# Implication of Rac1 GTPase in molecular and cellular mitochondrial functions

Christian Bailly, Claire Degand, William Laine, Vincent Sauzeau, Jérôme Kluza

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Christian Bailly, Claire Degand, William Laine, Vincent Sauzeau, Jérôme Kluza. Implication of Rac1 GTPase in molecular and cellular mitochondrial functions. Life Sciences, 2024, 342, pp.122510. 10.1016/j.lfs.2024.122510. hal-05122817

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# Implication of Rac1 GTPase in molecular and cellular mitochondrial functions

Christian Bailly<sup>a,b,c,*</sup>, Claire Degand<sup>a</sup>, William Laine<sup>a</sup>, Vincent Sauzeau<sup>d</sup>, Jérôme Kluza<sup>a</sup>

## ARTICLE INFO

Chemical compounds (10):

Ascorbic acid
Dihydroceramide
EHT-1864
GYS32661
JK-50561
MBQ-167
NSC-23766
Opipramol
Rhein
Tigecycline

Keywords:

Cancer
GTPase
Mitochondria
Oxidative stress
Rac1
Rac1 inhibitors

## ABSTRACT

Rac1 is a member of the Rho GTPase family which plays major roles in cell mobility, polarity and migration, as a fundamental regulator of actin cytoskeleton. Signal transduction by Rac1 occurs through interaction with multiple effector proteins, and its activity is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). The small protein is mainly anchored to the inner side of the plasma membrane but it can be found in endocellular compartments, notably endosomes and cell nuclei. The protein localizes also into mitochondria where it contributes to the regulation of mitochondrial dynamics, including both mitobiogenesis and mitophagy, in addition to signaling processes via different protein partners, such as the proapoptotic protein Bcl-2 and chaperone sigma-1 receptor (σ-1R). The mitochondrial form of Rac1 (mtRac1) has been understudied thus far, but it is as essential as the nuclear or plasma membrane forms, via its implication in regulation of oxidative stress and DNA damages. Rac1 is subject to diverse post-translational modifications, notably to a geranylgeranylation which contributes importantly to its mitochondrial import and its anchorage to mitochondrial membranes. In addition, Rac1 contributes to the mitochondrial translocation of other proteins, such as p53. The mitochondrial localization and functions of Rac1 are discussed here, notably in the context of human diseases such as cancers. Inhibitors of Rac1 have been identified (NSC-23766, EHT-1864) and some are being developed for the treatment of cancer (MBQ-167) or central nervous system diseases (JK-50561). Their effects on mtRac1 warrant further investigations. An overview of mtRac1 is provided here.

## 1. Introduction

The small protein Rac1 (Ras-related C3 botulinum toxin substrate 1) is a member of the GTPase protein family which canonically includes RhoA and Cdc42 (cell division cycle protein 42) (Fig. 1). The category comprises also atypical Rho GTPases which play roles in the occurrence and development of cancers [1]. These proteins are mainly responsible for regulating cell motility, cell polarity, cell cycle, membrane trafficking, and cell dynamic [2]. These low-molecular-weight entities (20–25 kDa) are monomeric guanine nucleotide-binding proteins implicated in the regulation of transcription factor activity and cell signaling. They are highly conserved proteins with a common G-domain

structural backbone involved in GTP-binding and GTPase activity, but each of them recognizes individual binding partners [3,4].

Rac1 is functionally implicated in different human diseases, notably in vascular pathologies such as pulmonary hypertension [5,6], diabetic retinopathy [7] and also in neurodevelopmental disorders or memory-related brain disorders including Alzheimer's disease [8–10]. Rac1 is a key regulatory actor in cancers, largely implicated in tumor cell migration, invasion and metastasis, and radio- or chemo-resistance [11–13]. Rac1 is considered a valid target to reduce progression of solid tumors, notably in cases of melanoma [14,15], advanced colorectal cancer [16], bladder cancer [17], hepatocellular carcinoma [18] and other solid tumors [19]. Rac proteins are implicated in leukemia and

Abbreviations: Bcl-2, B-cell lymphoma 2; ROS, reactive oxygen species; Rac1, ras-related C3 botulinum toxin substrate 1; Sig1R (or σ-1R), sigma-1 receptor; DDR, DNA damage response.

* Corresponding author at: University of Lille, CNRS, Inserm, CHU Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, France.

E-mail address: christian.bailly@univ-lille.fr (C. Bailly).

<footnote><sup>a</sup> University of Lille, CNRS, Inserm, CHU Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, France</footnote>

<footnote><sup>b</sup> University of Lille, Faculty of Pharmacy, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), 3 rue du Professeur Laguesse, 59000 Lille, France</footnote>

<footnote><sup>c</sup> OncoWitan, Consulting Scientific Office, Lille (Wasquehal) 59290, France</footnote>

<footnote><sup>d</sup> Université de Nantes, CHU Nantes, CNRS, INSERM, Institut du thorax, Nantes, France</footnote>
lymphoma, notably as key modulators of hematopoietic stem cell and progenitor transplantation [20,21]. In other words, Rac1 is a master regulator of cell migration implicated in numerous human pathologies. For these reasons, small molecules targeting Rac1 are actively searched.

Over the past ten years, potent and more or less selective Rac1 in-
hibitors have been identified and designed, such as the selective Rac
GTPase inhibitors NSC-23766, 1A-116, EHT-1864 and GYS32661, the
dual Rac/Cdc42 inhibitor MBQ-167 and a few others [22–24] (Fig. 1).
The largely used inhibitor NSC-23766 was designed initially to inhibit
Rac1 activation by specific GEFs [25]. It was a founder small molecule
for the development of MBQ-167, Ehop-016 and other inhibitors such as
AZA-1 and AZA-197 [26]. These compounds take advantage of the
intramolecular dynamics of the complex between Rac1 and the effector
partner protein to remodel the complex into an unproductive confor-
mation, as shown with the inhibitor C21 which inhibits the GEF protein
DOCK5 and the interaction with Rac1, for example [27]. MBQ-167 is
currently evaluated for the treatment of patients with advanced breast
cancer (NCT06075810) and analogues of this lead compound are
investigated [22]. There is also a small molecule Rac1 inhibitor desig-
nated JK-50561, in clinical development in China for the treatment of
Alzheimer's disease (phase 2a, NCT05811442) but there is no mecha-
nistic information about this potential (undisclosed) inhibitor [28]. The
protein target is promising but the pleiotropic roles and ubiquitous
expression of Rac1 make it a challenging target [23]. There is no Rac1-
specific inhibitor in clinical development at present.

