Mitochondrial-regulated Tregs: potential therapeutic targets for autoimmune diseases of the central nervous system

Abstract

Regulatory T cells (Tregs) can eliminate autoreactive lymphocytes, induce self-tolerance, and suppress the inflammatory response. Mitochondria, as the energy factories of cells, are essential for regulating the survival, differentiation, and function of Tregs. Studies have shown that patients with autoimmune diseases of the central nervous system, such as multiple sclerosis, neuromyelitis optica spectrum disorder, and autoimmune encephalitis, have aberrant Tregs and mitochondrial damage. However, the role of mitochondrial-regulated Tregs in autoimmune diseases of the central nervous system remains inconclusive. Therefore, this study reviews the mitochondrial regulation of Tregs in autoimmune diseases of the central nervous system and investigates the possible mitochondrial therapeutic targets.

1 Introduction

Regulatory T cells (Tregs) are negative immune-regulatory cells that play a significant role in immune tolerance and the normal function of the immune system by eliminating the autoreactive lymphocytes, inducing self-tolerance, and suppressing the inflammatory response through various mechanisms (1, 2). Recent studies have also indicated the ability of Tregs to promote tissue repair or regeneration by secreting tissue-specific regenerative factors (3–5). Consistently, aberrant Tregs are a major driver of many autoimmune diseases. Reduced number and impaired function of Tregs have been reported in various autoimmune diseases, including myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes (6–8). Some autoimmune diseases of the central nervous system (CNS) occur due to self-tolerance defects. Self-tolerance defect in multiple sclerosis (MS) occurs mainly due to impaired Treg function, but there are also cases of decreased Treg number (6, 9, 10). However, neuromyelitis optica spectrum disorder (NMOSD) and autoimmune encephalitis are characterized by reduced number of Tregs (11, 12). The absence of immunosuppressive capacity of Tregs and decreased number of Tregs activate autoreactive cells, promote B cells to produce autoantibodies and effector T cells to secrete pro-inflammatory cytokines and chemokines, and induce the infiltration of macrophages and effector T cells into the CNS, ultimately promoting the development of autoimmune diseases of the CNS (6, 11–14). However, the specific mechanisms leading to reduced number and impaired function of Tregs in autoimmune diseases of the CNS remain to be determined.

Among numerous cellular biological processes and molecular mechanisms associated with Tregs, their unique metabolic profile has recently drawn significant interest. In physiological conditions, Tregs exhibit increased mitochondrial metabolism, characterized by high levels of mitochondrial fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) and modest glycolysis (15–19). During FAO and OXPHOS, FoxP3, a critical transcription factor of Tregs, is transcriptionally upregulated, which is essential for maintaining the immunosuppressive function and stability of Tregs and can promote Treg differentiation by inhibiting RORγt binding to DNA (15, 16, 20–23). Glycolysis is necessary for the growth and proliferation of Tregs, but it reduces the immunosuppressive ability and stability of Tregs during growth and proliferation (24–26). Glycolysis is also a key energy source for Treg migration to inflammatory tissue (27). Moreover, mitochondrial metabolite α-ketoglutarate is a substrate for ten-eleven translocase (TET)-mediated demethylation of the FoxP3 locus in Tregs, which is required for optimal expression of FoxP3 and immunosuppressive function of Tregs (28–30). Mitochondrial damage, such as damaged respiratory chain complexes and abnormal mitochondrial morphology, can markedly impair the survival, differentiation, and function of Tregs. Therefore, maintaining mitochondrial structure and function is critical for Treg homeostasis and function.

Recent studies have found abnormal mitochondrial morphology, impaired cristae organization, reduced activity and expression of respiratory chain complexes, decreased expression of cytochrome C, increased content of mitochondrial DNA (mtDNA) and mitochondrial reactive oxygen species (mtROS), and damaged mitophagy in Tregs of patients with autoimmune diseases of the CNS such as MS and NMOSD (31–33). Therefore, mitochondrial-regulated Tregs may be involved in the occurrence and progression of autoimmune diseases of the CNS (31). This paper reviews the Treg regulation by mitochondria in autoimmune diseases of the CNS and introduces the possible mitochondrial therapeutic targets.

2 Mitochondrial regulation of Tregs in autoimmune diseases of the CNS

2.1 Accumulation of mtROS decreases the number of Tregs

As a signaling molecule, mtROS plays a significant role in activating signaling pathways and determining cell fate. mtROS level is strictly regulated by antioxidants such as superoxide dismutase and catalase (CAT) (34–36). However, the activities of manganese superoxide dismutase (MnSOD) and CAT are significantly decreased in Tregs of mice with experimental autoimmune encephalomyelitis (EAE), which impairs the ability of the antioxidant system to scavenge mtROS and results in mtROS accumulation (Figure 1) (31). Furthermore, aberrant mitochondrial morphology, impaired cristae organization, and reduced expression of respiratory chain complexes in MS and NMOSD can cause mitochondrial dysfunction and mtROS accumulation (Figure 1) (31–33, 37).

