 2012. PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria. *Nat. Commun.* 3:1016

34. Onishi M, Yamano K, Sato M, Matsuda N, Okamoto K. 2021. Molecular mechanisms and physiological functions of mitophagy. *EMBO J.* 40(3):e104705

35. Kim S-J, Syed GH, Siddiqui A. 2013. Hepatitis C virus induces the mitochondrial translocation of Parkin and subsequent mitophagy. *PLOS Pathog.* 9(3):e1003285

36. Yoshizumi T, Ichinohe T, Sasaki O, Otera H, Kawabata S, et al. 2014. Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity. *Nat. Commun.* 5(1):4713

37. Wang R, Zhu Y, Ren C, Yang S, Tian S, et al. 2021. Influenza A virus protein PB1-F2 impairs innate immunity by inducing mitophagy. *Autophagy* 17(2):496–511

38. Zhang B, Xu S, Liu M, Wei Y, Wang Q, et al. 2023. The nucleoprotein of influenza A virus inhibits the innate immune response by inducing mitophagy. *Autophagy* 19(7):1916–33

39. Li X, Hou P, Ma W, Wang X, Wang H, et al. 2022. SARS-CoV-2 ORF10 suppresses the antiviral innate immune response by degrading MAVS through mitophagy. *Cell. Mol. Immunol.* 19(1):67–78

40. Ponia SS, Robertson SJ, McNally KL, Subramanian G, Sturdevant GL, et al. 2021. Mitophagy antagonism by ZIKV reveals Ajuba as a regulator of PINK1 signaling, PKR-dependent inflammation, and viral invasion of tissues. *Cell Rep.* 37(4):109888

41. Teodorof-Diedrich C, Spector SA. 2018. Human immunodeficiency virus type 1 gp120 and Tat induce mitochondrial fragmentation and incomplete mitophagy in human neurons. *J. Virol.* 92(22):e00993-18

42. Rozzi SJ, Avdoshina V, Fields JA, Mocchetti I. 2018. Human immunodeficiency virus Tat impairs mitochondrial fission in neurons. *Cell Death Discov.* 4:8

43. Liesa M, Shirihai OS. 2013. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. *Cell Metab.* 17(4):491–506

44. Mahmoudabadi G, Milo R, Phillips R. 2017. Energetic cost of building a virus. *PNAS* 114(22):E4324–33

45. Luo X, Hong L, Cheng C, Li N, Zhao X, et al. 2018. DNMT1 mediates metabolic reprogramming induced by Epstein-Barr virus latent membrane protein 1 and reversed by grifolin in nasopharyngeal carcinoma. *Cell Death Dis.* 9(6):619

46. Pouysségur J, Marchiq I, Parks SK, Durivault J, Ždralević M, Vucetic M. 2022. “Warburg effect” controls tumor growth, bacterial, viral infections and immunity—genetic deconstruction and therapeutic perspectives. *Semin. Cancer Biol.* 86:334–46

47. Warburg O. 1956. On the origin of cancer cells. *Science* 123(3191):309–14

48. Wang L, Ning S. 2021. New look of EBV LMP1 signaling landscape. *Cancers* 13(21):5451
49. Tayeb S, Zakay-Rones Z, Panet A. 2015. Therapeutic potential of oncolytic Newcastle disease virus: a critical review. *Oncolytic Virother.* 4:49–62

50. Gong Y, Tang N, Liu P, Sun Y, Lu S, et al. 2022. Newcastle disease virus degrades SIRT3 via PINK1-PRKN-dependent mitophagy to reprogram energy metabolism in infected cells. *Autophagy* 18(7):1503–21

51. Archer SL, Dasgupta A, Chen KH, Wu D, Baid K, et al. 2022. SARS-CoV-2 mitochondriopathy in COVID-19 pneumonia exacerbates hypoxemia. *Redox Biol.* 58:102508

52. Zhu Y, Ramos da Silva S, He M, Liang Q, Lu C, et al. 2016. An oncogenic virus promotes cell survival and cellular transformation by suppressing glycolysis. *PLOS Pathog.* 12(5):e1005648