As for other GTPases, the activity of Rac1 is determined by its gua-
nine nucleotide-bound state and its cellular and tissular localization.
Binding of GTP to Rac1 activates the protein through a process which
exposes the effector binding domain, and then triggers downstream
signals via transducing partners. GTP activates the protein, whereas
GDP-binding locks the protein in an inactive conformation, masking the
effector binding domain. The switch from the GDP- (inactive) to GTP-
(active) bound states is controlled by diverse regulatory proteins.
GTPase activating proteins (GAPs) inactivate Rac1 whereas guanine

nucleotide exchange factors (GEFs) promote the dissociation of GDP
from Rac1 to facilitate GTP binding (Fig. 1). Different Rac1-activating
GEFs (such as Tiam1, Vav1, Trio, Dock2–6, kalirin) and inactivating
modulators GAPs (including several ARHGAPs), as well as guanosine
nucleotide dissociation inhibitors (GDIs), have been characterized over
the past ten years [29,30]. These proteins assemble to generate a dy-
namic cluster at the plasma membrane, including also GEF-partner
proteins (such as ELMO1) which contribute to regulate Rac activation
[31–33].

Rac1 is essentially associated with the plasma membranes, on the inner side, connected to different transduction pathways. Rac1 is tightly implicated in the formation of actin-rich membrane protrusions, such as lamellipodia, filopodia and membrane ruffles during micropinocytosis [34]. These structures are essential for cell motility. As such Rac1 contributes to the control of the plasma membrane dynamic and cell proliferation and invasion. The protein is also involved in the generation of membrane protrusions that form and encapsulate extracellular volumes, such as pinocytic and phagocytic vesicles [35]. Rac1 is found in lipid rafts which are specialized cholesterol/sphingolipid-rich membrane domains and signal transduction platforms involved in cell dynamic [36]. The disruption of lipid rafts can inhibit Rac1 activation [37]. The formation of Rac1/NADPH oxidase protein complexes into membrane lipid rafts initiates production of reactive oxygen species (ROS) [38]. Globally, Rac1 localizes at the surface of many cells and is often distributed in condensed/ordered membranes and actin-based cell protrusions (ruffles) [39–41] (Fig. 2).

Beyond the plasma membrane, Rac1 is found in other cells com-
partments and structures. A nuclear localization of Rac1 has been evi-
denced, more precisely an association of Rac1 with the nuclear envelope
[42]. In contrast to RhoA, Rac1 displays a nuclear localization sequence
(NLS) [43,44] and the nuclear translocation of Rac1 requires the pres-
ence of its C-terminal polybasic region (Rac1 PBR sequence: PVKKRKRKR) [45]. Phosphorylation of Rac1 at T108 position by ERK
(extracellular signal-regulated kinase) targets Rac1 to the nucleus [46].

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Rac1 activation and drug inhibition. (a) Simplified dendrogram showing Rac1's place within the subfamilies of the Ras GTPases superfamily. (b) Rac1 cycles between an inactive GDP-bound state and an active GTP-bound state. The cycle is regulated by guanine nucleotide exchange factors (GEF) which turns on signaling by catalyzing the exchange from G-protein-bound GDP to GTP, whereas GTPase activating proteins (GAP) terminate signaling by inducing GTP hydrolysis. Different pharmacological inhibitors are known to bind to Rac1 to inactivate the GTPase. (c) A molecular model of inhibitor EHT 1864 bound to Rac1 (PDB: 1I4D), with (d) a close-up view of the drug-binding cavity. EHT 1864 fits well into a protein cavity, interacting with key residues notably a H-bond with Lys166. The drug interaction probably maintains the protein into an inactive conformation. The model was generated using the crystal structure of Rac1 interacting with p21 (arfaptin) (PDB: 1I4D) and the docking analysis was performed using a described procedure [205,206]. (e) Structural formula of EHT1864.</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Subcellular distribution of Rac1. The GTPase essentially associates with the plasma membrane and participates in cellular signaling via different membrane receptors and effectors, upon regulation by GEFs and GAPs. GTP-bound Rac1 is involved in actin dynamic regulation and cell motility. Rac1 can also localize into the nuclear compartment, endosomes and mitochondria. Post-translational modifications of Rac1 play major roles in the cellular distribution of the protein, notably ubiquitination promotes protein degradation by the proteasomal machinery, and prenylation (geranylgeranylation) is essential for its association with any membrane including the mitochondrial membrane. This is a simplified representation of the spatio-temporal regulation of Rac1 (see text for more details).
(The figure is original, inspired in part from [71].)</figcaption></figure>

Nuclear Rac1 plays roles in mitotic progression to promote cell division [47] and in the regulation of DNA damages [48]. The import of Rac1 to the nucleus is mediated by different proteins, such as the nuclear import receptor karyopherin alpha2 (KPNA2) and nucleophosmin-1 [49]. Monomeric nuclear Rac1 is essential to regulate nuclear membrane organization and morphology, through the modulation of actin organization [50–52]. The link between nuclear Rac1 and the activation of the DNA damage response (DDR) has been refined recently. Active Rac1 in the nucleus functions as an activator of the DDR process [53–56]. Beyond DNA repair, activated nuclear Rac1 plays roles in transcription via interaction with transcription factors such as NFκB, STAT3 and STAT5 [57,58]. The regulation of the activation and activity of STATs and NFκB by Rac1 extends well beyond its nuclear localization [16,59,60]. However, more work is needed to better understand the roles and regulation of Rac1 within the nuclear compartment.

