Mitochondrial Metabolism in T-Cell Exhaustion
Abstract
1. Introduction
2. Mitochondrial Metabolism Determines T Cell Function and Fate
2.1. Mitochondrial Biogenesis Facilitates T Cell Metabolic Reprogramming
2.2. Mitochondria Dynamics Control T Cell Fate
2.3. Mitochondrial Autophagy (Mitophagy) Maintains Cellular Homeostasis
2.4. Mitochondrial Transfer Modulates Intercellular Communication
3. Changes in Mitochondrial Metabolism in T-Cell Exhaustion
4. Potential Therapeutic Strategies for Mitochondrial Metabolic Regulation in Reversing T-Cell Exhaustion
4.1. Inducing PGC-1α Expression
4.2. Alleviating ROS Production
4.3. Mitigating Hypoxia
4.4. Inducing ATP Production
4.5. Utilizing Mitochondrial Transfer
4.6. Other Strategies
Strategy | Intervention Methods | Intervention Mechanism | Ref. |
---|---|---|---|
Inducing the induction of PGC-1α | Bezafibrate | A PGC-1α agonist that enhances mitochondrial biogenesis | [88] |
C1QBP overexpression | Altering the impaired mitochondrial fitness | [89] | |
4-1BB agonists | Promoting PGC-1α-dependent mitochondrial fusion and biogenesis through activating p38-MAPK | [92] | |
Hydrogen gas | A PGC-1α activator and activating CoQ10 | [94] | |
Metformin | Activating AMPK and directly inducing PGC-1α expression and restoring mitochondrial FAO | [96,97,98] | |
IL-15 | Inducing PGC-1α expression and promoting mitochondrial biogenesis | [99] | |
Alleviating ROS production | N-acetylcysteine (NAC) | Neutralizing intracellular ROS | [75,101] |
Mitoquinone (MitoQ) | Reduce ROS production and effectively restore mitochondrial function | [80] | |
MitoTempo/Trolox | Attenuate ROS production and effectively restore mitochondrial function | [75,80] | |
MitoTempo combined with mdivi-1, M1, and IL-15 | Increasing T cell metabolic fitness and restoring cell function | [68] | |
Nicotinamide nucleoside (NR) | Alleviating mtROS levels and relieving depolarized mitochondria | [57,104] | |
Nicotinamide (NAM) | Reducing ROS generation and increasing differentiation of effector T cells | [105] | |
Metformin | Inhibiting intracellular ROS production by promoting mitochondrial biogenesis | [106] | |
Mitigating hypoxia | Axitinib | Mitigating hypoxia | [5] |
Deleting NADH | Alleviating hypoxia | [76] | |
Inducing ATP production | CD39 and CD73 blockade | Preventing the conversion of ATP to adenosine | [114] |
USP25 | Increasing ATP generation and maintaining mitochondrial morphology | [117] | |
ATPIF1 overexpression | Increasing the mitochondrial crista density and enhancing the mitochondrial OXPHOS | [122] | |
Utilizing mitochondrial transfer | Transporting normal mitochondria to exhausted T cells | Reversing impaired effector function and enhancing immune efficacy | [30,123] |
Intercellular TNTs-mediated mitochondrial transfer | Increasing mitochondrial mass and fitness, and improving the antitumor efficacy of T cells | [124] | |
Other strategies | IL-10/Fc fusion protein | Reprogramming T cell metabolism by promoting OXPHOS | [127,128] |
Linoleic acid (LA) | Enhancing the formation of MERCs, promoting memory differentiation, and preventing exhaustion | [130] | |
5-ALA/SFC | Activating mitochondrial functions | [134] | |
Autophagy inhibition | Inhibiting autophagy | [135] |
5. Conclusions and Perspectives
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
- Wherry, E.J.; Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 2015, 15, 486–499. [Google Scholar] [CrossRef]
- Angelosanto, J.M.; Blackburn, S.D.; Crawford, A.; Wherry, E.J. Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection. J. Virol. 2012, 86, 8161–8170. [Google Scholar] [CrossRef] [PubMed]
- Shin, H.; Blackburn, S.D.; Intlekofer, A.M.; Kao, C.; Angelosanto, J.M.; Reiner, S.L.; Wherry, E.J. A role for the transcriptional repressor Blimp-1 in CD8+ T cell exhaustion during chronic viral infection. Immunity 2009, 31, 309–320. [Google Scholar] [CrossRef] [PubMed]
- Scott, A.C.; Dündar, F.; Zumbo, P.; Chandran, S.S.; Klebanoff, C.A.; Shakiba, M.; Trivedi, P.; Menocal, L.; Appleby, H.; Camara, S.; et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 2019, 571, 270–274. [Google Scholar] [CrossRef] [PubMed]
- Scharping, N.E.; Rivadeneira, D.B.; Menk, A.V.; Vignali, P.D.A.; Ford, B.R.; Rittenhouse, N.L.; Peralta, R.; Wang, Y.; Wang, Y.; DePeaux, K.; et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat. Immunol. 2021, 22, 205–215. [Google Scholar] [CrossRef]
- Bengsch, B.; Johnson, A.L.; Kurachi, M.; Odorizzi, P.M.; Pauken, K.E.; Attanasio, J.; Stelekati, E.; McLane, L.M.; Paley, M.A.; Delgoffe, G.M.; et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity 2016, 45, 358–373. [Google Scholar] [CrossRef]