53. Fontana J, López-Iglesias C, Tzeng W-P, Frey TK, Fernández JJ, Risco C. 2010. Three-dimensional structure of Rubella virus factories. *Virology* 405(2):579–91

54. Beatch MD, Hobman TC. 2000. Rubella virus capsid associates with host cell protein p32 and localizes to mitochondria. *J. Virol.* 74(12):5569–76

55. Claus C, Schönefeld K, Hübner D, Chey S, Reibetanz U, Liebert UG. 2013. Activity increase in respiratory chain complexes by rubella virus with marginal induction of oxidative stress. *J. Virol.* 87(15):8481–92

56. Liu Y, Xu R, Gu H, Zhang E, Qu J, et al. 2021. Metabolic reprogramming in macrophage responses. *Biomark. Res.* 9(1):1

57. Li Y, Zhu Y, Feng S, Ishida Y, Chiu T-P, et al. 2022. Macrophages activated by hepatitis B virus have distinct metabolic profiles and suppress the virus via IL-1β to downregulate PPARα and FOXO3. *Cell Rep.* 38(4):110284

58. Combs JA, Norton EB, Saifudeen ZR, Bentrup KHZ, Katakam PV, et al. 2020. Human cytomegalovirus alters host cell mitochondrial function during acute infection. *J. Virol.* 94(2):e01183-19

59. Yu Y, Maguire TG, Alwine JC. 2011. Human cytomegalovirus activates glucose transporter 4 expression to increase glucose uptake during infection. *J. Virol.* 85(4):1573–80

60. Betsinger CN, Jankowski CSR, Hofstadter WA, Federspiel JD, Otter CJ, et al. 2021. The human cytomegalovirus protein pUL13 targets mitochondrial cristae architecture to increase cellular respiration during infection. *PNAS* 118(32):e2101675118

61. Passalacqua KD, Lu J, Goodfellow I, Kolawole AO, Arche JR, et al. 2019. Glycolysis is an intrinsic factor for optimal replication of a norovirus. *mBio* 10(2):e02175-18

62. Moniruzzaman M, Martinez-Gutierrez CA, Weinheimer AR, Aylward FO. 2020. Dynamic genome evolution and complex virocell metabolism of globally-distributed giant viruses. *Nat. Commun.* 11:1710

63. Bauernfeind F, Bartok E, Rieger A, Franchi L, Núñez G, Hornung V. 2011. Cutting edge: Reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. *J. Immunol.* 187(2):613–17

64. Hu M, Schulze KE, Ghildyal R, Henstridge DC, Kolanowski JL, et al. 2019. Respiratory syncytial virus co-opts host mitochondrial function to favour infectious virus production. *eLife* 8:e42448

65. Yang X, Liu X, Nie Y, Zhan F, Zhu B. 2023. Oxidative stress and ROS-mediated cellular events in RSV infection: potential protective roles of antioxidants. *Virol. J.* 20(1):224

66. Kang S-M, Kim S-J, Kim J-H, Lee W, Kim G-W, et al. 2009. Interaction of hepatitis C virus core protein with Hsp60 triggers the production of reactive oxygen species and enhances TNF-α-mediated apoptosis. *Cancer Lett.* 279(2):230–37

67. Machida K, Cheng KT-H, Lai C-K, Jeng K-S, Sung VM-H, Lai MMC. 2006. Hepatitis C virus triggers mitochondrial permeability transition with production of reactive oxygen species, leading to DNA damage and STAT3 activation. *J. Virol.* 80(14):7199–207

68. Yoshida T, Hanada T, Tokuhisa T, Kosai K, Sata M, et al. 2002. Activation of STAT3 by the hepatitis C virus core protein leads to cellular transformation. *J. Exp. Med.* 196(5):641–53

69. Gullberg RC, Steel JJ, Moon SL, Soltani E, Geiss BJ. 2015. Oxidative stress influences positive strand RNA virus genome synthesis and capping. *Virology* 475:219–29