Figure 1

mtROS upregulates the transcription of hypoxia-inducible factor 1α (HIF-1α) subunits through NF-κB activation and stabilizes HIF-1α subunits by inhibiting prolyl hydroxylase and asparaginyl hydroxylase (38–40). Stabilized HIF-1α subunits dimerize with HIF-1β subunits (also known as aryl hydrocarbon receptor nuclear translocator) to form HIF-1 (41). Subsequently, HIF-1 translocates into the nucleus and induces the transcription of genes encoding glycolytic enzymes and glucose transporters, leading to a metabolic shift from OXPHOS to glycolysis in the early stages of T cell differentiation (42, 43). Data from several animal studies suggest that glycolysis reduces the expression of FoxP3, CD25, PD-1, CTLA-4, and ICOS (Table 1), disrupts their stability, and inhibits induced Treg (iTreg) differentiation, thereby impairing the immunosuppressive function of iTregs and decreasing the number of iTregs (15, 25, 43, 49). Moreover, excessive activation of glycolysis reduces the stability of thymus-derived Tregs (tTregs) by downregulating the expression of FoxP3 and CD25 and converts tTregs into pathogenic cells with effector or memory T cell phenotype (25, 50–52). These cells contribute to autoimmune diseases of the CNS by producing pro-inflammatory cytokines, such as IFN-γ and IL-17 (51, 53–55). However, recent studies have shown that glycolysis is essential for Treg differentiation and function. For example, some in vitro studies have shown that glycolysis can induce the differentiation of naive T cells into iTreg and upregulate the expression of CTLA-4, PD-1, CD39, and ICOS (Table 1) to maintain the immunosuppressive function of iTregs (24, 56). These processes are achieved by regulating the expression of FoxP3 exon 2 splicing variants via glycolytic enzyme enolase-1 (24, 56). In addition, glycolysis is required for the optimal expression of the inhibitory molecules CTLA-4 and ICOS and is essential for the immunosuppressive function of tTregs (24, 57). The controversial roles of glycolysis in Treg differentiation and function may be due to differences in the origin of Tregs (thymic or peripheral T cells, human or animal), external and internal environments, metabolic requirements, and cytokines environments. Therefore, the effect of glycolysis on Tregs still needs to be explored. Interestingly, due to the dimerization of HIF-1α subunits and HIF-1β subunits and aryl hydrocarbon receptor degradation by HIF-1α subunits via the ubiquitin-proteasome pathway, the binding rate of aryl hydrocarbon receptor to HIF-1β subunits decreases, causing reduced transcriptional activity of genes encoding ectoenzymes and IL-10 during Treg differentiation and eventually inhibiting Treg differentiation and reducing the number of Tregs (58, 59). Furthermore, HIF-1 binds to the transcription factor FoxP3 in T cell cytoplasm to degrade the latter via the ubiquitin-proteasome pathway, thereby downregulating FoxP3 levels and inhibiting Treg differentiation (Figure 2) (60, 61). However, the exact role of HIF-1 in Tregs remains controversial. Clambey et al. (62) and Flück et al. (63) found that HIF-1 can promote the proliferation of Tregs by inducing FoxP3 transcription, thus inhibiting T cell-mediated colitis. The contradictory roles may be due to the tissue heterogeneity of Tregs, suggesting that HIF-1 expression is essential for Tregs in specific tissues. In addition to inhibiting Treg differentiation by stabilizing HIF-1, mtROS can induce DNA breaks. Subsequently, DNA breaks induce Treg apoptosis by initiating a DNA damage response, ultimately decreasing Treg number (Figure 2) (31, 64).

Figure 2

2.2 Effect of mtDNA release on Tregs

During mitochondrial dysfunction, mtDNA is cleaved into small fragments by endonucleases. The fragments are released into the cytosol through the permeability transition pore complex (PTPC, including mitochondrial permeability transition pores/MPTP and voltage-dependent anion channels/VDAC) (Figure 1) (65). Moreover, BAX and BAK oligomerize in the outer mitochondrial membrane and form BAX/BAK pores, which allow the inner mitochondrial membrane to herniate into the cytosol and release mtDNA (Figure 1) (66). Cytosolic mtDNA activates the inflammasome NLRP3, which in turn increases the release of mtDNA through a positive feedback mechanism (65, 67, 68). In the EAE model, the increase of mtDNA fluorescent particles in the cytoplasm confirmed the release of mtDNA fragments (31).

As an upstream effector, cytosolic mtDNA promotes the secretion of IL-6 and IL-10 by activating several signal pathways, including cGAS-STING and TLR9-MyD88 signals, finally affecting the number and function of Tregs (Figure 1) (68–70). Among them, IL-10 is an immunosuppressive cytokine that suppresses the activation of autoreactive T cells and downregulates pro-inflammatory cytokines to enhance the immunosuppressive function of Tregs in stress conditions (1, 71). In contrast, IL-6 activates STAT3 and promotes Foxp3 locus methylation in Tregs in a DNA methyltransferase 3a (Dnmt3a)-dependent manner, thereby decreasing the expression of FoxP3 (Figure 2) (55, 72). Low FoxP3 expression can downregulate co-inhibitory molecules and ectoenzymes on the surfaces of Tregs and turn Tregs into pathogenic cells with effector or memory T cell phenotype (20, 53, 55). On the other hand, IL-6 activates STAT3 in T cells by binding to IL-6 receptor and gp130, which can attenuate RORγt inhibition by FoxP3 and promote the transcription of HIF-1α subunits (Figure 2) (21, 60, 73). These alterations finally inhibit Treg differentiation and decrease Treg number (43, 61). Thus, the influence of mtDNA on the number and function of Tregs may depend on the balance between the mechanisms mentioned above.

2.3 Impairment of mitochondrial metabolic pathways decreases the number of Tregs and impairs their function

Recent studies have shown that Tregs mainly rely on high levels of FAO and modest glycolysis to meet their energy requirements in steady-state conditions (15, 16). FAO is also necessary for T cell differentiation to Tregs (74, 75). During FAO-driven OXPHOS, fatty acids increase the stability and immunosuppressive activity of Tregs by upregulating FoxP3 transcription and inducing CD25 and STAT5 expression (23, 76). At the same time, FoxP3 increases the transcription of FAO and OXPHOS-related genes and inhibits glycolysis by binding to the Myc promoter and downregulating the expression of Myc in Tregs, establishing a positive feedback loop to maximize the immunosuppressive function of Tregs (22, 25, 77). Carnitine palmitoyltransferase 1 (CPT1) on the outer mitochondrial membrane is a rate-limiting enzyme in FAO (Figure 1). Previous studies have demonstrated that CPT1 inhibitors can prevent Treg differentiation and significantly reduce the expression of granzymes, ectoenzymes, and co-inhibitory molecules in Tregs by suppressing FAO, thereby reducing the number and immunosuppressive activity of Tregs (15, 78, 79). Therefore, FAO impairment due to reduced or defective CPT1 activity reduces the number and immunosuppressive activity of Tregs. In addition, fatty acid concentrations in patients with MS are lower than those in healthy individuals, thereby decreasing FAO in Tregs and weakening the inhibitory function of Tregs (23).