In addition, Rac GTPases can associate with endomembranes such as endosomes and the Golgi apparatus where they regulate diverse cellular events such as receptor trafficking, cell proliferation and differentiation, cell migration and polarity [61,62]. For example, inside cells prenylated Rac1 is present in endosomal vesicles to promote receptor trafficking in axons [63]. In redox active endosomes (redoxosomes), Rac1 is recruited by NADPH oxidase to drive ROS production [64–66]. These endosomes which transport Rac1 to the plasma membrane play a role in signal transduction, notably for the control of proliferation and cell mobility [67]. The trafficking of Rac1 from endosomes to the cell border is controlled by different proteins, including RhoA and Rab11 [68–70]. Via endosomes, Rac1 shuttles back and forth between the nucleus, cytoplasm and plasma membrane in response to diverse stimuli (Fig. 2). The trafficking of the protein is regulated by multiple partner proteins and via various post-translational modifications including prenylation, palmitoylation, ubiquitination, phosphorylation, and adenylylation [71,72].

Another cell territory offers a place for Rac1: the mitochondrion. This aspect has not been deeply investigated and discussed in recent years. However, there are clear evidence that Rac1 can play a role in

mitochondrial functions. The present analysis offers an overview of the activity of Rac1 in mitochondria and the link with oxidative metabolism.

## 2. Mitochondrial localization and activities of Rac1

Mitochondria are double-membrane organelles playing a major role in oxidative cellular metabolism. They are the principal source of energy in cells. Different small GTPases are known to localize to mitochondria, such as Miro 1–2 GTPases which control mitochondrial morphology and distribution, among other processes [73,74]. The Rho-GTPase Miro1 localizes on outer mitochondrial membrane to regulate the motility, anterograde transport and subcellular distribution of mitochondria [75,76]. This is the case also for the GTPase OPA1 (Optic atrophy 1) localized on the inner membrane of mitochondria [77]. Other GTPases implicated in mitochondrial fission/fusion can be cited, such as Drp1 (Dysinamin-related protein 1), Fis-1 (Fission protein 1) and Mitofusin 1–2 [78,79]. This is the case also for Rac1.

The association of Rac1 with mitochondria was first mentioned about 30 years ago. A subcellular fractionation of rat kidney cortex cells showed that Rac1 was localized predominantly in mitochondria, whereas RhoA and Cdc42 were cytosolic or in the membrane fraction [80]. Later, the localization of Rac1 to the mitochondrial membranes was evidenced using leukemia-derived cell lines, such as Jurkat (human leukemia T cell) and Raji (human leukemia B cells used as antigen presenting cells), but also with primary cells from patients with B-cell lymphoma [81]. In the case of clinical biopsies, a strong colocalization of Rac1 and the well-known proapoptotic protein Bcl-2 (B-cell lymphoma 2) was demonstrated. During apoptosis, Bcl-2 proteins such as Bax and Bak cluster on the outer mitochondrial membrane to mediate the release of pro-apoptotic proteins from mitochondria. In the course of apoptosis, a molecular reorganization of the inner membrane and sequestration of outer membrane components into clusters occur, leading to the formation of outer membrane ruptures [82]. Formation of the Bcl-2/Rac1 complex in mitochondria is connected to the PI3K/Akt/mTOR survival pathway. The treatment of either PC12 cells cultured in
high glucose conditions, or diabetic rats with the Rac1 inhibitor NSC23766 was shown to suppress the interaction between Bcl-2 and Rac1 in mitochondria. This effect contributed to the neuroprotective effect of Rac1 inhibition against cerebral ischemic reperfusion injury, via modulation of the endogenous levels of the signaling molecules p-PI3K, p-Akt and p-mTOR connected to the Bcl-2/Rac1 complex [83]. There is a functional crosstalk between Bcl-2 and Rac1, which promotes the phosphorylation of Bcl-2 at Ser-70 to stabilize its antiapoptotic activity [84] (Fig. 3). The Bcl-2/Rac1 interaction implicates also other factors like STAT3, to control the pro-oxidant state in cancer cells [85,86]. The cross-talk between Bcl-2 and Rac1 at the mitochondria level can be exploited pharmacologically to modulate the cellular redox metabolism. It is an important cross-talk with a role in chemoresistance of cancer [87]. For example, in acute myeloid leukemia Rac1 hyper-activation leads to resistance via hyperphosphorylation of different proteins, including antiapoptotic Bcl-2. The combination of a Bcl-2 in-hibitor (venetoclax) and a Rac1 inhibitor (EHT-1864) has been shown to overcome resistance of AML cells to the FLT3 inhibitor midostaurin [88]. This is a potential strategy to treat certain leukemia [89] and brain tumors [90].

Another line of evidence for the presence of Rac1 in mitochondria comes from a confocal microscopy study using the mitochondrial marker Mitotracker which has been found to be associated with Rac1 in pancreatic β-TC3 cells [91]. A more robust proof of the localization of Rac1 into mitochondria derives from a study using alveolar macro-phages obtained from patients with asbestosis. In this case, the locali-zation of Rac1 into mitochondria was amplified (by a factor of 2.5) compared to normal subjects. A prominent mitochondrial import of Rac1 (but not Rac2) was observed and the protein was shown to play a role in the generation of hydrogen peroxide (H₂O₂), itself linked to the development of pulmonary fibrosis. The mitochondrial localization of Rac1 was induced upon treatment of macrophages with chrysotile asbestos (a layer silicate type of asbestos) and was shown to require geranylgeranylation of a key cysteine residue (Cys189). The generation of H₂O₂ mediated by mtRac1 necessitates an electron transfer from cy-tochrome c to another cysteine residue on Rac1 (Cys-178) [92]. More-over, it has been shown that a conditional deletion of Rac1 in macrophages protected mice from asbestos-induced pulmonary fibrosis

[93]. Similarly, Rac1 null mice were found to be protected from asbestos-induced pulmonary fibrosis [94].

