# Heart of the matter: Mitochondrial dynamics and genome alterations in cardiac aging

Claudie Gabillard-Lefort, Théophile Thibault, Guy Lenaers, Rudolf J

Wiesner, Jeanne Mialet-Perez, Olivier R Baris

► To cite this version:

Claudie Gabillard-Lefort, Théophile Thibault, Guy Lenaers, Rudolf J Wiesner, Jeanne Mialet-Perez, et al.. Heart of the matter: Mitochondrial dynamics and genome alterations in cardiac aging. Mechanisms of Ageing and Development, 2025, 224, pp.112044. 10.1016/j.mad.2025.112044. hal-05283281

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# Heart of the matter: Mitochondrial dynamics and genome alterations in cardiac aging

Claudie Gabillard-Lefort<sup>a,1</sup>, Théophile Thibault<sup>a,1</sup>, Guy Lenaers<sup>a,b</sup>, Rudolf J. Wiesner<sup>c,d,e</sup>,
Jeanne Mialet-Perez<sup>a</sup>, Olivier R. Baris<sup>a,*</sup>

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

## ARTICLE INFO

Keywords:

Aging

Cardiovascular diseases

MtDNA

Mitochondria

Inflammation

Senescence

Mitochondrial dynamics

## ABSTRACT

Cardiac pathological aging is a serious health issue, with cardiovascular diseases still being a leading cause of deaths worldwide. Therefore, there is an urgent need to identify culprit factors involved in this process. In the last decades, mitochondria, which are crucial for cardiac function, have emerged as major contributors. Mitochondria are organelles involved in a plethora of metabolic pathways and cell processes ranging from ATP production to calcium homeostasis or regulation of apoptotic pathways. This review provides a general overview of the pathomechanisms involving mitochondria during cardiac aging, with a focus on the role of mitochondrial dynamics and mitochondrial DNA (mtDNA). These mechanisms involve imbalanced mitochondrial fusion and fission, loss of mtDNA integrity leading to tissue mosaic of mitochondrial deficiency, as well as mtDNA release in the cytoplasm, promoting inflammation via the NLRP3, cGAS/STING and TLR9 pathways. Potential links between mtDNA, mitochondrial damage and the accumulation of senescent cells in the heart are also discussed. A better understanding of how these factors impact on heart function and accelerate its pathological aging should lead to the development of new therapies to promote healthy aging and restore age-induced cardiac dysfunction.

## 1. Cardiac aging: why do mitochondria matter?

Aging is a major risk factor for cardiovascular diseases, with approximately 20 % of people aged over 80 years at risk of developing heart failure (Mozaffarian et al., 2016), which is a major health issue in developed countries due to increased lifespan. Given the crucial role of the heart in oxygenation of the peripheral tissues, it is not surprising that heart diseases are among the leading causes of death worldwide.

Structural and functional changes occur in the aging heart, such as hypertrophy, fibrosis and increased stiffness, ultimately leading to a greater incidence of heart failure, defined by the inability of the heart to provide sufficient blood to peripheral tissues. Other frequent cardiac conditions in the elderly include atrial fibrillation and ventricular arrhythmia (irregular heartbeats in the atria and ventricles respectively), as well as coronary artery disease and impaired recovery from ischemic stress (Lazzeroni et al., 2022; Liu et al., 2021). Cardiac aging is

characterized by left ventricular wall thickness that gradually affects overall contractile efficiency, as well as an increase in elastic and collagenous tissue associated with inflammation, even in the absence of major cardiovascular risks (Izzo et al., 2018; Peverill, 2021). In contrast with neonatal heart, adult myocardial tissue has a low capacity for repair after injury, implying that the progressive decline in regenerative potential does not compensate for the progressive aging-driven cardiomyocyte loss (Lewis-McDougall et al., 2019; Li et al., 2019). At the cellular level, aged cardiomyocytes display increased size and volume, dysfunctional organelles, protein misfolding and accumulation of damaged proteins, ultimately leading to oxidative stress, decreased maintenance of cellular quality control mechanisms and ultimately cell death (Gude et al., 2018; Kolwicz et al., 2013).