OXPHOS is a critical metabolic pathway for the differentiation and immunosuppressive function of Tregs (15–17). Therefore, decreased activity and expression of respiratory chain complexes in autoimmune diseases of the CNS, such as MS and NMOSD, can contribute to the abnormal number and function of Tregs (32, 33, 77, 80, 81). Weinberg et al. (81) found that accumulation of succinate and 2-hydroxyglutarate (2-HG) can inhibit TET by competing with α-ketoglutarate in respiratory chain complex III-deficient Tregs (Figure 1), thereby causing DNA hypermethylation in specific regulatory regions of Tregs and reducing the expression of PDCD1 (encoding PD-1), NT5E (encoding CD73), TIGIT, and FGL2 genes associated with the immunosuppressive function of Tregs (Figure 2) (82, 83). These alterations finally downregulate co-inhibitory molecules and ectoenzymes, such as PD-1, CD73, TIGIT, and FGL2, and impair the immunosuppressive function of Tregs (Table 1) (44–46, 48, 81). On the other hand, succinate and 2-HG stabilize HIF-1α subunits by inhibiting prolyl hydroxylases, thereby inhibiting Treg differentiation and decreasing Treg number (Figure 2) (83–85). Similar to respiratory chain complex III inhibition, respiratory chain complex I inhibition can downregulate the expression of FoxP3 and decrease the number of Tregs (16). In addition, Angelin et al. (77) found that Tregs with mitochondrial ND6 gene mutations have reduced immunosuppressive function due to the inability of respiratory chain complex I to oxidize NADH to NAD.

2.4 Impairment of mitophagy decreases the number of Tregs

Mitophagy, a specific form of autophagy, is essential for clearing damaged mitochondria and maintaining cell homeostasis (86). Mitochondrial depolarization induces the ubiquitination of mitochondrial outer membrane proteins and promotes the recruitment of mitophagy receptors, followed by autophagosome formation to degrade damaged mitochondria (86). Therefore, impaired initiation of mitophagy, incorrect autophagosome formation, or aberrant lysosomal degradation in autoimmune diseases of the CNS can impair mitophagy in Tregs (Figure 1) (31, 87).

Crosstalk between mitochondria and lysosomes has been demonstrated. Lysosomal dysfunction induces mitochondrial defect and vice versa (88, 89). Mitochondrial dysfunction in Tregs of EAE mice can decrease the activity of several hydrolases in lysosomes and downregulate the expression of Rab7, which regulates the fusion of autophagosomes with lysosomes, thus preventing lysosomal degradation of damaged mitochondria (31, 88, 90). In addition, downregulation of the AMPK-PIKFYVE-PtdIns (3, 5) P2-MCOLN1 pathway in the presence of damaged respiratory chain complexes leads to lysosomal calcium accumulation and impairs lysosomal hydrolysis, thereby impairing mitophagy (91, 92). In addition to lysosomal dysfunction, significantly reduced expression of autophagy protein LC3-II in Tregs in patients with myasthenia gravis can impair autophagosome formation and reduce the number of autophagosomes, eventually impairing mitophagy (87). Thanks to the damaged mitophagy of Tregs, the accumulation of damaged mitochondria increases mtROS production and exacerbates mitochondrial oxidative stress, thereby forming a vicious circle (31). Eventually, mtROS accumulation induces DNA breaks, and DNA damage induces Treg apoptosis by initiating a DNA damage response (31, 64).

3 Mitochondrial-regulated Tregs may be potential therapeutic targets for autoimmune diseases of the CNS

Accumulation of mtROS decreases the number of Tregs; thus, a better understanding of the role of mitochondria-specific antioxidants in reducing mtROS may provide a new modality for immunotherapy of autoimmune diseases of the CNS. Animal studies applying mitochondrial antioxidants have reported promising results. Mito-TEMPO, a mitochondria-targeting antioxidant mimicking superoxide dismutase, can restore lysosome function and inhibit Treg apoptosis in the EAE mice model by reducing mtROS levels and mitigating mtROS damage, thereby inhibiting effector T cell infiltration into the spinal cord and increasing Treg infiltration to alleviate the symptoms (Table 2) (31, 93). The ability of superoxide dismutase mimics to delay the progression of EAE suggests that these novel antioxidants can be applied to autoimmune diseases of the CNS, such as NMOSD and autoimmune encephalitis, in the future. Furthermore, Cyclosporin A (CsA), an MPTP inhibitor, can reduce the production of mtROS and attenuate mitochondrial dysfunction by inhibiting MPTP opening through the blockade of the interaction of cyclophilin D with adenine nucleotide translocator (Table 2) (94, 101). Studies have found that CsA can induce Treg proliferation and prevent T cell proliferation by inhibiting calcineurin, thus ameliorating the symptoms of EAE, MS, and NMOSD (95, 96, 102). However, some immunosuppressive effects of CsA may be caused by MPTP inhibition, but this possibility has not been investigated and remains to be explored in the future. In addition, genetic or pharmacological downregulation of mtROS lowers HIF-1α levels, and HIF-1α-deficient mice with an increased number of Tregs are resistant to EAE (61, 103, 104). However, these results do not demonstrate a direct link between reduced mtROS levels, lowered HIF-1α levels, and an increased number of Tregs. In the future, it is necessary to explore whether mitochondrial antioxidants inhibit HIF-1α subunits and whether this inhibition affects Tregs in autoimmune diseases of the CNS.

mtDNA release affects the number and function of Tregs and induces the inflammatory response in autoimmune diseases of the CNS. Therefore, targeting mtDNA release may be another novel therapeutic approach for treating autoimmune diseases of CNS. VBIT-4 and VBIT-12, two VDAC1 oligomerization inhibitors, prevent VDAC1 oligomerization by directly interacting with VDAC1, thereby inhibiting apoptosis, reducing mtDNA release, inhibiting inflammatory cell infiltration and inflammasome NLRP3 activation, protecting against mitochondrial dysfunction, and reducing inflammatory response and disease severity (Table 2) (97, 98). This VDAC1-based treatment strategy has been effective in some animal models of autoimmune diseases, such as inflammatory bowel disease, systemic lupus erythematosus, and type 2 diabetes (97, 98, 105). Future studies on autoimmune diseases of the CNS are needed to determine the efficacy of VDAC1-based treatment for these diseases.