The mitochondrial import process is dependent upon the geranylgeranylation of the C-terminal cysteine residue Cys189 of Rac1 (Fig. 4). Indeed, the blockade of the cysteine prenylation with digeranyl bisphosphonate (DGBP is a selective inhibitor of geranylgeranyl pyrophosphate synthase) drastically reduced the extent of mitochondrial import and the ensuing oxidative stress linked to the progression of the fibrotic response [95]. Conversely, the induction of Rac1 geranylgeranylation (upon infection with influenza A virus for example) favored the translocation of the protein into mitochondria-associated endoplasmic reticulum (ER) membranes (at the mitochondria-ER junction) [96]. A mitochondrial expression of Rac1 has been evidenced in nasopharyngeal carcinoma CNE-1 cells and the expression was significantly enhanced when these cells were exposed to X-ray irradiation or a chemical radio-sensitizer [97]. These different observations provided key elements supporting a primary role for mitochondrial Rac1 in fibrosis development and suggested novel treatment strategies for lung fibrosis [98].

Rac1 plays a role in the communication between the endoplasmic reticulum (ER) and mitochondria, delimiting the so-called mitochon-drion-associated ER membrane (MAM) and this association is important for bioenergetics and cellular survival [99,100]. Different mitochondrial proteins are known to interact with Rac1, such as the mitochondrial antiviral signaling protein (MAVS) which activates a signaling cascade implicating the dynamin-mediated endocytosis inhibitor dynasore and transcription factor NF-κB [101]. The protein tomm7 (translocase of outer mitochondrial membrane 7) is another mitochondrial effector implicated in the mitochondrial import of Rac1 [102]. Clearly, there is a major compartmentalization of Rac1 in cells and a mitochondrial import of the protein dependent on its prenylation at position Cys189 [103].

Rac1 has been shown to form complexes with the membrane protein chaperone Sig1R (sigma-1 receptor, or σ-1R), itself associated with inositol 1,4,5-trisphosphate receptor (IP3R) and Bcl-2 to form a multi-protein complex assembly implicated in the regulation of oxidative stress and neuroplasticity [104,105] (Fig. 5). There are different Sig1R receptors involved in learning and memory. They act as endogenous regulators of dendritic spine formation in the hippocampus, via a free

<figure><img src="image_6.png" /><figcaption>**Fig. 3.** The formation of Bcl-2/Rac1 complex in mitochondria, connected to the PI3K/Akt/mTOR survival pathway. The crosstalk between the two proteins promotes Bcl-2 phosphorylation at Ser-70 and stabilizes Bcl-2 antiapoptotic activity. Inhibition of activated Rac1 with NSC23766 suppresses the interaction, thereby reducing the extent of apoptosis to favor cell survival, notably in a context of neuroprotection [83].</figcaption></figure>
<figure><img src="image_7.png" /><figcaption>**Fig. 4.** Geranylgeranylation of Rac1 triggers its localization into mitochondria. (a) The protein can be geranylgeranylated at position Cys189, farnesylated and palmitoylated at Cys178. Prenylation controls the membrane partitioning of the protein. (b) The geranylgeranyl moiety serves as a membrane anchor to attach the protein to the mitochondrial membrane, at the mitochondria-endoplasmic reticulum (ER) junction. There are other post-translational modifications of the protein, such as phosphorylation (Ser-71), glycosylation (Tyr32 and Thr35), ubiquitination (Lys116, Lys133, Lys147, and Lys153) and nitration (Tyr32), not represented here. (Rac1 structure: https://www.genecards.org/cgi-bin/carddisp.pl?gene=RAC1.)</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>**Fig. 5.** Localization of Rac1 to mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) at the mitochondria-ER junction [88]. A multiprotein complex implicating the chaperone receptor sigma-1 receptor (σ-1R), inositol-3-phosphate receptor (IP3R), Bcl-2 and Rac1 [92]. Rac1 can interact directly with σ-1R to as to induce a mild oxidative stress, through the generation of reactive oxygen species (ROS). The use of the antidepressant and anxiolytic drug opipramol (Insidon®) which is an agonist of σ-1R receptors, or the direct injection of the Rac1 inhibitor NSC23766 into the nucleus accumbens core (NAc), altered the σ-1R-Rac1 complex (Rac1 being overexpressed in the NAc of cocaine-treated rats), thereby reducing the neuronal plasticity caused by cocaine and diminished the craving. The study revealed the crucial role of Rac1 for disrupting addiction memory [107].</figcaption></figure>

radical-sensitive mechanism implicating the ER-mitochondrion axis and the activated (GTP-bound) form of Rac1 [106]. The interaction between Rac1 and Sig1R has pharmacological implications. The Sig1R agonist opipramol (a tricyclic drug [Insidon®] approved to treat depression and anxiety in some European countries) functions via Rac1 inhibition to attenuate cocaine-seeking behavior in a rat model (Fig. 5). A positive correlation has been observed between rat responders expressing both Rac1 and σ-1R mRNA. The data suggested that Rac1 inhibitors could be used to treat moderate to severe substance use disorder (addiction) [107]. It is thus important to define more precisely the functions of mtRac1 and its interaction partners.

**3. Mitochondrial Rac1 in mitobiogenesis and mitophagy**

There is a permanent dynamic of mitochondria in cells, sustained by continuous balance between fission and fusion of mitochondria, and a tight regulation of the biogenesis and autophagy of mitochondria [108]. There is a constant import into and export out of mitochondria of proteins, not only to ensure the correct functioning of the respiratory chain complexes but also to procure molecular chaperones, quality control

factors, and other elements essential to the organization and biology of these organelles [109]. Alterations of mitochondrial dynamics, in cases of compromised mitochondrial biogenesis and/or excessive mitochondrial fission or mitophagy, are observed in certain pathologies, notably in kidney diseases, heart diseases, cancers and other human pathologies [110–112]. The equilibrium between mitobiogenesis and mitophagy must be maintained and controlled. Rac1 plays a role in this regulatory mechanism.