- Tabana, Y.; Moon, T.C.; Siraki, A.; Elahi, S.; Barakat, K. Reversing T-cell exhaustion in immunotherapy: A review on current approaches and limitations. Expert. Opin. Ther. Targets 2021, 25, 347–363. [Google Scholar] [CrossRef]
- Yang, M.; Du, W.; Yi, L.; Wu, S.; He, C.; Zhai, W.; Yue, C.; Sun, R.; Menk, A.V.; Delgoffe, G.M.; et al. Checkpoint molecules coordinately restrain hyperactivated effector T cells in the tumor microenvironment. Oncoimmunology 2020, 9, 1708064. [Google Scholar] [CrossRef]
- Pearce, E.L.; Pearce, E.J. Metabolic pathways in immune cell activation and quiescence. Immunity 2013, 38, 633–643. [Google Scholar] [CrossRef]
- Chang, C.H.; Curtis, J.D.; Maggi, L.B., Jr.; Faubert, B.; Villarino, A.V.; O’Sullivan, D.; Huang, S.C.; van der Windt, G.J.; Blagih, J.; Qiu, J.; et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013, 153, 1239–1251. [Google Scholar] [CrossRef]
- Kumar, A.; Chamoto, K. Immune metabolism in PD-1 blockade-based cancer immunotherapy. Int. Immunol. 2021, 33, 17–26. [Google Scholar] [CrossRef] [PubMed]
- O’Sullivan, D.; van der Windt, G.J.; Huang, S.C.; Curtis, J.D.; Chang, C.H.; Buck, M.D.; Qiu, J.; Smith, A.M.; Lam, W.Y.; DiPlato, L.M.; et al. Memory CD8+ T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 2014, 41, 75–88. [Google Scholar] [CrossRef] [PubMed]
- Li, F.; Liu, H.; Zhang, D.; Ma, Y.; Zhu, B. Metabolic plasticity and regulation of T cell exhaustion. Immunology 2022, 167, 482–494. [Google Scholar] [CrossRef] [PubMed]
- Blackburn, S.D.; Shin, H.; Freeman, G.J.; Wherry, E.J. Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade. Proc. Natl. Acad. Sci. USA 2008, 105, 15016–15021. [Google Scholar] [CrossRef]
- Chen, Z.; Ji, Z.; Ngiow, S.F.; Manne, S.; Cai, Z.; Huang, A.C.; Johnson, J.; Staupe, R.P.; Bengsch, B.; Xu, C.; et al. TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision. Immunity 2019, 51, 840–855.e5. [Google Scholar] [CrossRef]
- Miller, B.C.; Sen, D.R.; Al Abosy, R.; Bi, K.; Virkud, Y.V.; LaFleur, M.W.; Yates, K.B.; Lako, A.; Felt, K.; Naik, G.S.; et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 2019, 20, 326–336. [Google Scholar] [CrossRef]
- Im, S.J.; Hashimoto, M.; Gerner, M.Y.; Lee, J.; Kissick, H.T.; Burger, M.C.; Shan, Q.; Hale, J.S.; Lee, J.; Nasti, T.H.; et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 2016, 537, 417–421. [Google Scholar] [CrossRef]
- Reya, T.; Duncan, A.W.; Ailles, L.; Domen, J.; Scherer, D.C.; Willert, K.; Hintz, L.; Nusse, R.; Weissman, I.L. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003, 423, 409–414. [Google Scholar] [CrossRef]
- Adams, W.C.; Chen, Y.H.; Kratchmarov, R.; Yen, B.; Nish, S.A.; Lin, W.W.; Rothman, N.J.; Luchsinger, L.L.; Klein, U.; Busslinger, M.; et al. Anabolism-associated mitochondrial stasis driving lymphocyte differentiation over self-renewal. Cell Rep. 2016, 17, 3142–3152. [Google Scholar] [CrossRef]
- Siska, P.J.; Beckermann, K.E.; Mason, F.M.; Andrejeva, G.; Greenplate, A.R.; Sendor, A.B.; Chiang, Y.J.; Corona, A.L.; Gemta, L.F.; Vincent, B.G.; et al. Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight 2017, 2, e93411. [Google Scholar] [CrossRef]
- Scharping, N.E.; Menk, A.V.; Moreci, R.S.; Whetstone, R.D.; Dadey, R.E.; Watkins, S.C.; Ferris, R.L.; Delgoffe, G.M. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 2016, 45, 374–388. [Google Scholar] [CrossRef]
- Schurich, A.; Pallett, L.J.; Jajbhay, D.; Wijngaarden, J.; Otano, I.; Gill, U.S.; Hansi, N.; Kennedy, P.T.; Nastouli, E.; Gilson, R.; et al. Distinct metabolic requirements of exhausted and functional virus-specific CD8 T cells in the same host. Cell Rep. 2016, 16, 1243–1252. [Google Scholar] [CrossRef] [PubMed]
- Sena, L.A.; Li, S.; Jairaman, A.; Prakriya, M.; Ezponda, T.; Hildeman, D.A.; Wang, C.R.; Schumacker, P.T.; Licht, J.D.; Perlman, H.; et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 2013, 38, 225–236. [Google Scholar] [CrossRef] [PubMed]
- Desdín-Micó, G.; Soto-Heredero, G.; Mittelbrunn, M. Mitochondrial activity in T cells. Mitochondrion 2018, 41, 51–57. [Google Scholar] [CrossRef] [PubMed]
- Chen, S.; Lee, L.F.; Fisher, T.S.; Jessen, B.; Elliott, M.; Evering, W.; Logronio, K.; Tu, G.H.; Tsaparikos, K.; Li, X.; et al. Combination of 4-1BB agonist and PD-1 antagonist promotes antitumor effector/memory CD8 T cells in a poorly immunogenic tumor model. Cancer Immunol. Res. 2015, 3, 149–160. [Google Scholar] [CrossRef]