Increased mitochondrial metabolism promotes Treg differentiation, while inhibition of mitochondrial metabolism or increased glycolysis inhibits Treg differentiation. Therefore, shifting cellular energy metabolism to OXPHOS may be a treatment strategy for autoimmune diseases of the CNS. Animal studies of cellular metabolic reprogramming have yielded promising results in autoimmune diseases of the CNS. For example, inhibition of glycolysis by HIF-1α gene knockout or application of 2-deoxyglucose or rapamycin can promote Treg differentiation, increase the number of Tregs, and reduce spinal cord inflammation in EAE mice (Table 2) (43, 49). Similarly, decreasing pyruvate dehydrogenase kinase activity genetically (gene knockout) or pharmacologically (by dichloroacetate) can enhance OXPHOS levels, promote Treg differentiation, increase the number of Tregs, and protect mice against EAE (Table 2) (16, 99). The development of this therapeutic strategy requires further research. In the future, we should explore whether these drugs affecting cellular metabolic reprogramming can modulate the activity of Tregs in autoimmune diseases of the human CNS. Furthermore, IL-15 has been shown to improve mitochondrial mass and OXPHOS in Tregs from HIV-infected immune non-responders by inducing the expression of mitochondrial transcription factor A and peroxisome proliferator-activated receptor-γ coactivator-1α (Table 2) (100). Currently, IL-15 and some of its derivatives, such as IL-15 super-agonists, are in clinical trials for cancer and AIDS. Future studies are needed to investigate the immunologic role of IL-15 in autoimmune diseases of the CNS.

4 Conclusion and prospect

Recent studies have investigated the role of mitochondrial regulation on Treg number and function. However, the details of the mitochondrial regulation process remain to be elucidated. For example, the type of E3 ligase responsible for HIF-1-mediated ubiquitination of FoxP3 is still unclear. Similarly, the effects of glycolysis on Tregs, the mechanisms by which mtDNA affects Tregs and the mechanisms by which respiratory chain complex I damage causes Treg dysfunction need more studies. Moreover, whether drugs targeting mitochondria can improve human autoimmune diseases of the CNS by selectively modulating Treg activity remains to be explored.

In conclusion, understanding the mechanisms by which mitochondrial dysfunction affects the number and function of Tregs in autoimmune diseases may pave the way for developing new therapeutic approaches. Future in-depth studies in this field will be a significant entry point for exploring the molecular mechanisms and therapeutic targets in autoimmune diseases of the CNS.

References

• 1

  Grover P Goel PN Greene MI . Regulatory T cells: regulation of identity and function. Front Immunol (2021) 12:750542. doi: 10.3389/fimmu.2021.750542

  • CrossRef
  • Google Scholar

• 2

  Shevyrev D Tereshchenko V . Treg heterogeneity, function, and homeostasis. Front Immunol (2019) 10:3100. doi: 10.3389/fimmu.2019.03100

  • CrossRef
  • Google Scholar

• 3

  Kikuchi K . New function of zebrafish regulatory T cells in organ regeneration. Curr Opin Immunol (2020) 63:7–13. doi: 10.1016/j.coi.2019.10.001

  • CrossRef
  • Google Scholar

• 4

  Dombrowski Y O'Hagan T Dittmer M Penalva R Mayoral SR Bankhead P et al . Regulatory T cells promote myelin regeneration in the central nervous system. Nat Neurosci (2017) 20(5):674–80. doi: 10.1038/nn.4528

  • CrossRef
  • Google Scholar

• 5

  Arpaia N Green Jesse A Moltedo B Arvey A Hemmers S Yuan S et al . A distinct function of regulatory T cells in tissue protection. Cell (2015) 162(5):1078–89. doi: 10.1016/j.cell.2015.08.021

  • CrossRef
  • Google Scholar

• 6

  Danikowski KM Jayaraman S Prabhakar BS . Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflamm (2017) 14(1):117. doi: 10.1186/s12974-017-0892-8

  • CrossRef
  • Google Scholar

• 7

  Goschl L Scheinecker C Bonelli M . Treg cells in autoimmunity: from identification to Treg-based therapies. Semin Immunopathol (2019) 41(3):301–14. doi: 10.1007/s00281-019-00741-8

  • CrossRef
  • Google Scholar

• 8

  Long SA Buckner JH . CD4+FOXP3+ T regulatory cells in human autoimmunity: more than a numbers game. J Immunol (2011) 187(5):2061–6. doi: 10.4049/jimmunol.1003224

  • CrossRef
  • Google Scholar

• 9

  Kouchaki E Salehi M Reza Sharif M Nikoueinejad H Akbari H . Numerical status of CD4(+)CD25(+)FoxP3(+) and CD8(+)CD28(-) regulatory T cells in multiple sclerosis. Iranian J Basic Med Sci (2014) 17(4):250–5.

  • Google Scholar

• 10

  Viglietta V Baecher-Allan C Weiner HL Hafler DA . Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med (2004) 199(7):971–9. doi: 10.1084/jem.20031579

  • CrossRef
  • Google Scholar

• 11

  Platt MP Bolding KA Wayne CR Chaudhry S Cutforth T Franks KM et al . Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis. Proc Natl Acad Sci USA (2020) 117(12):6708–16. doi: 10.1073/pnas.1911097117

  • CrossRef
  • Google Scholar

• 12

  Ma X Qin C Chen M Yu HH Chu YH Chen TJ et al . Regulatory T cells protect against brain damage by alleviating inflammatory response in neuromyelitis optica spectrum disorder. J Neuroinflamm (2021) 18(1):201. doi: 10.1186/s12974-021-02266-0

  • CrossRef
  • Google Scholar

• 13

  Liba Z Kayserova J Elisak M Marusic P Nohejlova H Hanzalova J et al . Anti-N-methyl-D-aspartate receptor encephalitis: the clinical course in light of the chemokine and cytokine levels in cerebrospinal fluid. J Neuroinflamm (2016) 13(1):55. doi: 10.1186/s12974-016-0507-9

  • CrossRef
  • Google Scholar

• 14

  Kleinewietfeld M Hafler DA . Regulatory T cells in autoimmune neuroinflammation. Immunol Rev (2014) 259(1):231–44. doi: 10.1111/imr.12169

  • CrossRef
  • Google Scholar

• 15

  Michalek RD Gerriets VA Jacobs SR Macintyre AN MacIver NJ Mason EF et al . Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol (2011) 186(6):3299–303. doi: 10.4049/jimmunol.1003613