The role of Rac1 in mitochondrial biogenesis (mitobiogenesis) has been studied using the microRNA miR-144 which targets the *Rac-1* gene. The decrease of *Rac-1* expression with miR-144 leads to increased mitochondrial biogenesis and reduced cell apoptosis. miR-144 can protect the heart from hyperglycemia-induced injury by improving mitochondrial biogenesis and decreasing cell apoptosis in a Rac1-dependent manner [113]. *Rac1* is also the target gene of miR-142-3p which has been shown to down-regulate the expression and activation of Rac1, and to regulate mitochondrial biogenesis. The use of miR-142-3p agonists improved mitochondrial biogenesis and function, whereas the opposite effects were observed with miR-142-3p antagonists [114].

Mitophagy is a quality control process used by cells to eliminate
excess or damaged or non-functional mitochondria via the formation of autophagosomes and their fusion with lysosomes. This type of cellular autophagy is tightly regulated but it can present abnormalities in diverse pathologies, such as major depressive disorder, neurodegenerative diseases and cancers [115-117]. For this reason, mitophagy regulators are actively searched [118]. Rac1 plays a role in the selective degradation of mitochondria by autophagy. This has been essentially demonstrated in biological systems using the yeast *Saccharomyces cerevisiae* and the small GTPase Rho5 which is the homolog of mammalian Rac1. Under an oxidative stress (generally a treatment with hydrogen peroxide), Rho5 and its activators Dck1 and Lmo1 quickly relocate to mitochondria to trigger cell death. The participation of Dck1 is essential because activated Rho5 by itself did not strongly associate with mitochondria [119]. Recently, the same process has been evidenced in the yeast *Kluyveromyces lactis* (well known for its involvement in dairy processes) with a rapid translocation of the same two activating guanine-nucleotide-exchange factor (GEF) Dck1 and Lmo1 upon oxidative stress and carbon starvation [120]. In both yeast models, the Rho5 deletion mutants were found to be hyper-resistant towards hydrogen peroxide. Via this GEF-mediated relocation process, Rho5 regulates the oxidative stress by inducing mitophagy and then apoptosis. However, apparently the GTPase must be activated at the plasma membrane prior to its translocation in order to control the oxidative stress response [121]. Rho5 is a central component in the detection of oxidative stress via the trigger of mitophagy and apoptosis of damaged cells [122]. It is not entirely clear at present if this process evidenced in yeasts with Rho5 can occur similarly in human with Rac1 because Rho5 includes in its C-terminal hypervariable region a CAAX box for lipid modification and a 98 amino acid-specific insertion only present in Rho5 but not in its human homolog Rac1 [123]. However, the process is conceivable because other experiments have shown that a knockdown of Rac1 potentiated mitophagy associated to the protein FUNDC1 (FUN14 domain-containing 1). Under hyperglycemia, both Rac1 and FUNDC1 were shown to colocalize in mitochondria [124]. The use of the specific chemical inhibitor of Rac1 NSC23766 inhibited production of ROS and suppressed mitochondria-related apoptosis triggered by a siRNA against MEG3 (Maternally Expressed Gene 3), a protein implicated in the pathogenesis of cancer, ischemic brain, and several central nervous system diseases. When MEG3 is down-regulated, as in the case in diabetes (Fig. 6), Rac1 is activated and the process leads to an enhanced and excessive production of ROS and a suppression of FUNDC1-dependent mitophagy which then can trigger mitochondria-associated apoptosis. In contrast, the reintroduction of MEG3 or the inhibition of Rac1 or its knockdown can potentiate FUNDC1-associated mitophagy [124].

The orphan nuclear receptor Nur77 normally interacts with the GEF protein TIAM1 (T-cell lymphoma invasion and metastasis 1) but Rac1 inhibition promotes Nur77 translocation to the cytoplasm [125]. Interestingly, it has been shown that Nur77 was translocated from nucleus to mitochondria, upon inhibition of connexin 32 (Cx32), in cases of cerebral ischemia-reperfusion. The expression of Nur77 translocated from nucleus to mitochondria was correlated with Rac1, and the protein was shown to stimulate mitophagy. As such, it cleared off dysfunctional mitochondrial, thereby protecting against cerebral ischemia [126]. Rac1 is a regulator of Nur77 [127].

Rac1 may serve as a cargo to help some of its protein partners to cycle on and off mitochondria or conversely, specific proteins may help Rac1 to reside into mitochondria. This is case potentially for the oncogenic kinase Pak 5 (p21cdc42/rac1)-activated kinase 5) which is known to interact with different Rho GTPases via its Cdc42/Rac-interactive binding (CRIB) domain [128]. Pak5 is constitutively localized to mitochondria where it plays an important role in apoptosis [129], notably via ceramide production and the synthesis of FasL [130]. Pak5 promotes migration and invasion of cancer cells, notably in the metastasis colorectal cancer cells [131]. It is an effector of both Rac1 and Cdc42 [132]. The kinase is known to form complexes with multiple partners, such as the signaling effector Raf-1 which regulates the ERK/MAPK pathway. Pak5 activates Raf-1 through phosphorylation and the association of Raf-1 with Pak5 targets a subpopulation of Raf-1 to mitochondria [133]. This kinase may contribute to the mitochondrial localization of Rac1. We can refer also to the homologous kinase Pak1 (p21-activated kinase 1) which has been shown to block the effect of activated Rac1 on mitochondrial motility [134]. The effect of Rac1 and Pak1 kinase on mitochondria depends on phosphorylation of the Ser-55 of the cytoskeletal protein vimentin. Rac1 regulates the binding of mitochondria to vimentin intermediate filaments and activation of Rac1 promotes mitochondrial motility [135]. Parenthetically, it is worth pointing out here that a widely used antibody for visualizing active Rac1 does not recognize Rac1-GTP but instead recognizes vimentin filaments [136,137].