- Buck, M.D.; O’Sullivan, D.; Klein Geltink, R.I.; Curtis, J.D.; Chang, C.H.; Sanin, D.E.; Qiu, J.; Kretz, O.; Braas, D.; van der Windt, G.J.; et al. Mitochondrial dynamics controls T cell Fate through metabolic programming. Cell 2016, 166, 63–76. [Google Scholar] [CrossRef]
- Liu, X.; Peng, G. Mitochondria orchestrate T cell fate and function. Nat. Immunol. 2021, 22, 276–278. [Google Scholar] [CrossRef]
- Rambold, A.S.; Pearce, E.L. Mitochondrial dynamics at the interface of immune cell metabolism and function. Trends Immunol. 2018, 39, 6–18. [Google Scholar] [CrossRef]
- Torralba, D.; Baixauli, F.; Sánchez-Madrid, F. Mitochondria know no boundaries: Mechanisms and functions of intercellular mitochondrial transfer. Front. Cell Dev. Biol. 2016, 4, 107. [Google Scholar] [CrossRef]
- Xia, Y.; Gao, B.; Zhang, X. Targeting mitochondrial quality control of T cells: Regulating the immune response in HCC. Front. Oncol. 2022, 12, 993437. [Google Scholar] [CrossRef]
- Fischer, M.; Bantug, G.R.; Dimeloe, S.; Gubser, P.M.; Burgener, A.V.; Grählert, J.; Balmer, M.L.; Develioglu, L.; Steiner, R.; Unterstab, G.; et al. Early effector maturation of naïve human CD8+ T cells requires mitochondrial biogenesis. Eur. J. Immunol. 2018, 48, 1632–1643. [Google Scholar] [CrossRef]
- Fernandez-Marcos, P.J.; Auwerx, J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am. J. Clin. Nutr. 2011, 93, 884S–890S. [Google Scholar] [CrossRef]
- Abu Shelbayeh, O.; Arroum, T.; Morris, S.; Busch, K.B. PGC-1α is a master regulator of mitochondrial lifecycle and ROS stress response. Antioxidants 2023, 12, 1075. [Google Scholar] [CrossRef]
- Ježek, P.; Jabůrek, M.; Holendová, B.; Engstová, H.; Dlasková, A. Mitochondrial cristae morphology reflecting metabolism, superoxide formation, redox homeostasis, and pathology. Antioxid. Redox Signal. 2023, 39, 635–683. [Google Scholar] [CrossRef]
- Chakrabarty, R.P.; Chandel, N.S. Beyond ATP, new roles of mitochondria. Biochemist 2022, 44, 2–8. [Google Scholar] [CrossRef]
- Youle, R.J.; van der Bliek, A.M. Mitochondrial fission, fusion, and stress. Science 2012, 337, 1062–1065. [Google Scholar] [CrossRef] [PubMed]
- Mishra, P.; Chan, D.C. Metabolic regulation of mitochondrial dynamics. J. Cell Biol. 2016, 212, 379–387. [Google Scholar] [CrossRef] [PubMed]
- Zacharioudakis, E.; Gavathiotis, E. Mitochondrial dynamics proteins as emerging drug targets. Trends Pharmacol. Sci. 2023, 44, 112–127. [Google Scholar] [CrossRef] [PubMed]
- van der Bliek, A.M.; Shen, Q.; Kawajiri, S. Mechanisms of mitochondrial fission and fusion. Cold Spring Harb. Perspect. Biol. 2013, 5, a011072. [Google Scholar] [CrossRef]
- Pearce, E.L.; Poffenberger, M.C.; Chang, C.H.; Jones, R.G. Fueling immunity: Insights into metabolism and lymphocyte function. Science 2013, 342, 1242454. [Google Scholar] [CrossRef]
- Buck, M.D.; O’Sullivan, D.; Pearce, E.L. T cell metabolism drives immunity. J. Exp. Med. 2015, 212, 1345–1360. [Google Scholar] [CrossRef]
- Campello, S.; Lacalle, R.A.; Bettella, M.; Mañes, S.; Scorrano, L.; Viola, A. Orchestration of lymphocyte chemotaxis by mitochondrial dynamics. J. Exp. Med. 2006, 203, 2879–2886. [Google Scholar] [CrossRef]
- Yu, T.; Robotham, J.L.; Yoon, Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc. Natl. Acad. Sci. USA 2006, 103, 2653–2658. [Google Scholar] [CrossRef]
- Simula, L.; Pacella, I.; Colamatteo, A.; Procaccini, C.; Cancila, V.; Bordi, M.; Tregnago, C.; Corrado, M.; Pigazzi, M.; Barnaba, V.; et al. Drp1 controls effective T cell immune-surveillance by regulating T cell migration, proliferation, and cMyc-dependent metabolic reprogramming. Cell Rep. 2018, 25, 3059–3073.e10. [Google Scholar] [CrossRef] [PubMed]
- Song, J.; Yi, X.; Gao, R.; Sun, L.; Wu, Z.; Zhang, S.; Huang, L.; Han, C.; Ma, J. Impact of Drp1-mediated mitochondrial dynamics on T cell immune modulation. Front. Immunol. 2022, 13, 873834. [Google Scholar] [CrossRef] [PubMed]
- Cassidy-Stone, A.; Chipuk, J.E.; Ingerman, E.; Song, C.; Yoo, C.; Kuwana, T.; Kurth, M.J.; Shaw, J.T.; Hinshaw, J.E.; Green, D.R.; et al. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev. Cell 2008, 14, 193–204. [Google Scholar] [CrossRef] [PubMed]
- Wang, D.; Wang, J.; Bonamy, G.M.; Meeusen, S.; Brusch, R.G.; Turk, C.; Yang, P.; Schultz, P.G. A small molecule promotes mitochondrial fusion in mammalian cells. Angew. Chem. Int. Ed. Engl. 2012, 51, 9302–9305. [Google Scholar] [CrossRef]
- Lanna, A.; Dustin, M.L. Mitochondrial fusion fuels T cell memory. Cell Res. 2016, 26, 969–970. [Google Scholar] [CrossRef]
- Li, A.; Gao, M.; Liu, B.; Qin, Y.; Chen, L.; Liu, H.; Wu, H.; Gong, G. Mitochondrial autophagy: Molecular mechanisms and implications for cardiovascular disease. Cell Death Dis. 2022, 13, 444. [Google Scholar] [CrossRef]