  • CrossRef
  • Google Scholar

• 16

  Gerriets VA Kishton RJ Nichols AG Macintyre AN Inoue M Ilkayeva O et al . Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J Clin Invest (2015) 125(1):194–207. doi: 10.1172/JCI76012

  • CrossRef
  • Google Scholar

• 17

  Beier UH Angelin A Akimova T Wang L Liu Y Xiao H et al . Essential role of mitochondrial energy metabolism in Foxp3(+) T-regulatory cell function and allograft survival. FASEB J (2015) 29(6):2315–26. doi: 10.1096/fj.14-268409

  • CrossRef
  • Google Scholar

• 18

  Cluxton D Petrasca A Moran B Fletcher JM . Differential regulation of human treg and Th17 cells by fatty acid synthesis and glycolysis. Front Immunol (2019) 10:115. doi: 10.3389/fimmu.2019.00115

  • CrossRef
  • Google Scholar

• 19

  Newton R Priyadharshini B Turka LA . Immunometabolism of regulatory T cells. Nat Immunol (2016) 17(6):618–25. doi: 10.1038/ni.3466

  • CrossRef
  • Google Scholar

• 20

  Williams LM Rudensky AY . Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol (2007) 8(3):277–84. doi: 10.1038/ni1437

  • CrossRef
  • Google Scholar

• 21

  Zhou L Lopes JE Chong MM Ivanov II Min R Victora GD et al . TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature (2008) 453(7192):236–40. doi: 10.1038/nature06878

  • CrossRef
  • Google Scholar

• 22

  Howie D Cobbold SP Adams E Ten Bokum A Necula AS Zhang W et al . Foxp3 drives oxidative phosphorylation and protection from lipotoxicity. JCI Insight (2017) 2(3):e89160. doi: 10.1172/jci.insight.89160

  • CrossRef
  • Google Scholar

• 23

  Pompura SL Wagner A Kitz A LaPerche J Yosef N Dominguez-Villar M et al . Oleic acid restores suppressive defects in tissue-resident FOXP3 Tregs from patients with multiple sclerosis. J Clin Invest (2021) 131(2):e138519. doi: 10.1172/JCI138519

  • CrossRef
  • Google Scholar

• 24

  Tanimine N Germana SK Fan M Hippen K Blazar BR Markmann JF et al . Differential effects of 2-deoxy-D-glucose on in vitro expanded human regulatory T cell subsets. PloS One (2019) 14(6):e0217761. doi: 10.1371/journal.pone.0217761

  • CrossRef
  • Google Scholar

• 25

  Gerriets VA Kishton RJ Johnson MO Cohen S Siska PJ Nichols AG et al . Foxp3 and Toll-like receptor signaling balance T(reg) cell anabolic metabolism for suppression. Nat Immunol (2016) 17(12):1459–66. doi: 10.1038/ni.3577

  • CrossRef
  • Google Scholar

• 26

  Procaccini C Carbone F Di Silvestre D Brambilla F De Rosa V Galgani M et al . The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements. Immunity (2016) 44(2):406–21. doi: 10.1016/j.immuni.2016.01.028

  • CrossRef
  • Google Scholar

• 27

  Kishore M Cheung KCP Fu H Bonacina F Wang G Coe D et al . Regulatory T cell migration is dependent on glucokinase-mediated glycolysis. Immunity (2017) 47(5):875–89.e10. doi: 10.1016/j.immuni.2017.10.017

  • CrossRef
  • Google Scholar

• 28

  Kaelin William G McKnight Steven L . Influence of metabolism on epigenetics and disease. Cell (2013) 153(1):56–69. doi: 10.1016/j.cell.2013.03.004

  • CrossRef
  • Google Scholar

• 29

  Yue X Trifari S Aijo T Tsagaratou A Pastor WA Zepeda-Martinez JA et al . Control of Foxp3 stability through modulation of TET activity. J Exp Med (2016) 213(3):377–97. doi: 10.1084/jem.20151438

  • CrossRef
  • Google Scholar

• 30

  Floess S Freyer J Siewert C Baron U Olek S Polansky J et al . Epigenetic control of the foxp3 locus in regulatory T cells. PloS Biol (2007) 5(2):e38. doi: 10.1371/journal.pbio.0050038

  • CrossRef
  • Google Scholar

• 31

  Alissafi T Kalafati L Lazari M Filia A Kloukina I Manifava M et al . Mitochondrial oxidative damage underlies regulatory T cell defects in autoimmunity. Cell Metab (2020) 32(4):591–604 e7. doi: 10.1016/j.cmet.2020.07.001

  • CrossRef
  • Google Scholar

• 32

  Foolad F Khodagholi F Nabavi SM Javan M . Changes in mitochondrial function in patients with neuromyelitis optica; correlations with motor and cognitive disabilities. PloS One (2020) 15(3):e0230691. doi: 10.1371/journal.pone.0230691

  • CrossRef
  • Google Scholar

• 33

  Gonzalo H Nogueras L Gil-Sanchez A Hervas JV Valcheva P Gonzalez-Mingot C et al . Impairment of mitochondrial redox status in peripheral lymphocytes of multiple sclerosis patients. Front Neurosci (2019) 13:938. doi: 10.3389/fnins.2019.00938

  • CrossRef
  • Google Scholar

• 34

  Wang Y Branicky R Noe A Hekimi S . Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling. J Cell Biol (2018) 217(6):1915–28. doi: 10.1083/jcb.201708007

  • CrossRef
  • Google Scholar

• 35

  Galasso M Gambino S Romanelli MG Donadelli M Scupoli MT . Browsing the oldest antioxidant enzyme: catalase and its multiple regulation in cancer. Free Radic Biol Med (2021) 172:264–72. doi: 10.1016/j.freeradbiomed.2021.06.010

  • CrossRef
  • Google Scholar

• 36

  Holley AK Bakthavatchalu V Velez-Roman JM St Clair DK . Manganese superoxide dismutase: guardian of the powerhouse. Int J Mol Sci (2011) 12(10):7114–62. doi: 10.3390/ijms12107114

  • CrossRef
  • Google Scholar

• 37

  Wang Y Hekimi S . Mitochondrial dysfunction and longevity in animals: Untangling the knot. Science (2015) 350(6265):1204–7. doi: 10.1126/science.aac4357