Studies from the last decades have supported the culprit relevance of mitochondrial dysfunction in the development of aging-related cardiac diseases, which is not surprising, since the heart strongly relies on

<footnote><sup>a</sup> University of Angers, MitoLab, Unité MITOVASC, UMR CNRS 6015, INSERM U1083, SFR ICAT, Angers, France</footnote>

<footnote><sup>b</sup> Department of Neurology, University Hospital of Angers, Angers, France</footnote>

<footnote><sup>c</sup> Center for Physiology and Pathophysiology, Institute of Systems Physiology, University of Cologne, Cologne, Germany</footnote>

<footnote><sup>d</sup> Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany</footnote>

<footnote><sup>e</sup> Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: olivier.baris@univ-angers.fr (O.R. Baris).</footnote>

<footnote n="1">¹ equal contribution</footnote>
mitochondrial energy production (reviewed in Bonora et al., 2019). Mitochondria are intracellular organelles occupying ~30 % of the cardiomyocyte volume that play an essential role in cell metabolism by producing the major amount of Adenosine-TriPhosphate (ATP) using the oxidative phosphorylation system which couples electron flow through the respiratory chain to the ATP synthase (Barth et al., 1992; Brown et al., 2017). They are also essential for lipid synthesis from carbohydrates, biosynthesis of amino acids or nucleotides, and are key regulators of cardiomyocyte survival (da Cunha et al., 2015; Kaniak-Golik and Skoneczna, 2015). In addition, mitochondria play a crucial role in cellular calcium homeostasis, via their close cooperation with the sarcoplasmic reticulum. The voltage dependent anion channel 2 (VDAC2), an outer mitochondrial membrane porin, allows the uptake of $Ca^{2+}$ released by the sarcoplasmic reticulum via the ryanodine receptor 2 (RYR2), thereby directly influencing cardiac contraction, through the control of cytoplasmic $Ca^{2+}$ availability, and mitochondrial energy production, via the regulation of key enzymes such as pyruvate dehydrogenase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase (Rosenberg, 2022).

During cardiac aging, many structural, and functional changes have been documented in mitochondria including fragmentation, swelling, imbalance of mitochondrial populations (intermyofibrillar versus sub-sarcolemmal), decreased cardiolipin content in the inner membrane changing membrane fluidity, and decreased OXPHOS activity (reviewed in Xie et al., 2023). Mitochondrial capacity to buffer $Ca^{2+}$ is also altered during aging, as leaky RYR2 can lead to mitochondrial $Ca^{2+}$ overload, increased ROS production and global mitochondrial dysfunction, contributing to heart failure (Hamilton et al., 2020; Santulli et al., 2015). Thus, given the importance of mitochondrial energetics in the heart, maintenance of mitochondrial integrity and functions is crucial for preventing cardiovascular and metabolic diseases.

## 2. Mitochondrial dynamics: network disturbances in the aged heart?

Mitochondrial homeostasis is maintained through the regulation of two opposing mechanisms: generation of new mitochondria by biogenesis and removal of damaged mitochondria by mitophagy, a selective form of autophagy (Ploumi et al., 2017). Both processes constantly adapt in response to cellular energy demand, developmental signals and environmental stimuli to maintain an equilibrium. During aging, the impairment of mitochondrial biogenesis is associated with decreased mitophagy, leading to an imbalance between newly formed and damaged mitochondria, and consequently to a disturbed bioenergetic potential. Moreover, mitochondria are organized in a dynamic intracellular network that constantly adapts to cell needs via mitochondrial fusion and fission (Wai and Langer, 2016). Several large GTPases have already been identified as key players in mitochondrial dynamics, such as optic atrophy 1 (OPA1) (Alexander et al., 2000; Delettre et al., 2000) and mitofusin 1/2 (MFN1/2) (Santel and Fuller, 2001) for fusion, and dynamin-related protein 1 (DRP1) (Shin et al., 1997) for fission. This dynamism of the network is essential for mitochondrial quality control and especially for the maintenance of mitochondrial DNA (mtDNA) integrity, which encodes thirteen essential respiratory chain subunits, as fission facilitates the elimination of defective organelles via mitophagy (Slavin et al., 2022).