70. Missiroli S, Patergnani S, Caroccia N, Pedriali G, Perrone M, et al. 2018. Mitochondria-associated membranes (MAMs) and inflammation. *Cell Death Dis.* 9(3):329

71. Yoboue ED, Sitia R, Simmen T. 2018. Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages. *Cell Death Dis.* 9(3):331
72. Patergnani S, Suski JM, Agnoletto C, Bononi A, Bonora M, et al. 2011. Calcium signaling around mitochondria associated membranes (MAMs). *Cell Commun. Signal.* 9(1):19

73. Barazzuol L, Giamogante F, Calì T. 2021. Mitochondria associated membranes (MAMs): architecture and physiopathological role. *Cell Calcium* 94:102343

74. Berridge MJ, Bootman MD, Roderick HL. 2003. Calcium signalling: dynamics, homeostasis and remodelling. *Nat. Rev. Mol. Cell Biol.* 4(7):517-29

75. Romero-Garcia S, Prado-Garcia H. 2019. Mitochondrial calcium: transport and modulation of cellular processes in homeostasis and cancer. *Int. J. Oncol.* 54(4):1155-67

76. Zhang S, Zeng L, Su B-Q, Yang G-Y, Wang J, et al. 2023. The glycoprotein 5 of porcine reproductive and respiratory syndrome virus stimulates mitochondrial ROS to facilitate viral replication. *mBio* 14(6):e0265123

77. Sun M-X, Huang L, Wang R, Yu Y-L, Li C, et al. 2012. Porcine reproductive and respiratory syndrome virus induces autophagy to promote virus replication. *Autophagy* 8(10):1434-47

78. Biasizzo M, Kopitar-Jerala N. 2020. Interplay between NLRP3 inflammasome and autophagy. *Front. Immunol.* 11:591803

79. Görlach A, Bertram K, Hudecova S, Krizanova O. 2015. Calcium and ROS: a mutual interplay. *Redox Biol.* 6:260-71

80. Brisac C, Téoulé F, Autret A, Pelletier I, Colbère-Garapin F, et al. 2010. Calcium flux between the endoplasmic reticulum and mitochondrion contributes to poliovirus-induced apoptosis. *J. Virol.* 84(23):12226

81. Rossi A, Pizzo P, Filadi R. 2019. Calcium, mitochondria and cell metabolism: a functional triangle in bioenergetics. *Biochim. Biophys. Acta Mol. Cell Res.* 1866(7):1068-78

82. Bauer TM, Murphy E. 2020. Role of mitochondrial calcium and the permeability transition pore in regulating cell death. *Circ. Res.* 126(2):280-93

83. Bernardi P, Gerle C, Halestrap AP, Jonas EA, Karch J, et al. 2023. Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions. *Cell Death Differ.* 30(8):1869-85

84. Elmore S. 2007. Apoptosis: a review of programmed cell death. *Toxicol. Pathol.* 35(4):495-516

85. Poon IKH, Lucas CD, Rossi AG, Ravichandran KS. 2014. Apoptotic cell clearance: basic biology and therapeutic potential. *Nat. Rev. Immunol.* 14(3):166-80

86. McIlwain DR, Berger T, Mak TW. 2013. Caspase functions in cell death and disease. *Cold Spring Harb. Perspect. Biol.* 5(4):a008656

87. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, et al. 2018. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. *Cell Death Differ.* 25(3):486-541

88. Singh R, Letai A, Sarosiek K. 2019. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. *Nat. Rev. Mol. Cell Biol.* 20(3):175-93

89. Bao Q, Shi Y. 2007. Apoptosome: a platform for the activation of initiator caspases. *Cell Death Differ.* 14(1):56-65

90. Yu Z, Wang Y, Liu L, Zhang X, Jiang S, Wang B. 2021. Apoptosis disorder, a key pathogenesis of HCMV-related diseases. *Int. J. Mol. Sci.* 22(8):4106

91. Zhang A, Hildreth RL, Colberg-Poley AM. 2013. Human cytomegalovirus inhibits apoptosis by proteasome-mediated degradation of Bax at endoplasmic reticulum-mitochondrion contacts. *J. Virol.* 87(10):5657-68