  • CrossRef
  • Google Scholar

• 38

  Lee G Won HS Lee YM Choi JW Oh TI Jang JH et al . Oxidative Dimerization of PHD2 is Responsible for its Inactivation and Contributes to Metabolic Reprogramming via HIF-1alpha Activation. Sci Rep (2016) 6:18928. doi: 10.1038/srep18928

  • CrossRef
  • Google Scholar

• 39

  Masson N Singleton RS Sekirnik R Trudgian DC Ambrose LJ Miranda MX et al . The FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity. EMBO Rep (2012) 13(3):251–7. doi: 10.1038/embor.2012.9

  • CrossRef
  • Google Scholar

• 40

  Bonello S Zahringer C BelAiba RS Djordjevic T Hess J Michiels C et al . Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site. Arterioscler Thromb Vasc Biol (2007) 27(4):755–61. doi: 10.1161/01.ATV.0000258979.92828.bc

  • CrossRef
  • Google Scholar

• 41

  Liu YV Semenza GL . RACK1 vs. HSP90: Competition for HIF-1α Degradation vs. Stabilization. Cell Cycle (2014) 6(6):656–9. doi: 10.4161/cc.6.6.3981

  • CrossRef
  • Google Scholar

• 42

  Kierans SJ Taylor CT . Regulation of glycolysis by the hypoxia-inducible factor (HIF): implications for cellular physiology. J Physiol (2020) 599(1):23–37. doi: 10.1113/jp280572

  • CrossRef
  • Google Scholar

• 43

  Shi LZ Wang R Huang G Vogel P Neale G Green DR et al . HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med (2011) 208(7):1367–76. doi: 10.1084/jem.20110278

  • CrossRef
  • Google Scholar

• 44

  Zhang B Chikuma S Hori S Fagarasan S Honjo T . Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model. Proc Natl Acad Sci USA (2016) 113(30):8490–5. doi: 10.1073/pnas.1608873113

  • CrossRef
  • Google Scholar

• 45

  Sauer AV Brigida I Carriglio N Hernandez RJ Scaramuzza S Clavenna D et al . Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID. Blood (2012) 119(6):1428–39. doi: 10.1182/blood-2011-07-366781

  • CrossRef
  • Google Scholar

• 46

  Joller N Lozano E Burkett PR Patel B Xiao S Zhu C et al . Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity (2014) 40(4):569–81. doi: 10.1016/j.immuni.2014.02.012

  • CrossRef
  • Google Scholar

• 47

  Yu X Harden K Gonzalez LC Francesco M Chiang E Irving B et al . The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol (2009) 10(1):48–57. doi: 10.1038/ni.1674

  • CrossRef
  • Google Scholar

• 48

  Shalev I Liu H Koscik C Bartczak A Javadi M Wong KM et al . Targeted deletion of fgl2 leads to impaired regulatory T cell activity and development of autoimmune glomerulonephritis. J Immunol (2008) 180(1):249–60. doi: 10.4049/jimmunol.180.1.249

  • CrossRef
  • Google Scholar

• 49

  Chen X Li S Long D Shan J Li Y . Rapamycin facilitates differentiation of regulatory T cells via enhancement of oxidative phosphorylation. Cell Immunol (2021) 365:104378. doi: 10.1016/j.cellimm.2021.104378

  • CrossRef
  • Google Scholar

• 50

  Wei J Long L Yang K Guy C Shrestha S Chen Z et al . Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat Immunol (2016) 17(3):277–85. doi: 10.1038/ni.3365

  • CrossRef
  • Google Scholar

• 51

  Bailey-Bucktrout SL Martinez-Llordella M Zhou X Anthony B Rosenthal W Luche H et al . Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity (2013) 39(5):949–62. doi: 10.1016/j.immuni.2013.10.016

  • CrossRef
  • Google Scholar

• 52

  Huynh A DuPage M Priyadharshini B Sage PT Quiros J Borges CM et al . Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol (2015) 16(2):188–96. doi: 10.1038/ni.3077

  • CrossRef
  • Google Scholar

• 53

  Zhou X Bailey-Bucktrout SL Jeker LT Penaranda C Martinez-Llordella M Ashby M et al . Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol (2009) 10(9):1000–7. doi: 10.1038/ni.1774

  • CrossRef
  • Google Scholar

• 54

  Dominguez-Villar M Baecher-Allan CM Hafler DA . Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat Med (2011) 17(6):673–5. doi: 10.1038/nm.2389

  • CrossRef
  • Google Scholar

• 55

  Garg G Muschaweckh A Moreno H Vasanthakumar A Floess S Lepennetier G et al . Blimp1 prevents methylation of foxp3 and loss of regulatory T cell identity at sites of inflammation. Cell Rep (2019) 26(7):1854–68 e5. doi: 10.1016/j.celrep.2019.01.070

  • CrossRef
  • Google Scholar

• 56

  De Rosa V Galgani M Porcellini A Colamatteo A Santopaolo M Zuchegna C et al . Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat Immunol (2015) 16(11):1174–84. doi: 10.1038/ni.3269

  • CrossRef
  • Google Scholar

• 57

  Zeng H Yang K Cloer C Neale G Vogel P Chi H . mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature (2013) 499(7459):485–90. doi: 10.1038/nature12297

  • CrossRef
  • Google Scholar

• 58

  Mascanfroni ID Takenaka MC Yeste A Patel B Wu Y Kenison JE et al . Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-alpha. Nat Med (2015) 21(6):638–46. doi: 10.1038/nm.3868

  • CrossRef
  • Google Scholar

• 59

  Quintana FJ Sherr DH Insel PA . Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol Rev (2013) 65(4):1148–61. doi: 10.1124/pr.113.007823

  • CrossRef
  • Google Scholar

• 60

  Barbi J Pardoll DM Pan F . Ubiquitin-dependent regulation of Foxp3 and Treg function. Immunol Rev (2015) 266(1):27–45. doi: 10.1111/imr.12312

  • CrossRef
  • Google Scholar

• 61

  Dang EV Barbi J Yang HY Jinasena D Yu H Zheng Y et al . Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell (2011) 146(5):772–84. doi: 10.1016/j.cell.2011.07.033

  • CrossRef
  • Google Scholar

• 62

  Clambey ET McNamee EN Westrich JA Glover LE Campbell EL Jedlicka P et al . Hypoxia-inducible factor-1 alpha–dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci (2012) 109(41):E2784–93. doi: 10.1073/pnas.1202366109