In vivo studies in mouse models with altered expression or ablation of fission or fusion proteins revealed that imbalanced mitochondrial dynamics is critical for cardiac function (Maneechote et al., 2024). Heart-specific ablation of fusion proteins MFN1/2 or fission proteins DRP1 and the mitochondrial fission factor MFF all resulted in cardiomyopathy, a pathological condition that could be mitigated by concomitant knockout of a gene involved in the opposite process, thus rebalancing mitochondrial dynamics (Chen et al., 2015; Song et al., 2017). Moreover, haploinsufficiency in OPA1 protein leads to late onset cardiomyopathy in mice (Chen et al., 2012), as well as increased

sensitivity to ischemia/reperfusion injuries (Le Page et al., 2016), and imbalanced OPA1 processing in the heart leads to mitochondrial fragmentation, dilated cardiomyopathy (characterized by enlarged ventricular chamber) and heart failure (Wai et al., 2015). In contrast, haploinsufficiency in DRP1 is protective against ischemia/reperfusion injuries (Bouche et al., 2021).

Mitophagy plays a critical role in cardiac physiology, by ensuring an efficient removal of dysfunctional mitochondria, thereby preserving ATP production and proper $Ca^{2+}$ homeostasis. Therefore, its decline during cardiac aging contributes to the development of associated pathologies (Liang and Gustafsson, 2020; Martínez and Blasco, 2018). This decreased mitophagic potential has been linked to several factors, including hyperactivation of the mammalian target of rapamycin (mTOR) pathway (Hua et al., 2011), and reduced activity of the AMP-activated protein kinase (AMPK, Turdi et al., 2010). The mTOR pathway is involved in cell growth, nutrient sensing and metabolism, and its activation leads to autophagy inhibition. AMPK is sensitive to variations of the cellular ATP/AMP ratio, and upon energy deprivation, it blocks mTOR complex 1 (mTORC1) activity to favor autophagy/mitophagy. Further emphasizing the importance of preserving mitophagy during cardiac aging, pharmacological modulations with rapamycin, an inhibitor of mTOR or urolithin A, a natural postbiotic that stimulates mitophagy, both improve cardiac health during aging (Flynn et al., 2013; Gu et al., 2016; Liu et al., 2025).

Altogether, during cardiac aging, dysregulation of mitochondrial dynamics causes progressive mitochondrial defects that expand until a critical threshold is surpassed, thus impairing cardiac function (Picca et al., 2018). Despite the fact that conflicting observations have been made in the heart of aged rodents, with studies highlighting an increased mitochondrial fragmentation, while others describing exacerbated fusion (Chen et al., 2022; Maneechote et al., 2024), the common point is that the equilibrium between fusion and fission is not maintained anymore, and mitophagy is impaired, thus contributing to pathological dysfunction/alterations.

## 3. Mitochondrial DNA (mtDNA) alterations: a driving force in cardiac aging?

Mitochondrial dysfunction observed during aging is also explained by a compromised mtDNA integrity. Mitochondrial DNA is a small multi-copy circular genome (Anderson et al., 1981), encoding 2 ribosomal RNAs, 22 transfer RNAs and 13 crucial subunits of the mitochondrial respiratory chain complexes. Therefore, mtDNA alterations, either point mutations or large-scale deletions, have critical consequences on mitochondrial and cardiac physiology. The common cardiac symptoms linked to mtDNA mutations are arrhythmias and other cardiomyopathies, with a high level of clinical heterogeneity, since patients with the same mutation can display different cardiac phenotypes, and the same cardiac manifestation can occur in patients with multiple variants in different mtDNA genes (Bates et al., 2012; Chinnery, 2015).