92. Bélanger C, Gravel A, Tomoiu A, Janelle ME, Gosselin J, et al. 2001. Human herpesvirus 8 viral FLICE-inhibitory protein inhibits Fas-mediated apoptosis through binding and prevention of procaspase-8 maturation. *J. Hum. Virol.* 4(2):62-73

93. Kvansakul M, Caria S, Hinds MG. 2017. The Bcl-2 family in host-virus interactions. *Viruses* 9(10):290

94. Flanagan AM, Letai A. 2008. BH3 domains define selective inhibitory interactions with BHRF-1 and KSHV BCL-2. *Cell Death Differ.* 15(3):580-88

95. Huang C-Y, Chiang S-F, Lin T-Y, Chiou S-H, Chow K-C. 2012. HIV-1 Vpr triggers mitochondrial destruction by impairing Mfn2-mediated ER-mitochondria interaction. *PLOS ONE* 7(3):e33657
96. Jacotot E, Ravagnan L, Loeffler M, Ferri KF, Vieira HLA, et al. 2000. The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore. *J. Exp. Med.* 191(1):33-46

97. Tang H, Hammack C, Ogden SC, Wen Z, Qian X, et al. 2016. Zika virus infects human cortical neural progenitors and attenuates their growth. *Cell Stem Cell* 18(5):587-90

98. Han X, Wang J, Yang Y, Qu S, Wan F, et al. 2021. Zika virus infection induced apoptosis by modulating the recruitment and activation of proapoptotic protein Bax. *J. Virol.* 95(8):e01445-20

99. Li T, Zhao G, Zhang T, Zhang Z, Chen X, et al. 2021. African swine fever virus pE199L induces mitochondrial-dependent apoptosis. *Viruses* 13(11):2240

100. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, et al. 2004. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. *Nat. Immunol.* 5(7):730-37

101. Kang D, Gopalkrishnan RV, Wu Q, Jankowsky E, Pyle AM, Fisher PB. 2002. *mda-5*: an interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. *PNAS* 99(2):637-42

102. Sun L, Wu J, Du F, Chen X, Chen ZJ. 2013. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type-I interferon pathway. *Science* 339(6121):786-91

103. Seth RB, Sun L, Ea C-K, Chen ZJ. 2005. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF3. *Cell* 122(5):669-82

104. Ishikawa H, Barber GN. 2008. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. *Nature* 455(7213):674-78

105. Samuel CE. 2001. Antiviral actions of interferons. *Clin. Microbiol. Rev.* 14(4):778-809

106. Ren Z, Ding T, Zuo Z, Xu Z, Deng J, Wei Z. 2020. Regulation of MAVS expression and signaling function in the antiviral innate immune response. *Front. Immunol.* 11:1030

107. Li X-D, Sun L, Seth RB, Pineda G, Chen ZJ. 2005. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. *PNAS* 102(49):17717-22

108. Wei C, Ni C, Song T, Liu Y, Yang X, et al. 2010. The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein. *J. Immunol.* 185(2):1158-68

109. Barral PM, Sarkar D, Fisher PB, Racaniello VR. 2009. RIG-I is cleaved during picornavirus infection. *Virology* 391(2):171-76

110. Feng Q, Langereis MA, Lork M, Nguyen M, Hato SV, et al. 2014. Enterovirus 2A<sup>pro</sup> targets MDA5 and MAVS in infected cells. *J. Virol.* 88(6):3369-78

111. Rui Y, Su J, Wang H, Chang J, Wang S, et al. 2017. Disruption of MDA5-mediated innate immune responses by the 3C proteins of coxsackievirus A16, coxsackievirus A6, and enterovirus D68. *J. Virol.* 91(13):e00546-17

112. Chan YK, Gack MU. 2016. Viral evasion of intracellular DNA and RNA sensing. *Nat. Rev. Microbiol.* 14(6):360-73

113. Cárdenas WB, Loo Y-M, Gale M, Hartman AL, Kimberlin CR, et al. 2006. Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling. *J. Virol.* 80(11):5168-78