- Tal, M.C.; Sasai, M.; Lee, H.K.; Yordy, B.; Shadel, G.S.; Iwasaki, A. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc. Natl. Acad. Sci. USA 2009, 106, 2770–2775. [Google Scholar] [CrossRef]
- Hsu, C.C.; Tseng, L.M.; Lee, H.C. Role of mitochondrial dysfunction in cancer progression. Exp. Biol. Med. 2016, 241, 1281–1295. [Google Scholar] [CrossRef]
- Sullivan, L.B.; Chandel, N.S. Mitochondrial reactive oxygen species and cancer. Cancer Metab. 2014, 2, 17. [Google Scholar] [CrossRef]
- Zemirli, N.; Morel, E.; Molino, D. Mitochondrial dynamics in basal and stressful conditions. Int. J. Mol. Sci. 2018, 19, 564. [Google Scholar] [CrossRef]
- Ma, X.; McKeen, T.; Zhang, J.; Ding, W.X. Role and mechanisms of mitophagy in liver diseases. Cells 2020, 9, 837. [Google Scholar] [CrossRef] [PubMed]
- Geisler, S.; Holmström, K.M.; Skujat, D.; Fiesel, F.C.; Rothfuss, O.C.; Kahle, P.J.; Springer, W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 2010, 12, 119–131. [Google Scholar] [CrossRef]
- Palikaras, K.; Lionaki, E.; Tavernarakis, N. Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat. Cell Biol. 2018, 20, 1013–1022. [Google Scholar] [CrossRef] [PubMed]
- Yu, Y.R.; Imrichova, H.; Wang, H.; Chao, T.; Xiao, Z.; Gao, M.; Rincon-Restrepo, M.; Franco, F.; Genolet, R.; Cheng, W.C.; et al. Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion. Nat. Immunol. 2020, 21, 1540–1551. [Google Scholar] [CrossRef] [PubMed]
- Murera, D.; Arbogast, F.; Arnold, J.; Bouis, D.; Muller, S.; Gros, F. CD4 T cell autophagy is integral to memory maintenance. Sci. Rep. 2018, 8, 5951. [Google Scholar] [CrossRef]
- Xu, X.; Araki, K.; Li, S.; Han, J.H.; Ye, L.; Tan, W.G.; Konieczny, B.T.; Bruinsma, M.W.; Martinez, J.; Pearce, E.L.; et al. Autophagy is essential for effector CD8+ T cell survival and memory formation. Nat. Immunol. 2014, 15, 1152–1161. [Google Scholar] [CrossRef]
- Zhang, Z.; Yan, C.; Miao, J.; Pu, K.; Ma, H.; Wang, Q. Muscle-derived mitochondrial transplantation reduces inflammation, enhances bacterial clearance, and improves survival in sepsis. Shock 2021, 56, 108–118. [Google Scholar] [CrossRef]
- Chen, R.; Chen, J. Mitochondrial transfer—A novel promising approach for the treatment of metabolic diseases. Front. Endocrinol. 2024, 14, 1346441. [Google Scholar] [CrossRef]
- Mistry, J.J.; Marlein, C.R.; Moore, J.A.; Hellmich, C.; Wojtowicz, E.E.; Smith, J.G.W.; Macaulay, I.; Sun, Y.; Morfakis, A.; Patterson, A.; et al. ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection. Proc. Natl. Acad. Sci. USA 2019, 116, 24610–24619. [Google Scholar] [CrossRef] [PubMed]
- Geng, Z.; Guan, S.; Wang, S.; Yu, Z.; Liu, T.; Du, S.; Zhu, C. Intercellular mitochondrial transfer in the brain, a new perspective for targeted treatment of central nervous system diseases. CNS Neurosci. Ther. 2023, 29, 3121–3135. [Google Scholar] [CrossRef] [PubMed]
- Liu, Z.; Sun, Y.; Qi, Z.; Cao, L.; Ding, S. Mitochondrial transfer/transplantation: An emerging therapeutic approach for multiple diseases. Cell Biosci. 2022, 12, 66. [Google Scholar] [CrossRef] [PubMed]
- Saha, T.; Dash, C.; Jayabalan, R.; Khiste, S.; Kulkarni, A.; Kurmi, K.; Mondal, J.; Majumder, P.K.; Bardia, A.; Jang, H.L.; et al. Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells. Nat. Nanotechnol. 2022, 17, 98–106. [Google Scholar] [CrossRef]
- Luz-Crawford, P.; Hernandez, J.; Djouad, F.; Luque-Campos, N.; Caicedo, A.; Carrère-Kremer, S.; Brondello, J.M.; Vignais, M.L.; Pène, J.; Jorgensen, C. Mesenchymal stem cell repression of Th17 cells is triggered by mitochondrial transfer. Stem Cell Res. Ther. 2019, 10, 232. [Google Scholar] [CrossRef]
- Baldari, C.T. Nanotube-mediated mitochondrial transfer: Power to the T cells! Trends Immunol. 2024, 45, 917–919. [Google Scholar] [CrossRef]
- Alrubayyi, A.; Moreno-Cubero, E.; Hameiri-Bowen, D.; Matthews, R.; Rowland-Jones, S.; Schurich, A.; Peppa, D. Functional restoration of exhausted CD8 T cells in chronic HIV-1 infection by targeting mitochondrial dysfunction. Front. Immunol. 2022, 13, 908697. [Google Scholar] [CrossRef]
- Zhang, L.; Zhang, W.; Li, Z.; Lin, S.; Zheng, T.; Hao, B.; Hou, Y.; Zhang, Y.; Wang, K.; Qin, C.; et al. Mitochondria dysfunction in CD8+ T cells as an important contributing factor for cancer development and a potential target for cancer treatment: A review. J. Exp. Clin. Cancer Res. 2022, 41, 227. [Google Scholar] [CrossRef]
- Franco, F.; Jaccard, A.; Romero, P.; Yu, Y.R.; Ho, P.C. Metabolic and epigenetic regulation of T-cell exhaustion. Nat. Metab. 2020, 2, 1001–1012. [Google Scholar] [CrossRef]