The cause for compromised mtDNA integrity during aging is still debated. The historical "free radical theory of aging" stipulates that reactive oxygen species (ROS) are involved in mtDNA mutations (Harman, 1956). Indeed, ROS gradually accumulate during aging, because of redox imbalance and impaired mitochondrial oxidative phosphorylation, leading to electron leakage from the respiratory complexes (Dai et al., 2012). ROS thus promote oxidative damage of mtDNA, increasing in an age-dependent manner, as well as alterations of mitochondrial morphology and increase of the Bax/Bcl-2 ratio, shifting the balance towards apoptosis (Giorgi et al., 2018). This theory has yet been challenged in recent years with several studies showing that base transversions following ROS-induced damage are not over-represented in mtDNA during aging (Kauppila and Stewart, 2015) and suggesting that mtDNA mutations are rather generated by replication errors that are amplified over life time (Picard et al., 2016; Sanchez-Contreras et al., 2023).
mtDNA exists in thousands of copies per cell, with mutated and wild-type molecules coexisting, a phenomenon known as heteroplasmy (Stewart and Chinnery, 2015). Thus, mitochondrial dysfunction occurs if the proportion of mutated mtDNA exceeds a critical threshold, leading to the presence of defective cells among normal ones, a hallmark of tissue aging (Larsson, 2010). In humans, this mosaic pattern of mitochondrial deficiency was observed first in heart and skeletal muscle tissues (Müller-Höcker, 1990, 1989) and visualized via cytochrome c oxidase/succinate dehydrogenase staining (Sciacco and Bonilla, 1996), which stains normal cells in brown (COX-positive cells) and defective cells in blue (COX-negative cells). In muscle, such COX-negative cells and mtDNA deletions have been suggested to be a driving force of sarcomenia, the age-related loss of muscle mass (Herbst et al., 2016; Kimoloi et al., 2022). Cardiac arrhythmias were reported in patients suffering from diseases caused by massive accumulation of mtDNA deletions, such as Kearns-Sayre syndrome (KSS) or progressive external ophtalmoplegia (PEO) (Maeluch and Niedziela, 2006; Van Goethem et al., 2003), with high proportions of COX-negative cardiac cells. In contrast, in the aged human heart, COX-negative cells are of low abundance (0.5% at around age 70), and their pathophysiological role is unclear. Nonetheless, heart function, which shows a clear age-related increase in the incidence of cardiac disorders (Lok and Lau, 1996; Tresch and Thakur, 1998), could be impaired even by the presence of few dysfunctional cells, especially proper conduction of action potentials.

Genetically engineered mouse models mimicking the accumulation of mtDNA alterations helped in further delineating the detrimental role of COX- cells in the heart during aging. The mito-mouse (Inoue et al., 2000), harboring a 4696-bp mtDNA deletion leading to COX deficiency in many tissues, shows altered cardiac function with elongated PQ intervals (time interval between atrial and ventricular contraction) and atrioventricular conduction blocks (Nakada et al., 2001), although only at a very high proportion of COX-negative cardiomyocytes, thus not mimicking what is observed in aged human hearts. In contrast, three other mouse models illustrated that even low proportions of COX-negative cells can be detrimental for the heart. The mtDNA mutator mouse (Trifunovic et al., 2004), accumulating mtDNA point mutations due to a defective proofreading function of the mitochondrial DNA polymerase, was shown to develop cardiomyopathy with heart hypertrophy and dilatation, as well as impairment of systolic and diastolic functions (Dai et al., 2010). Another model harboring a single pathogenic mtDNA point mutation at various heteroplasmy levels, the C5024T tRNA<sup>Ala</sup> mouse, also displays a cardiomyopathy with increased heart mass, paralleling the presence of few COX-negative cardiomyocytes (Filograna et al., 2019; Kauppila et al., 2016). Last, the K320E-Twin-kle<sup>Myo</sup> mouse, which expresses a pathogenic variant of the mtDNA helicase TWINKLE in the heart, mimic the age-dependent accumulation of mtDNA deletions and COX-negative cardiomyocytes observed in aged humans, responsible for cardiac arrhythmias including ventricular premature contractions and atrioventricular blocks (Baris et al., 2015). Altogether, these 3 mouse models highlight the critical role of mtDNA mutations in cardiac aging.