## 4. Rac1: ROS production and mitochondrial damages

The production of ROS in cells is a vital process. It can be beneficial by participating in signaling and energy production, or detrimental by damaging cellular macromolecules, notably in cases of an overproduction. A fine-tuning of ROS production is essential, notably for mitochondrial-derived ROS produced mainly by mitochondrial respiration. To avoid an imbalance or overaccumulation of ROS, cells are

<figure><img src="image_9.png" /><figcaption>**Fig. 6.** Hyperactivation of Rac1 has been observed in hyperglycemia-exposed PC12 cells and in streptozotocin-induced diabetic rats. The high expression of active Rac1-GTP was coupled with a down-regulation of MEG3 (Maternally expressed 3). Activated Rac1 enhanced excessive ROS production and suppressed mitophagy dependent on the required mitophagy receptor FUNDC1 (FUN14 domain-containing 1). These combined effects concur to causing mitochondria-associated apoptosis. The process can be blocked with the Rac1 inhibitor NSC23766 [124].</figcaption></figure>
equipped with antioxidant enzymes, such as heme oxygenase-1 (HO-1), that scavenge excess ROS and with enzymes which produce ROS, such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. The expression and activity of these pro- and anti-oxidant enzymes are regulated in response to oxidative stress. The main sources of ROS are NADPH oxidases and mitochondria, notably in the heart, and Rac1 contributes to both processes which are interconnected [138].

In the cytosol, the production of ROS driven by Rac1-NADPH oxidase complex is a key parameter of oxidative stress and the activity of this complex can be pharmacologically modulated, for example with 8-hydroxydeoxyguanosine (8-OHdG) [139], the rhubarb-derived anthraquinone rhein [140] and dihydroceramide [141]. Excessive dihydroceramide was shown to alter Rac1 association with membranes of different compartments (including but not limited to mitochondria), leading to Rac1 mislocalization [141]. Dihydroceramide (a precursor of ceramide in sphingolipid biosynthesis) may thus increase mtRac1 level. Different drug categories may interfere with mtRac1, notably flavonoids which are well-known to exert modulatory effects on mitochondria [142,143].

There is a cross-talk between ROS derived from NADPH oxidases and mitochondria (termed "ROS-induced ROS release" [144,145]) and this process is implicated in tumorigenesis [146,147]. Rac1 inhibition with molecules such as NSC23766 inhibits NADPH oxidase activity and ROS generation in β-cells maintained under a high glucose level, thereby reducing the extent of mitochondrial dysfunction. This process implicates other proteins, such as the fatty acid translocase CD36 which promotes cellular uptake of fatty acids [148]. CD36 is considered as a target for lung adenocarcinoma therapy [149]. Like Rac1, CD36 can be localized on the cell surface, ER, endosomes and mitochondria to play a role in oxidative stress injury and apoptosis [150].

The excessive production of ROS is associated with the pathogenesis of various diseases, notably type 2 diabetes. In diabetes an excessive production of cytosolic ROS by NADPH oxidase 2 (Nox2) concurs to damage retinal mitochondria and leads to the development of retinopathy. Active Rac1 helps in the assembly of Nox2 holoenzyme. The activation of Rac1-Tiam1 signaling axis is necessary for Nox2 activation and ROS generation leading to mitochondrial damage [151]. Activation of Rac1-Nox2 signaling exacerbates cytosolic ROS production which triggers mitochondrial damages (Fig. 7). In diabetic patients with dyslipidemia, Rac1 transcription is enhanced and the Rac1-Nox2-ROS signaling activity is increased, worsening thus the extent of mitochondrial damages; it is a key factor associated with the development of diabetic retinopathy [152,153]. The better knowledge of the Rac1-Nox2-ROS pathway makes both Nox-2 and Rac1 good targets for therapeutic interventions in diabetes and diabetic retinopathy [7,154].

The Nox2-ROS pathway can be exploited to combat other diseases, such as cardiac arrhythmia (notably in cases of atrial fibrillation) with the use of Nox inhibitors to control mitochondria-derived oxidative

stress [155]. Similarly, modulation of the Nox2 pathway has been proposed to treat infection with the bacterium *Porphyromonas gingivalis*, a major opportunistic pathogen in the etiology of chronic periodontitis. Modulation of the Nox2 pathway can lead to a relocalization and activation of cytosolic molecules including Rac1 [156]. There is a possibility to proceed with a pharmacological inhibition of Rac1 activation to afford protection against Nox-induced oxidative stress and mitochondrial dysfunction. The idea was underlined more than 12 years ago, but it remains a challenging approach because Rac1 displays "friendly and not so friendly" roles [157] or in other words there are promises and limitations for Rac1 as a drug target [23].

## 5. Mitochondrial Rac1 (mtRac1) in cancer

Rac1 activation is dependent on the activity of various proteins, such as the GEF protein Sos1 (Son of Sevenless 1) and its 66-kDa adaptor protein p66Shc. This latter protein has a dual role in the development of several diseases, including diabetic retinopathy and cancers. On the one hand, it controls Rac1-ROS production and the other hand, it displays an oxidoreductase activity and can directly stimulate mitochondrial ROS generation [158]. p66Shc is central in the control of mitochondria-dependent oxidative balance; it mediates Rac1 activation, ROS production and cell death [159]. Like Rac1, p66Shc can translocate from the cytoplasm to mitochondria to play a role in mitochondrial injury [160]. Ascorbic acid (vitamin C) is a classical antioxidant which potently down-regulates ROS production and this effect contributes to reducing cell migration of cancer cells [161,162]. But at high doses, ascorbic acid can induce Rac1 activation, ROS production and apoptosis of cancer cells, via a process dependent on the phosphorylation of p66Shc [163]. Recently, a model has been proposed whereby p66Shc acts as a rheostat to promote or antagonize apoptosis [164]. In the same way, the mitochondrial delivery of the antioxidant vitamin E abrogates the production of mitochondrial ROS production, via a Rac1-dependent process [165]. The function of the p66Shc-Rac1 complex in mitochondria remains to be clarified.