- Wu, H.; Zhao, X.; Hochrein, S.M.; Eckstein, M.; Gubert, G.F.; Knöpper, K.; Mansilla, A.M.; Öner, A.; Doucet-Ladevèze, R.; Schmitz, W.; et al. Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming. Nat. Commun. 2023, 14, 6858. [Google Scholar] [CrossRef]
- Ogando, J.; Sáez, M.E.; Santos, J.; Nuevo-Tapioles, C.; Gut, M.; Esteve-Codina, A.; Heath, S.; González-Pérez, A.; Cuezva, J.M.; Lacalle, R.A.; et al. PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8+ T lymphocytes. J. Immunother. Cancer 2019, 7, 151. [Google Scholar] [CrossRef]
- Simula, L.; Antonucci, Y.; Scarpelli, G.; Cancila, V.; Colamatteo, A.; Manni, S.; De Angelis, B.; Quintarelli, C.; Procaccini, C.; Matarese, G.; et al. PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism. Mol. Oncol. 2022, 16, 188–205. [Google Scholar] [CrossRef]
- Geltink, R.I.K.; Kyle, R.L.; Pearce, E.L. Unraveling the complex interplay between T cell metabolism and function. Annu. Rev. Immunol. 2018, 36, 461–488. [Google Scholar] [CrossRef] [PubMed]
- Vardhana, S.A.; Hwee, M.A.; Berisa, M.; Wells, D.K.; Yost, K.E.; King, B.; Smith, M.; Herrera, P.S.; Chang, H.Y.; Satpathy, A.T.; et al. Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nat. Immunol. 2020, 21, 1022–1033. [Google Scholar] [CrossRef] [PubMed]
- Vignali, P.D.A.; DePeaux, K.; Watson, M.J.; Ye, C.; Ford, B.R.; Lontos, K.; McGaa, N.K.; Scharping, N.E.; Menk, A.V.; Robson, S.C.; et al. Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity. Nat. Immunol. 2023, 24, 267–279. [Google Scholar] [CrossRef] [PubMed]
- Tiwari-Heckler, S.; Lee, G.R.; Harbison, J.; Ledderose, C.; Csizmadia, E.; Melton, D.; Zhang, Q.; Junger, W.; Chen, G.; Hauser, C.J.; et al. Extracellular mitochondria drive CD8 T cell dysfunction in trauma by upregulating CD39. Thorax 2023, 78, 151–159. [Google Scholar] [CrossRef]
- Gupta, P.K.; Godec, J.; Wolski, D.; Adland, E.; Yates, K.; Pauken, K.E.; Cosgrove, C.; Ledderose, C.; Junger, W.G.; Robson, S.C.; et al. CD39 expression identifies terminally exhausted CD8+ T cells. PLoS Pathog. 2015, 11, e1005177. [Google Scholar] [CrossRef]
- Canale, F.P.; Ramello, M.C.; Núñez, N.; Araujo Furlan, C.L.; Bossio, S.N.; Gorosito Serrán, M.; Tosello Boari, J.; Del Castillo, A.; Ledesma, M.; Sedlik, C.; et al. CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells. Cancer Res. 2018, 78, 115–128. [Google Scholar] [CrossRef]
- Fisicaro, P.; Barili, V.; Montanini, B.; Acerbi, G.; Ferracin, M.; Guerrieri, F.; Salerno, D.; Boni, C.; Massari, M.; Cavallo, M.C.; et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat. Med. 2017, 23, 327–336. [Google Scholar] [CrossRef]
- van der Windt, G.J.; Everts, B.; Chang, C.H.; Curtis, J.D.; Freitas, T.C.; Amiel, E.; Pearce, E.J.; Pearce, E.L. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 2012, 36, 68–78. [Google Scholar] [CrossRef]
- Baixauli, F.; Acín-Pérez, R.; Villarroya-Beltrí, C.; Mazzeo, C.; Nuñez-Andrade, N.; Gabandé-Rodriguez, E.; Ledesma, M.D.; Blázquez, A.; Martin, M.A.; Falcón-Pérez, J.M.; et al. Mitochondrial respiration controls lysosomal function during inflammatory T cell responses. Cell Metab. 2015, 22, 485–498. [Google Scholar] [CrossRef]
- Soto-Heredero, G.; Desdín-Micó, G.; Mittelbrunn, M. Mitochondrial dysfunction defines T cell exhaustion. Cell Metab. 2021, 33, 470–472. [Google Scholar] [CrossRef]
- Chen, C.; Zheng, H.; Horwitz, E.M.; Ando, S.; Araki, K.; Zhao, P.; Li, Z.; Ford, M.L.; Ahmed, R.; Qu, C.K. Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity. Sci. Adv. 2023, 9, eadf9522. [Google Scholar] [CrossRef]
- Molon, B.; Calì, B.; Viola, A. T cells and cancer: How metabolism shapes immunity. Front. Immunol. 2016, 7, 20. [Google Scholar] [CrossRef]
- Zong, Y.; Li, H.; Liao, P.; Chen, L.; Pan, Y.; Zheng, Y.; Zhang, C.; Liu, D.; Zheng, M.; Gao, J. Mitochondrial dysfunction: Mechanisms and advances in therapy. Signal Transduct. Target. Ther. 2024, 9, 124. [Google Scholar] [CrossRef] [PubMed]
- Huang, S.; Jin, Y.; Zhang, L.; Zhou, Y.; Chen, N.; Wang, W. PPAR γ and PGC-1α activators protect against diabetic nephropathy by suppressing the inflammation and NF-kappaB activation. Nephrology 2024, 29, 858–872. [Google Scholar] [CrossRef] [PubMed]
- Chamoto, K.; Chowdhury, P.S.; Kumar, A.; Sonomura, K.; Matsuda, F.; Fagarasan, S.; Honjo, T. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc. Natl. Acad. Sci. USA 2017, 114, E761–E770. [Google Scholar] [CrossRef] [PubMed]