## 4. Inflammation in the aged heart: a role for mtDNA?

"Inflammating" is a new concept of the aging process characterized by low-grade, sterile inflammation, which persists over time and progressively causes tissue damage (Franceschi et al., 2018). Inflammating has been associated with mitochondrial dysfunction and increased extracellular release of mtDNA (Picca et al., 2022). Under oxidative stress conditions, oxidized mtDNA (ox-mtDNA) fragments of up to 700 bp are generated and released through a mechanism requiring the coordination of two mitochondrial pores: the voltage-dependent anion channel (VDAC) located in the outer mitochondrial membrane and the mitochondrial permeability transition pore (mPTP) located in the inner mitochondrial membrane (Xian et al., 2022). When ox-mtDNA is present in the intermembrane space, it binds to lysine and arginine residues at

the N-terminal end of VDAC, causing channel oligomerization and the release of ox-mtDNA into the cytosol (Kim et al., 2019). VDAC-dependent mtDNA cytosolic release was recently shown in aged myofibers, associated with increased oxidative damage to mtDNA and innate immune activation (Li et al., 2024). Indeed, mtDNA contains unmethylated immunogenic CpG motifs that trigger inflammation through activation of Toll-Like Receptor-9 (TLR9) (Ries et al., 2013; Yamazoe et al., 2021). TLR9 is expressed in cardiomyocytes and activates the adaptor myeloid differentiation primary response protein 88 (MyD88)/mitogen-activated protein kinases (MAPKs)/NF-κB pathway (Bliksøen et al., 2016). High levels of circulating mtDNA have been associated with the development of cardiovascular diseases, including atherosclerosis, hypertension, acute myocardial infarction and heart failure, by triggering the TLR9-dependent inflammatory pathway (McCarthy et al., 2015; Oka et al., 2012; Wang et al., 2015). Among other receptors activated by the mtDNA, the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome complex consists of a C-terminal leucine-rich repeat (LRR) domain, a central NOD domain with ATPase activity and a N-terminal pyrin domain (PYD), which interacts with the pyrin domain of apoptosis speck protein (ASC) to initiate inflammasome assembly (Kelley et al., 2019; Sandall et al., 2020; Xian et al., 2022). Ultimately, the NLRP3 inflammasome provides the signal for cleavage of pro-caspase-1 to active caspase-1, which processes the final maturation of pro-Interleukin (IL)-1β and pro-IL-18 to active IL-1β and IL-18. Caspase-1 cleavage by NLRP3 induces IL-1β secretion from immune cells and cardiac fibroblasts, contributing to cardiac inflammation and damage, following myocardial ischemia/reperfusion (Sandanger et al., 2013). Enhanced NLRP3 expression in cardiomyocytes was also demonstrated to be involved in atrial fibrillation (Yao et al., 2018). Some studies have assessed the impact of NLRP3 inflammasome during cardiac aging, revealing that inhibition of NLRP3 preserves cardiac function in aged mice (Marín-Aguilar et al., 2020) and ROS-mediated activation of NLRP3 inflammasome contributes to the pathogenesis of cardiomyocyte aging (Liao et al., 2021). Interestingly, cytosolic mtDNA release caused by increased mitochondrial ROS production promotes inflammatory response in cardiomyocytes in a NLRP3-dependent manner, leading to myocardial hypertrophy during the progression of diabetic cardiomyopathy (Yan et al., 2022). Cytosolic mtDNA also activates the cyclic GMP-AMP synthase (cGAS) / STIMulator of Interferons Genes (STING) pathway, which promotes the transcription of interferon (IFN) genes and the activation of Nuclear Factor-κB (NF-κB) to boost the inflammatory process (Kim et al., 2023). Upregulation of the cGAS/STING pathway was recently demonstrated in heart lysates from normal aged mice, contributing to age-associated inflammation (Gao et al., 2024).