  • CrossRef
  • Google Scholar

• 63

  Flück K Breves G Fandrey J Winning S . Hypoxia-inducible factor 1 in dendritic cells is crucial for the activation of protective regulatory T cells in murine colitis. Mucosal Immunol (2016) 9(2):379–90. doi: 10.1038/mi.2015.67

  • CrossRef
  • Google Scholar

• 64

  Corrado M Campello S . Autophagy inhibition and mitochondrial remodeling join forces to amplify apoptosis in activation-induced cell death. Autophagy (2016) 12(12):2496–7. doi: 10.1080/15548627.2016.1226738

  • CrossRef
  • Google Scholar

• 65

  Xian H Watari K Sanchez-Lopez E Offenberger J Onyuru J Sampath H et al . Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling. Immunity (2022) 55(8):1370–85 e8. doi: 10.1016/j.immuni.2022.06.007

  • CrossRef
  • Google Scholar

• 66

  McArthur K Whitehead LW Heddleston JM Li L Padman BS Oorschot V et al . BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science (2018) 359(6378):eaao6047. doi: 10.1126/science.aao6047

  • CrossRef
  • Google Scholar

• 67

  Nakahira K Haspel JA Rathinam VA Lee SJ Dolinay T Lam HC et al . Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol (2011) 12(3):222–30. doi: 10.1038/ni.1980

  • CrossRef
  • Google Scholar

• 68

  Marchi S Guilbaud E Tait SWG Yamazaki T Galluzzi L . Mitochondrial control of inflammation. Nat Rev Immunol (2022) 23(3):159–73. doi: 10.1038/s41577-022-00760-x

  • CrossRef
  • Google Scholar

• 69

  Field CS Baixauli F Kyle RL Puleston DJ Cameron AM Sanin DE et al . Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for Treg suppressive function. Cell Metab (2020) 31(2):422–37.e5. doi: 10.1016/j.cmet.2019.11.021

  • CrossRef
  • Google Scholar

• 70

  Yang D Sun H Hu Z Tang J . Mitochondrial DNA-toll-like receptor 9 pathway mediated inflammatory responses. Med Recapitulate (2019) 25(21):4201–6. doi: 10.3969/j.issn.1006-2084.2019.21.008

  • CrossRef
  • Google Scholar

• 71

  Stewart CA Metheny H Iida N Smith L Hanson M Steinhagen F et al . Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation. J Clin Invest (2013) 123(11):4859–74. doi: 10.1172/JCI65180

  • CrossRef
  • Google Scholar

• 72

  Lal G Zhang N van der Touw W Ding Y Ju W Bottinger EP et al . Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol (2009) 182(1):259–73. doi: 10.4049/jimmunol.182.1.259

  • CrossRef
  • Google Scholar

• 73

  Yang XO Nurieva R Martinez GJ Kang HS Chung Y Pappu BP et al . Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity (2008) 29(1):44–56. doi: 10.1016/j.immuni.2008.05.007

  • CrossRef
  • Google Scholar

• 74

  Gualdoni GA Mayer KA Göschl L Boucheron N Ellmeier W Zlabinger GJ . The AMP analog AICAR modulates the Treg/Th17 axis through enhancement of fatty acid oxidation. FASEB J (2016) 30(11):3800–9. doi: 10.1096/fj.201600522R

  • CrossRef
  • Google Scholar

• 75

  Berod L Friedrich C Nandan A Freitag J Hagemann S Harmrolfs K et al . De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med (2014) 20(11):1327–33. doi: 10.1038/nm.3704

  • CrossRef
  • Google Scholar

• 76

  Goverman JM . Regulatory T cells in multiple sclerosis. N Engl J Med (2021) 384(6):578–80. doi: 10.1056/NEJMcibr2033544

  • CrossRef
  • Google Scholar

• 77

  Angelin A Gil-de-Gomez L Dahiya S Jiao J Guo L Levine MH et al . Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab (2017) 25(6):1282–93 e7. doi: 10.1016/j.cmet.2016.12.018

  • CrossRef
  • Google Scholar

• 78

  Zhang Q Fang Y Lv C Zhu Y Xia Y Wei Z et al . Norisoboldine induces the development of Treg cells by promoting fatty acid oxidation-mediated H3K27 acetylation of Foxp3. FASEB J (2022) 36(4):e22230. doi: 10.1096/fj.202101643R

  • CrossRef
  • Google Scholar

• 79

  Miska J Lee-Chang C Rashidi A Muroski ME Chang AL Lopez-Rosas A et al . HIF-1α Is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of Tregs in glioblastoma. Cell Rep (2019) 27(1):226–37.e4. doi: 10.1016/j.celrep.2019.03.029

  • CrossRef
  • Google Scholar

• 80

  Dutta R McDonough J Yin X Peterson J Chang A Torres T et al . Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol (2006) 59(3):478–89. doi: 10.1002/ana.20736

  • CrossRef
  • Google Scholar

• 81

  Weinberg SE Singer BD Steinert EM Martinez CA Mehta MM Martinez-Reyes I et al . Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature (2019) 565(7740):495–9. doi: 10.1038/s41586-018-0846-z

  • CrossRef
  • Google Scholar

• 82

  Xiao M Yang H Xu W Ma S Lin H Zhu H et al . Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev (2012) 26(12):1326–38. doi: 10.1101/gad.191056.112

  • CrossRef
  • Google Scholar

• 83

  Xu W Yang H Liu Y Yang Y Wang P Kim SH et al . Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell (2011) 19(1):17–30. doi: 10.1016/j.ccr.2010.12.014

  • CrossRef
  • Google Scholar

• 84

  Steinert EM Vasan K Chandel NS . Mitochondrial metabolism regulation of T cell-mediated immunity. Annu Rev Immunol (2021) 39:395–416. doi: 10.1146/annurev-immunol-101819-082015

  • CrossRef
  • Google Scholar

• 85

  King A Selak MA Gottlieb E . Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene (2006) 25(34):4675–82. doi: 10.1038/sj.onc.1209594

  • CrossRef
  • Google Scholar

• 86

  Xu Y Shen J Ran Z . Emerging views of mitophagy in immunity and autoimmune diseases. Autophagy (2020) 16(1):3–17. doi: 10.1080/15548627.2019.1603547