We can also evoke the Rac1-associated anti-migration activity reported with local anesthetic drugs, such as mepivacaine, lidocaine, ropivacaine and bupivacaine. All four local anesthetics have been shown to inhibit proliferation of esophageal carcinoma cells and to exert growth inhibitory and apoptosis-inducing activities, attributed to mitochondrial dysfunction and oxidative damages. A link with Rac1 has been proposed because bupivacaine and ropivacaine (but not lidocaine or bupivacaine) were found to decrease Rac1 activity [166]. Moreover, ropivacaine has been shown previously to inhibit prenylation and to significantly decrease GTPases activities (Rac1 but also RhoA and Ras) in esophageal cancer cells [167]. Bupivacaine has been shown to alter mitochondrial functions as well as RhoA and Rac1 activities, independently of its primary sodium channel blockade action [168]. These local

<figure><img src="image_10.png" /><figcaption>**Fig. 7.** Crosstalk between NADPH oxidase, Rac1 and mitochondria. Rac1 is involved in the assembly and activation of NADPH oxidase 2 (Nox2) complex, which includes the three cytosolic proteins p47phox, p40phox and p67phox, and the two membrane subunits gp91phox and p22phox. When Nox is activated, the cytosolic subunits translocate to the plasma membrane and interact with membrane subunits, together with Rac1. The protein complex produces superoxide radical ($O_2^ {-}$) after electrons are transferred from NADPH through FAD and hemes to molecular oxygen leading to ROS production [134].</figcaption></figure>
anesthetics are more than just “simple” sodium channel blockers [169]; they interact with other proteins so as to impact Rac1 localization and activities.

Other anticancer drugs likely exploit mtRac1 to trigger their activity. For example, it was shown recently that the FDA-approved glycylcycline antibiotic tigecycline exerts antiproliferative effects in hepatocellular carcinoma cell lines via an increased expression of Rac1 coupled to reduced mitochondrial function [170]. The drug functions as an inhibitor oxidative phosphorylation in mitochondria in cancer cells, notably in acute myeloid leukemia (AML) cells [171]. The combination of tigecycline and cytarabine is an option to reduce leukemia progression [172,173]. A mitochondrial adaptation occurs during AML therapy [174]. mtRac1 might play a role in this process. We are investigating this aspect with AML cell lines and patient blasts, using oxygraphic assays [175]. Targeting Rac1 is a promising strategy to treat AML [88].

The role of Rac1 in the mitochondrial translocation of proteins merits to be underlined as well. This is the case notably for the mitochondrial translocation of the stress sensor protein p53 which can be suppressed upon treatment of cells or streptozotocin-induced diabetic rats with the Rac1 inhibitor NSC23766 [176]. There is a cross-talk between transcriptional factor p53 and Rac1. Rac1 is known to mediate inhibition of p53 and this action contributes to hypoxia-driven angiogenesis, notably via the upregulation of HIF-1α expression [177]. The nuclear translocation of Rac1 promotes nuclear translocation of p53 and prolongs its residence time in the nucleus, thereby promoting the transcription of factors implicated in apoptosis [178]. The Rac1-p53 cross-talk is essential because the tumor suppressor p53 is the most frequently mutated gene in human cancer. Gain of function mutants of p53 have been shown to activate Rac1 signaling so as to trigger AKT activation and this activity is a key factor of tumorigenesis [179]. Both mRac1 and Rac-induced mitochondrial translocation of proteins are key determinants, to be further considered for novel anticancer therapeutic approaches.

We shall evoke also the glycolytic enzyme lactate dehydrogenase A (LDHA) which is an essential metabolic enzyme frequently overexpressed in cancer and an important activator for Rac1. LDHA is a cytosolic protein acting as a major regulator of aerobic glycolysis (Warburg effect) capable of interacting with Rac1 which thus contributes to the oncogenic action of the enzyme [180]. Is there a role for mtRac1 here? It is known that mitochondrial metabolic dysfunctions contribute to the induction of a Warburg metabolic state of enhanced glycolysis [181]. Moreover, Rac1-dependent chemoresistance involves the upregulation of glycolytic flux and the pentose phosphate pathway [182]. It would be interesting to determine how aerobic glycolysis can affect the location of Rac1.

Finally, future studies will undoubtedly address also the potential presence of Rac1 mutant forms in mitochondria. There are several mutants of Rac1, such as RAC1P29S as a driver mutation in cutaneous melanoma, and Rac1A159V that occurs in head and neck cancer [2,183,184]. They provide atypical, fast-cycling forms of Rac1 with oncogenic functions in certain cancer types [13,185]. But their eventual presence and role in mitochondria is unknown at present. There is also an alternatively spliced form designated Rac1b known to cause an increase in cellular ROS leading to DNA damages and genomic instability [186]. The phosphorylation of Rac1b at Ser71 increases production of ROS via a reinforced interaction between Rac1b and cytochrome c, associated with mitochondrial dysfunctions [187]. Like Rac1, Rac1b is phosphorylated by the Rho-associated protein kinase (Rock) but the mitochondrial role of Rac1b, if any, remains unknown at present.

## 6. Discussion and future directions

Rac1 is a highly conserved small GTP-binding protein in the Rho GTPase family. Over the past two decades, the knowledge of Rac1 biology and its implications in many human pathologies has considerably progressed. It is now possible to modulate the activation of Rac1

with different small molecule inhibitors, but the development of drug candidates targeting selectively Rac1 is difficult, owing to the functional similarities of Rho GTPases and the multiple functions of Rac1, with both favorable and less favorable roles. Modulation of the Rac1-Nox2-ROS signaling axis is an actionable strategy to combat diverse diseases, including highly prevalent pathologies such as diabetes, cardiovascular diseases and cancers. Nevertheless, many shadows persist about the specific roles of Rac1 in cells and in different organs. The roles of plasma membrane-anchored Rac1 has been largely investigated, much more deeply than its vesicular and nuclear forms. Mitochondrial Rac1 (mt-Rac1) is certainly the less known form, which nevertheless plays also major physiological functions. mtRac1 contributes to the regulation of mitophagy, to the communication with the ER compartment and to the apoptosis process, as discussed above (Fig. 8). Other functions are less clear, notably the role of mtRac1 in mitochondrial respiration. The regulation of the mitochondrial membrane potential and the respiratory chain complex by Rac1 (and mtRac1 in particular) has been little investigated [135]. This aspect should be further investigated, taking profit of the different inhibitors of the GTPase. The role of mtRac1 in many aspects of mitochondria biology remains unclear at present but nevertheless, numerous pharmacological studies have confirmed the positive effects of Rac1 activation on mitochondrial function, and vice versa the role of mitochondria on Rac1 expression and function.