- Tian, H.; Wang, G.; Wang, Q.; Zhang, B.; Jiang, G.; Li, H.; Chai, D.; Fang, L.; Wang, M.; Zheng, J. Complement C1q binding protein regulates T cells’ mitochondrial fitness to affect their survival, proliferation, and anti-tumor immune function. Cancer Sci. 2022, 113, 875–890. [Google Scholar] [CrossRef]
- Dumauthioz, N.; Tschumi, B.; Wenes, M.; Marti, B.; Wang, H.; Franco, F.; Li, W.; Lopez-Mejia, I.C.; Fajas, L.; Ho, P.C.; et al. Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity. Cell Mol. Immunol. 2021, 18, 1761–1771. [Google Scholar] [CrossRef]
- Long, A.H.; Haso, W.M.; Shern, J.F.; Wanhainen, K.M.; Murgai, M.; Ingaramo, M.; Smith, J.P.; Walker, A.J.; Kohler, M.E.; Venkateshwara, V.R.; et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med. 2015, 21, 581–590. [Google Scholar] [CrossRef]
- Menk, A.V.; Scharping, N.E.; Rivadeneira, D.B.; Calderon, M.J.; Watson, M.J.; Dunstane, D.; Watkins, S.C.; Delgoffe, G.M. 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J. Exp. Med. 2018, 215, 1091–1100. [Google Scholar] [CrossRef]
- Teijeira, A.; Labiano, S.; Garasa, S.; Etxeberria, I.; Santamaría, E.; Rouzaut, A.; Enamorado, M.; Azpilikueta, A.; Inoges, S.; Bolaños, E.; et al. Mitochondrial morphological and functional reprogramming following CD137 (4-1BB) costimulation. Cancer Immunol. Res. 2018, 6, 798–811. [Google Scholar] [CrossRef]
- Akagi, J.; Baba, H. Hydrogen gas activates coenzyme Q10 to restore exhausted CD8(+) T cells, especially PD-1(+)Tim3(+)terminal CD8(+) T cells, leading to better nivolumab outcomes in patients with lung cancer. Oncol. Lett. 2020, 20, 258. [Google Scholar] [CrossRef]
- Herzig, S.; Shaw, R.J. AMPK: Guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 2018, 19, 121–135. [Google Scholar] [CrossRef]
- Russell, S.L.; Lamprecht, D.A.; Mandizvo, T.; Jones, T.T.; Naidoo, V.; Addicott, K.W.; Moodley, C.; Ngcobo, B.; Crossman, D.K.; Wells, G.; et al. Compromised metabolic reprogramming is an early indicator of CD8+ T cell dysfunction during chronic Mycobacterium tuberculosis infection. Cell Rep. 2019, 29, 3564–3579.e5. [Google Scholar] [CrossRef] [PubMed]
- Verdura, S.; Cuyàs, E.; Martin-Castillo, B.; Menendez, J.A. Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy. Oncoimmunology 2019, 8, e1633235. [Google Scholar] [CrossRef] [PubMed]
- Qiu, J.; Wang, Y.M.; Shi, C.M.; Yue, H.N.; Qin, Z.Y.; Zhu, G.Z.; Cao, X.G.; Ji, C.B.; Cui, Y.; Guo, X.R. NYGGF4 (PID1) effects on insulin resistance are reversed by metformin in 3T3-L1 adipocytes. J. Bioenerg. Biomembr. 2012, 44, 665–671. [Google Scholar] [CrossRef] [PubMed]
- Quinn, L.S.; Anderson, B.G.; Conner, J.D.; Wolden-Hanson, T. IL-15 overexpression promotes endurance, oxidative energy metabolism, and muscle PPARδ, SIRT1, PGC-1α, and PGC-1β expression in male mice. Endocrinology 2013, 154, 232–245. [Google Scholar] [CrossRef]
- Poljsak, B.; Šuput, D.; Milisav, I. Achieving the balance between ROS and antioxidants: When to use the synthetic antioxidants. Oxid. Med. Cell Longev. 2013, 2013, 956792. [Google Scholar] [CrossRef]
- Li, W.; Cheng, H.; Li, G.; Zhang, L. Mitochondrial damage and the road to exhaustion. Cell Metab. 2020, 32, 905–907. [Google Scholar] [CrossRef] [PubMed]
- Mehmel, M.; Jovanović, N.; Spitz, U. Nicotinamide riboside-the current state of research and therapeutic uses. Nutrients 2020, 12, 1616. [Google Scholar] [CrossRef] [PubMed]
- Rajman, L.; Chwalek, K.; Sinclair, D.A. Therapeutic potential of NAD-boosting molecules: The in vivo evidence. Cell Metab. 2018, 27, 529–547. [Google Scholar] [CrossRef] [PubMed]
- Xiao, Y.; Pang, N.; Ma, S.; Gao, M.; Yang, L. Effect of nicotinamide riboside against the exhaustion of CD8+ T cells via alleviating mitochondrial dysfunction. Nutrients 2024, 16, 3577. [Google Scholar] [CrossRef]
- Alavi, S.; Emran, A.A.; Tseng, H.Y.; Tiffen, J.C.; McGuire, H.M.; Hersey, P. Nicotinamide inhibits T cell exhaustion and increases differentiation of CD8 effector T cells. Cancers 2022, 14, 323. [Google Scholar] [CrossRef]
- Kukidome, D.; Nishikawa, T.; Sonoda, K.; Imoto, K.; Fujisawa, K.; Yano, M.; Motoshima, H.; Taguchi, T.; Matsumura, T.; Araki, E. Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 2006, 55, 120–127. [Google Scholar] [CrossRef]
- Dai, H.; Fan, Q.; Wang, C. Recent applications of immunomodulatory biomaterials for disease immunotherapy. Exploration 2022, 2, 20210157. [Google Scholar] [CrossRef]
- Liu, R.; Luo, C.; Pang, Z.; Zhang, J.; Ruan, S.; Wu, M.; Wang, L.; Sun, T.; Li, N.; Han, L.; et al. Advances of nanoparticles as drug delivery systems for disease diagnosis and treatment. Chin. Chem. Lett. 2023, 34, 107518. [Google Scholar] [CrossRef]