114. Müller M, Herrmann A, Fujita S, Uriu K, Kruth C, et al. 2023. ORF3c is expressed in SARS-CoV-2-infected cells and inhibits innate sensing by targeting MAVS. *EMBO Rep.* 24(12):e57137

115. Jiang H, Zhang H, Meng Q, Xie J, Li Y, et al. 2020. SARS-CoV-2 Orf9b suppresses type I interferon responses by targeting TOM70. *Cell Mol. Immunol.* 17(9):998-1000

116. Gao X, Zhu K, Qin B, Olieric V, Wang M, Cui S. 2021. Crystal structure of SARS-CoV-2 Orf9b in complex with human TOM70 suggests unusual virus-host interactions. *Nat. Commun.* 12(1):2843

117. Zheng Y, Liu Q, Wu Y, Ma L, Zhang Z, et al. 2018. Zika virus elicits inflammation to evade antiviral response by cleaving cGAS via NS1-caspase-1 axis. *EMBO J.* 37(18):e99347

118. Aguirre S, Luthra P, Sanchez-Aparicio MT, Maestre AM, Patel J, et al. 2017. Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection. *Nat. Microbiol.* 2(5):17037

119. Webb LG, Veloz J, Pintado-Silva J, Zhu T, Rangel MV, et al. 2020. Chikungunya virus antagonizes cGAS-STING mediated type-I interferon responses by degrading cGAS. *PLOS Pathog.* 16(10):e1008999
120. Cook KC, Tsopurashvili E, Needham JM, Thompson SR, Cristea IM. 2022. Restructured membrane contacts rewire organelles for human cytomegalovirus infection. *Nat. Commun.* 13(1):4720

121. Chiu Y-H, Macmillan JB, Chen ZJ. 2009. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. *Cell* 138(3):576-91

122. Liu H, Zhu Z, Xue Q, Yang F, Li Z, et al. 2023. Innate sensing of picornavirus infection involves cGAS-STING-mediated antiviral responses triggered by mitochondrial DNA release. *PLOS Pathog.* 19(2):e1011132

123. Cong H, Du N, Yang Y, Song L, Zhang W, Tien P. 2016. Enterovirus 71 2B induces cell apoptosis by directly inducing the conformational activation of the proapoptotic protein Bax. *J. Virol.* 90(21):9862-77

124. Pinto LH, Lamb RA. 2006. The M2 proton channels of influenza A and B viruses. *J. Biol. Chem.* 281(14):8997-9000

125. Rossman JS, Jing X, Leser GP, Lamb RA. 2010. Influenza virus M2 protein mediates ESCRT-independent membrane scission. *Cell* 142(6):902-13

126. Moriyama M, Koshiba T, Ichinohe T. 2019. Influenza A virus M2 protein triggers mitochondrial DNA-mediated antiviral immune responses. *Nat. Commun.* 10:4624

127. Domizio JD, Gulen MF, Saidoune F, Thacker VV, Yatim A, et al. 2022. The cGAS-STING pathway drives type I IFN immunopathology in COVID-19. *Nature* 603(7899):145-51

128. Khalfi P, Suspène R, Raymond KA, Caval V, Caignard G, et al. 2023. Antagonism of ALAS1 by the measles virus V protein contributes to degradation of the mitochondrial network and promotes interferon response. *PLOS Pathog.* 19(2):e1011170

129. Berry N, Suspène R, Caval V, Khalfi P, Beauclair G, et al. 2021. Herpes simplex virus type 1 infection disturbs the mitochondrial network, leading to type I interferon production through the RNA polymerase III/RIG-I pathway. *mBio* 12(6):e0255721

130. Babajani A, Hosseini-Monfared P, Abbaspour S, Jamshidi E, Niknejad H. 2021. Targeted mitochondrial therapy with over-expressed MAVS protein from mesenchymal stem cells: a new therapeutic approach for COVID-19. *Front. Cell Dev. Biol.* 9:695362

131. Bachman LO, Zwezdaryk KJ. 2023. Targeting the host mitochondria as a novel human cytomegalovirus antiviral strategy. *Viruses* 15(5):1083