mt-Rac1 must be considered as a fully-fledged entity contributing to the biological functions of the GTPase, as the better-known membrane, nuclear and vesicular forms of Rac1. Notably, the role of mt-Rac1 in oxidative stress must be closely considered. We have underlined here the many contributions of the protein to mitochondria-dependent processes, notably the implication of mt-Rac1 in the regulation of the oxidative stress, and the link with mitophagy. Nevertheless, there remain several unanswered questions about mt-Rac1, such as the contribution of mtRac1 to the regulation of actin cytoskeleton dynamic which affects lamellipodia formation and cell motility. At this level, plasma membrane Rac1 (pmRac1) plays a dominant role whereas the contribution of mtRac1 has been little documented. However, there are indications that the mitochondrial Ca²⁺ homeostasis plays a role in cytoskeleton dynamics and cell migration, through the modulation of ATP and ROS production [188,189]. It is plausible that mtRac1 plays a role in this process, in a manner similar to that reported with GTPases Dynamin and Miro1 [190,191]. There is an implication of Rho GTPases in cytoskeletal remodeling during oxidative stress [192]. The mitochondrial Rho GTPase Miro1 functions as a Ca²⁺-sensor with roles in mitochondrial transport and mitophagy [193]. The relationships between mtRac1 and Ca sensing should be further investigated. In the same vein, more studies are also needed to define the role of mtRac1 in mitochondrial oxidative phosphorylation (Oxphos), aerobic glycolysis and mitochondrial energy metabolic functions in general. There are links between Miro1 and Oxphos [194,195], but no information about mtRac1 and Oxphos. The modulator protein Rich2, acting as a RhoGAP mainly for Rac1 and Cdc42, has been shown recently to contribute to mitochondrial dynamics, mitogenesis and mitochondrial function, notably by inhibiting mitochondrial fusion [196]. Because Rich2 functions via inhibition of Rac1 [197], it will be interesting to investigate its specific interaction with mtRac1.

Researches must be extended to better understand the roles of mtRac1 in cells but also in isolated mitochondria. This may help to better comprehend the function of Rac1, notably when these organelles are directly released into the blood circulation from adipocytes in case of obesity [198]. The intercellular transfer of mitochondria plays role in physiological and pathological processes, including wound healing, immune regulation, and cancer [199]. In the same vein, non-microvesicular, non-exosomal extracellular vesicles of mitochondrial origin, designated mitovesicles, have been identified from brain tissues recently [200,201]. It will be interesting to determine if they can embark Rac1 in addition to a subset of mitochondrial constituents and if they can
<figure><img src="image_11.png" /><figcaption>**Fig. 8.** Trafficking of Rac1. The GTPase is principally anchored to the plasma membranes, acting as a primary regulator of cell motility and dynamic, but also as a signalization factor. The protein shuttles back and forth to the nucleus and different cell compartments. In addition, the less-known mitochondrial entity mtRac1 has been evidenced, with roles in the regulation of mitochondria mobility, mitophagy and as a regulator of apoptosis. But many functions of mtRac1 remain to be more clearly defined.</figcaption></figure>

carry GTPases between mitochondria and other organelles. Mitochondria-derived vesicles carry mtDNA, proteins, and lipids [202,203]. The protein composition of these mitovesicles is drug-sensitive, as shown recently with the psychoactive drug cocaine [204]. It will be interesting to investigate the eventual presence of mtRac1 as a cargo protein in mitochondria-derived vesicles. More generally, we would recommend to consider mtRac1 in studies of mitochondria dynamics during oxidative stress.

In conclusion, the present review underlined the localization and diverse contributions of Rac1 in mitochondria. This small GTPase can locate in all cell compartments, from the plasma membrane to the nucleus, in all types of intracellular vesicles including mitochondria. The functions of mtRac1 remains incompletely known, and probably underestimated. However, key mitochondrial partners have been identified (Bcl-2, σ-1R) and the implications of the mitochondrial protein in the regulation of oxidative stress, mitophagy and apoptosis is indisputable. More studies on the biology and pathological implications of mtRac1 are warranted. There are appreciable tools and drugs for this endeavor.

## Funding

V.S. has received grants from the Institut National de la Santé et de la Recherche Médicale (Inserm) and the TTO Ouest Valorisation (Oracle and Oracle2 projects) for the discovery of Rac1 inhibitors. Research studies in J.K. laboratory received financial supports from the Inserm, University of Lille, and the "Ligue Contre le Cancer". C.D. is the recipient of a PhD contract from the University of Lille. The Rac1-based literature analysis reported here did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

## CRediT authorship contribution statement

**Christian Bailly:** Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Formal analysis, Conceptualization. **Claire Degand:** Investigation, Data curation. **William Laine:** Formal analysis, Data curation. **Vincent Sauzeau:** Writing – original draft, Investigation, Data curation, Conceptualization. **Jérôme Kluza:** Writing – review & editing, Writing – original draft, Data curation, Conceptualization.

## Declaration of competing interest

The authors declare no conflict of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

## Acknowledgments

The OncoLille Institute has been supported by a grant from Contrat de Plan Etat-Région CPER Cancer 2015–2020. The author thanks Prof. Gérard Vergoten (University of Lille, Faculty of Pharmacy, France) who kindly provided the modeling images shown in Fig. 1c-d.

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