- Wu, J.; Wang, X.; Wang, Q.; Lou, Z.; Li, S.; Zhu, Y.; Qin, L.; Wei, H. Nanomaterials with enzyme-like characteristics (nanozymes): Next-generation artificial enzymes (II). Chem. Soc. Rev. 2019, 48, 1004–1076. [Google Scholar] [CrossRef]
- Jiang, D.; Ni, D.; Rosenkrans, Z.T.; Huang, P.; Yan, X.; Cai, W. Nanozyme: New horizons for responsive biomedical applications. Chem. Soc. Rev. 2019, 48, 3683–3704. [Google Scholar] [CrossRef]
- Schaaf, M.B.; Garg, A.D.; Agostinis, P. Defining the role of the tumor vasculature in antitumor immunity and immunotherapy. Cell Death Dis. 2018, 9, 115. [Google Scholar] [CrossRef]
- Zhang, Y.; Hu, J.; Ji, K.; Jiang, S.; Dong, Y.; Sun, L.; Wang, J.; Hu, G.; Chen, D.; Chen, K.; et al. CD39 inhibition and VISTA blockade may overcome radiotherapy resistance by targeting exhausted CD8+ T cells and immunosuppressive myeloid cells. Cell Rep. Med. 2023, 4, 101151. [Google Scholar] [CrossRef] [PubMed]
- Yuan, C.S.; Teng, Z.; Yang, S.; He, Z.; Meng, L.Y.; Chen, X.G.; Liu, Y. Reshaping hypoxia and silencing CD73 via biomimetic gelatin nanotherapeutics to boost immunotherapy. J. Control. Release 2022, 351, 255–271. [Google Scholar] [CrossRef] [PubMed]
- Perrot, I.; Michaud, H.A.; Giraudon-Paoli, M.; Augier, S.; Docquier, A.; Gros, L.; Courtois, R.; Déjou, C.; Jecko, D.; Becquart, O.; et al. Blocking antibodies targeting the CD39/CD73 immunosuppressive pathway unleash immune responses in combination cancer therapies. Cell Rep. 2019, 27, 2411–2425.e9. [Google Scholar] [CrossRef] [PubMed]
- Bingol, B.; Tea, J.S.; Phu, L.; Reichelt, M.; Bakalarski, C.E.; Song, Q.; Foreman, O.; Kirkpatrick, D.S.; Sheng, M. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 2014, 510, 370–375. [Google Scholar] [CrossRef]
- Wang, Y.; Serricchio, M.; Jauregui, M.; Shanbhag, R.; Stoltz, T.; Di Paolo, C.T.; Kim, P.K.; McQuibban, G.A. Deubiquitinating enzymes regulate PARK2-mediated mitophagy. Autophagy 2015, 11, 595–606. [Google Scholar] [CrossRef]
- Li, J.; Wang, J.; Pan, T.; Zhou, X.; Yang, H.; Wang, L.; Huang, G.; Dai, C.; Yang, B.; Zhang, B.; et al. USP25 deficiency promotes T cell dysfunction and transplant acceptance via mitochondrial dynamics. Int. Immunopharmacol. 2023, 117, 109917. [Google Scholar] [CrossRef]
- Kelam, L.M.; Wani, M.A.; Dhaked, D.K. An update on ATP synthase inhibitors: A unique target for drug development in M. tuberculosis. Prog. Biophys. Mol. Biol. 2023, 180–181, 87–104. [Google Scholar] [CrossRef]
- García-Aguilar, A.; Cuezva, J.M. A review of the inhibition of the mitochondrial ATP synthase by IF1 in vivo: Reprogramming energy metabolism and inducing mitohormesis. Front. Physiol. 2018, 9, 1322. [Google Scholar] [CrossRef]
- Wang, K.; Chen, H.; Zhou, Z.; Zhang, H.; Zhou, H.J.; Min, W. ATPIF1 maintains normal mitochondrial structure which is impaired by CCM3 deficiency in endothelial cells. Cell Biosci. 2021, 11, 11. [Google Scholar] [CrossRef]
- Campanella, M.; Casswell, E.; Chong, S.; Farah, Z.; Wieckowski, M.R.; Abramov, A.Y.; Tinker, A.; Duchen, M.R. Regulation of mitochondrial structure and function by the F1Fo-ATPase inhibitor protein, IF1. Cell Metab. 2008, 8, 13–25. [Google Scholar] [CrossRef]
- Zhong, G.; Wang, Q.; Wang, Y.; Guo, Y.; Xu, M.; Guan, Y.; Zhang, X.; Wu, M.; Xu, Z.; Zhao, W.; et al. scRNA-seq reveals ATPIF1 activity in control of T cell antitumor activity. Oncoimmunology 2022, 11, 2114740. [Google Scholar] [CrossRef]
- Headley, C.A.; Gautam, S.; Olmo-Fontanez, A.; Garcia-Vilanova, A.; Dwivedi, V.; Schami, A.; Weintraub, S.; Tsao, P.S.; Torrelles, J.B.; Turner, J. Mitochondrial transplantation promotes protective effector and memory CD4+ T cell response during mycobacterium tuberculosis infection and diminishes exhaustion and senescence in elderly CD4+ T cells. Adv. Sci. 2024, 11, e2401077. [Google Scholar] [CrossRef]
- Baldwin, J.G.; Heuser-Loy, C.; Saha, T.; Schelker, R.C.; Slavkovic-Lukic, D.; Strieder, N.; Hernandez-Lopez, I.; Rana, N.; Barden, M.; Mastrogiovanni, F.; et al. Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy. Cell 2024, 187, 6614–6630.e21. [Google Scholar] [CrossRef] [PubMed]
- Li, C.J.; Chen, P.K.; Sun, L.Y.; Pang, C.Y. Enhancement of mitochondrial transfer by antioxidants in human mesenchymal stem cells. Oxid. Med. Cell Longev. 2017, 2017, 8510805. [Google Scholar] [CrossRef] [PubMed]
- Wang, J.; Liu, X.; Qiu, Y.; Shi, Y.; Cai, J.; Wang, B.; Wei, X.; Ke, Q.; Sui, X.; Wang, Y.; et al. Cell adhesion-mediated mitochondria transfer contributes to mesenchymal stem cell-induced chemoresistance on T cell acute lymphoblastic leukemia cells. J. Hematol. Oncol. 2018, 11, 11. [Google Scholar] [CrossRef] [PubMed]