## 5. Mitochondrial damage, mtDNA and senescence: is there a causal link?

The persistent activation of low-grade inflammation that characterizes aging could also be linked to the process of senescence. Senescence consists in a deep remodeling of the cell phenotype, with increased expression of cyclin-dependent kinase inhibitors (CDKi), cell enlargement, lysosomal expansion and the release of the senescence-associated secretory phenotype (SASP) composed of cytokines, chemokines, proteases and growth factors (Tchkonia et al., 2013). The SASP promotes bystander senescence of surrounding cells and is a major driver of inflamming (Tchkonia et al., 2013; Xu et al., 2018). Since the heart is a post-mitotic tissue, whether cell senescence was occurring in the heart has long eluded the scientific community. At present, accumulating evidences show that different cell types can undergo senescence in the heart such as endothelial cells, fibroblasts and also cardiomyocytes (Abdellatif et al., 2023; Mehdizadeh et al., 2022). Senescence is not only induced by successive replications, termed "replicative senescence", but also by external stressors such as irradiation, oncogenes, oxidative stress and mitochondrial dysfunction, termed "Stress-induced premature
senescence” (Toussaint et al., 2002). In the murine heart, a recent study identified an age-dependent accumulation of persistent telomeric damage that act as a key driver of cardiomyocyte senescence (Anderson et al., 2019). This telomeric damage was triggered by oxidative stress, resulting from age-related mitochondrial dysfunction and occurred independently of telomere length and cell cycle activity. Pharmacological or genetic removal of senescent cells reduced cardiac hypertrophy and fibrosis, two main deleterious features of cardiac aging (Anderson et al., 2019), ameliorated the response to stress (Baker et al., 2016) and improved left ventricular remodeling following ischemia-reperfusion (Dookun et al., 2020).

Dramatic changes in mitochondrial mass, dynamics and function are characteristics of senescent cells (Martini and Passos, 2023). Interestingly, clearance of mitochondria in fibroblasts or even total depletion of mtDNA (Rho0 osteosarcoma cells) prevented some pro-oxidant features of senescence and potently inhibited SASP secretion in response to irradiation, without any effect on proliferation (Correia-Melo et al., 2016). The link between mitochondria and SASP is therefore intriguing and could involve different mechanisms such as ROS production, mTOR or AMPK activation, and decreased NAD⁺/NADH ratio (Wiley et al., 2016). However, whether mtDNA plays a role in senescence and SASP remains unclear. The analysis of the PolG mutator mouse, which rapidly

accumulates mtDNA point mutations, demonstrated a specific type of cell senescence with a distinct secretory profile in adipose tissue (Wiley et al., 2016). Also, Victorelli et al. demonstrated that senescent cells release mtDNA through the Bax/Bak macropore and stimulate the SASP through the activation of the cGAS/STING and type 1 IFN pathways (Victorelli et al., 2023). The majority of the released mtDNA co-localized with TFAM, a core component of the mtDNA nucleoids, and TFAM-mediated autophagic removal of cytoplasmic mtDNA did restrict inflammation (Liu et al., 2024; Victorelli et al., 2023). Mitochondrial dynamics also plays an important role in the regulation of the SAS-P/senescence pathway, as mitochondrial hyperfusion in senescent cells prevents mtDNA cytoplasmic release. In this respect, Mfn2 knock-down, inducing mitochondrial fragmentation, exacerbated the release of SASP factors without any effect on CDKi expression (Victorelli et al., 2023). At present, whether such pathways are operating in cardiac aging will require further investigations.