  • CrossRef
  • Google Scholar

• 87

  Wang N Yuan J Karim MR Zhong P Sun YP Zhang HY et al . Effects of mitophagy on regulatory T cell function in patients with myasthenia gravis. Front Neurol (2020) 11:238. doi: 10.3389/fneur.2020.00238

  • CrossRef
  • Google Scholar

• 88

  Demers-Lamarche J Guillebaud G Tlili M Todkar K Belanger N Grondin M et al . Loss of mitochondrial function impairs lysosomes. J Biol Chem (2016) 291(19):10263–76. doi: 10.1074/jbc.M115.695825

  • CrossRef
  • Google Scholar

• 89

  Gusdon AM Zhu J Van Houten B Chu CT . ATP13A2 regulates mitochondrial bioenergetics through macroautophagy. Neurobiol Dis (2012) 45(3):962–72. doi: 10.1016/j.nbd.2011.12.015

  • CrossRef
  • Google Scholar

• 90

  Wang T Ming Z Xiaochun W Hong W . Rab7: role of its protein interaction cascades in endo-lysosomal traffic. Cell Signal (2011) 23(3):516–21. doi: 10.1016/j.cellsig.2010.09.012

  • CrossRef
  • Google Scholar

• 91

  Fernandez-Mosquera L Yambire KF Couto R Pereyra L Pabis K Ponsford AH et al . Mitochondrial respiratory chain deficiency inhibits lysosomal hydrolysis. Autophagy (2019) 15(9):1572–91. doi: 10.1080/15548627.2019.1586256

  • CrossRef
  • Google Scholar

• 92

  Baixauli F Acin-Perez R Villarroya-Beltri C Mazzeo C Nunez-Andrade N Gabande-Rodriguez E et al . Mitochondrial respiration controls lysosomal function during inflammatory T cell responses. Cell Metab (2015) 22(3):485–98. doi: 10.1016/j.cmet.2015.07.020

  • CrossRef
  • Google Scholar

• 93

  Trnka J Blaikie FH Smith RAJ Murphy MP . A mitochondria-targeted nitroxide is reduced to its hydroxylamine by ubiquinol in mitochondria. Free Radical Biol Med (2008) 44(7):1406–19. doi: 10.1016/j.freeradbiomed.2007.12.036

  • CrossRef
  • Google Scholar

• 94

  Gan X Zhang L Liu B Zhu Z He Y Chen J et al . CypD-mPTP axis regulates mitochondrial functions contributing to osteogenic dysfunction of MC3T3-E1 cells in inflammation. J Physiol Biochem (2018) 74(3):395–402. doi: 10.1007/s13105-018-0627-z

  • CrossRef
  • Google Scholar

• 95

  Satake A Schmidt AM Archambault A Leichner TM Wu GF Kambayashi T . Differential targeting of IL-2 and T cell receptor signaling pathways selectively expands regulatory T cells while inhibiting conventional T cells. J Autoimmun (2013) 44:13–20. doi: 10.1016/j.jaut.2013.06.009

  • CrossRef
  • Google Scholar

• 96

  Swanson SK Born T Zydowsky LD Cho H Chang HY Walsh CT et al . Cyclosporin-mediated inhibition of bovine calcineurin by cyclophilins A and B. Proc Natl Acad Sci USA (1992) 89(9):3741–5. doi: 10.1073/pnas.89.9.3741

  • CrossRef
  • Google Scholar

• 97

  Kim J Gupta R Blanco LP Yang S Shteinfer-Kuzmine A Wang K et al . VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease. Science (2019) 366(6472):1531–6. doi: 10.1126/science.aav4011

  • CrossRef
  • Google Scholar

• 98

  Verma A Pittala S Alhozeel B Shteinfer-Kuzmine A Ohana E Gupta R et al . The role of the mitochondrial protein VDAC1 in inflammatory bowel disease: a potential therapeutic target. Mol Ther (2022) 30(2):726–44. doi: 10.1016/j.ymthe.2021.06.024

  • CrossRef
  • Google Scholar

• 99

  Makita N Ishiguro J Suzuki K Nara F . Dichloroacetate induces regulatory T-cell differentiation and suppresses Th17-cell differentiation by pyruvate dehydrogenase kinase-independent mechanism. J Pharm Pharmacol (2017) 69(1):43–51. doi: 10.1111/jphp.12655

  • CrossRef
  • Google Scholar

• 100

  Younes SA Talla A Pereira Ribeiro S Saidakova EV Korolevskaya LB Shmagel KV et al . Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction. J Clin Invest (2018) 128(11):5083–94. doi: 10.1172/JCI120245

  • CrossRef
  • Google Scholar

• 101

  Bonora M Giorgi C Pinton P . Molecular mechanisms and consequences of mitochondrial permeability transition. Nat Rev Mol Cell Biol (2022) 23(4):266–85. doi: 10.1038/s41580-021-00433-y

  • CrossRef
  • Google Scholar

• 102

  Kageyama T Komori M Miyamoto K Ozaki A Suenaga T Takahashi R et al . Combination of cyclosporine A with corticosteroids is effective for the treatment of neuromyelitis optica. J Neurol (2012) 260(2):627–34. doi: 10.1007/s00415-012-6692-2

  • CrossRef
  • Google Scholar

• 103

  Guzy RD Hoyos B Robin E Chen H Liu L Mansfield KD et al . Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab (2005) 1(6):401–8. doi: 10.1016/j.cmet.2005.05.001

  • CrossRef
  • Google Scholar

• 104

  Lin X David CA Donnelly JB Michaelides M Chandel NS Huang X et al . A chemical genomics screen highlights the essential role of mitochondria in HIF-1 regulation. Proc Natl Acad Sci USA (2008) 105(1):174–9. doi: 10.1073/pnas.0706585104

  • CrossRef
  • Google Scholar

• 105

  Zhang E Mohammed Al-Amily I Mohammed S Luan C Asplund O Ahmed M et al . Preserving insulin secretion in diabetes by inhibiting VDAC1 overexpression and surface translocation in beta cells. Cell Metab (2019) 29(1):64–77 e6. doi: 10.1016/j.cmet.2018.09.008

  • CrossRef
  • Google Scholar