- Guo, Y.; Xie, Y.Q.; Gao, M.; Zhao, Y.; Franco, F.; Wenes, M.; Siddiqui, I.; Bevilacqua, A.; Wang, H.; Yang, H.; et al. Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity. Nat. Immunol. 2021, 22, 746–756. [Google Scholar] [CrossRef]
- Ryan, D.; Frezza, C. IL-10-mediated refueling of exhausted T cell mitochondria boosts anti-tumour immunity. Immunometabolism 2021, 3, e210030. [Google Scholar] [CrossRef]
- Manzo, T.; Prentice, B.M.; Anderson, K.G.; Raman, A.; Schalck, A.; Codreanu, G.S.; Nava Lauson, C.B.; Tiberti, S.; Raimondi, A.; Jones, M.A.; et al. Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells. J. Exp. Med. 2020, 217, e20191920. [Google Scholar] [CrossRef]
- Nava Lauson, C.B.; Tiberti, S.; Corsetto, P.A.; Conte, F.; Tyagi, P.; Machwirth, M.; Ebert, S.; Loffreda, A.; Scheller, L.; Sheta, D.; et al. Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity. Cell Metab. 2023, 35, 633–650.e9. [Google Scholar] [CrossRef]
- Masud, A.; Mohapatra, A.; Lakhani, S.A.; Ferrandino, A.; Hakem, R.; Flavell, R.A. Endoplasmic reticulum stress-induced death of mouse embryonic fibroblasts requires the intrinsic pathway of apoptosis. J. Biol. Chem. 2007, 282, 14132–14139. [Google Scholar] [CrossRef]
- Missiroli, S.; Patergnani, S.; Caroccia, N.; Pedriali, G.; Perrone, M.; Previati, M.; Wieckowski, M.R.; Giorgi, C. Mitochondria-associated membranes (MAMs) and inflammation. Cell Death Dis. 2018, 9, 329. [Google Scholar] [CrossRef]
- Bantug, G.R.; Fischer, M.; Grählert, J.; Balmer, M.L.; Unterstab, G.; Develioglu, L.; Steiner, R.; Zhang, L.; Costa, A.S.H.; Gubser, P.M.; et al. Mitochondria-endoplasmic reticulum contact sites function as immunometabolic hubs that orchestrate the rapid recall response of memory CD8+ T cells. Immunity 2018, 48, 542–555.e6. [Google Scholar] [CrossRef] [PubMed]
- Hu, X.; Que, W.; Hirano, H.; Wang, Z.; Nozawa, N.; Ishii, T.; Ishizuka, M.; Ito, H.; Takahashi, K.; Nakajima, M.; et al. 5-Aminolevulinic acid/sodium ferrous citrate enhanced the antitumor effects of programmed cell death-ligand 1 blockade by regulation of exhausted T cell metabolism in a melanoma model. Cancer Sci. 2021, 112, 2652–2663. [Google Scholar] [CrossRef] [PubMed]
- Habib, S.; El Andaloussi, A.; Elmasry, K.; Handoussa, A.; Azab, M.; Elsawey, A.; Al-Hendy, A.; Ismail, N. PDL-1 blockade prevents T cell exhaustion, inhibits autophagy, and promotes clearance of leishmania donovani. Infect. Immun. 2018, 86, 10–1128. [Google Scholar] [CrossRef] [PubMed]
- Wu, B.; Zhao, T.V.; Jin, K.; Hu, Z.; Abdel, M.P.; Warrington, K.J.; Goronzy, J.J.; Weyand, C.M. Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation. Nat. Immunol. 2021, 22, 1551–1562. [Google Scholar] [CrossRef]
- McKinney, E.F.; Lee, J.C.; Jayne, D.R.; Lyons, P.A.; Smith, K.G. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature 2015, 523, 612–616. [Google Scholar] [CrossRef]
- Qiu, J.; Wu, B.; Goodman, S.B.; Berry, G.J.; Goronzy, J.J.; Weyand, C.M. Metabolic control of autoimmunity and tissue inflammation in rheumatoid arthritis. Front. Immunol. 2021, 12, 652771. [Google Scholar] [CrossRef]
- Li, Y.; Shen, Y.; Jin, K.; Wen, Z.; Cao, W.; Wu, B.; Wen, R.; Tian, L.; Berry, G.J.; Goronzy, J.J.; et al. The DNA repair nuclease MRE11A functions as a mitochondrial protector and prevents T cell pyroptosis and tissue inflammation. Cell Metab. 2019, 30, 477–492.e476. [Google Scholar] [CrossRef]
- Smith, R.A.; Porteous, C.M.; Gane, A.M.; Murphy, M.P. Delivery of bioactive molecules to mitochondria in vivo. Proc. Natl. Acad. Sci. USA 2003, 100, 5407–5412. [Google Scholar] [CrossRef]
- Battogtokh, G.; Choi, Y.S.; Kang, D.S.; Park, S.J.; Shim, M.S.; Huh, K.M.; Cho, Y.Y.; Lee, J.Y.; Lee, H.S.; Kang, H.C. Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: Current strategies and future perspectives. Acta Pharm. Sin. B 2018, 8, 862–880. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Li, F.; Feng, Y.; Yin, Z.; Wang, Y. Mitochondrial Metabolism in T-Cell Exhaustion. Int. J. Mol. Sci. 2025, 26, 7400. https://doi.org/10.3390/ijms26157400
Li F, Feng Y, Yin Z, Wang Y. Mitochondrial Metabolism in T-Cell Exhaustion. International Journal of Molecular Sciences. 2025; 26(15):7400. https://doi.org/10.3390/ijms26157400
Chicago/Turabian StyleLi, Fei, Yu Feng, Zesheng Yin, and Yahong Wang. 2025. "Mitochondrial Metabolism in T-Cell Exhaustion" International Journal of Molecular Sciences 26, no. 15: 7400. https://doi.org/10.3390/ijms26157400
APA StyleLi, F., Feng, Y., Yin, Z., & Wang, Y. (2025). Mitochondrial Metabolism in T-Cell Exhaustion. International Journal of Molecular Sciences, 26(15), 7400. https://doi.org/10.3390/ijms26157400