## 6. Conclusions

With cardiovascular diseases being a leading cause of deaths worldwide, there is an urgent need to identify factors responsible for the pathological aging process of the heart. In the last two decades,

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Imbalanced mitochondrial dynamics and loss of mtDNA integrity contribute to pathological cardiac aging. In adult cardiomyocytes, mitochondrial homeostasis requires a fine-tuned and adaptive balance between fusion, involving OPA1, MFN1 and MFN2 and fission, involving DRP1 and MFF, to either favor mitochondrial biogenesis or the elimination of dysfunctional organelles. Balanced mitochondrial dynamics also contributes to the maintenance of mtDNA to sustain ATP production by the OXPHOS system. During cardiac aging, regularly resulting in hypertrophic cardiomyocytes, imbalanced mitochondrial dynamics, elevated ROS production and amplified mtDNA replication errors contribute to mtDNA loss of integrity, directly impairing OXPHOS activity and thus ATP production. Cytosolic release of mtDNA triggers an increased expression of pro-inflammatory genes via the NLRP3 inflammasome, cGAS/Sting and TLR9 pathways. Imbalanced mitochondrial dynamics also contribute to this inflammatory response and leads to altered mitochondrial biogenesis and mitophagy. This mitochondria-driven inflammatory response is hypothesized to contribute to cardiomyocyte senescence, further aggravating heart dysfunction. Abbreviations: **OPA1**: optic atrophy 1; **MFN1/2**: mitofusin 1/2; **DRP1**: dynamin-related protein 1; **MFF**: mitochondrial fission factor; **mtDNA**: mitochondrial DNA; **OXPHOS**: oxidative phosphorylation; **ROS**: reactive oxygen species; **NLRP3**: NOD-like receptor family, pyrin domain containing 3; **cGAS**: cyclic GMP-AMP synthase; **STING**: stimulator of interferon genes; **TLR9**: Toll-like receptor 9.</figcaption></figure>
mitochondria have emerged as major contributors of this process (Fig. 1), since age-related changes in mitochondrial function, dynamics and quality control mechanisms were demonstrated to contribute significantly to the decline in cardiac functions in animal models. Mounting evidence points to a critical role of mtDNA, via the accumulation of age-induced alterations, and its propensity to trigger inflammation when released into the cytoplasm. Future research is needed to determine whether it also influences the development of senescence in cardiomyocytes, thus amplifying cardiac aging. Nevertheless, mitochondria represent a target of choice for the development of new therapies to promote healthy aging and restore age-induced cardiac dysfunction.

## Funding

CGL, RJW and ORB were funded by Agence Nationale de la Recherche (ANR-20-CE92-0020). JJT was funded by University of Angers and Région Pays de la Loire. JJMP was funded by Agence Nationale de la Recherche (ANR-19-CE14-0038-01), Fédération Française de Cardiologie (FFC), Région Pays de la Loire.

## CRediT authorship contribution statement

**Thibault Théophile:** Writing – review & editing, Writing – original draft, Conceptualization. **Wiesner Rudolf:** Writing – review & editing, Funding acquisition. **Lenaers Guy:** Writing – review & editing. **Baris Olivier:** Writing – review & editing, Writing – original draft, Validation, Supervision, Funding acquisition, Conceptualization. **Mialet-Perez Jeanne:** Writing – review & editing, Writing – original draft, Funding acquisition, Conceptualization. **Gabillard-Lefort Claudie:** Writing – review & editing, Writing – original draft, Conceptualization.

## Declaration of Competing Interest

The authors have no conflicts of interest.

## Data availability

No data was used for the research described in the article.

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