Skip to main content

Advertisement

SpringerLink
Log in

Mitochondrial Metabolic Programming and Crosstalk to Nucleus

  • Published:
Current Tissue Microenvironment Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The metabolic reprogramming of immune cells is vital for an effective immune response. This review delves into the intricate mechanisms that govern the communication between mitochondria and the nucleus within immune cells, influencing their phenotypic and functional states. Understanding these processes is essential for unraveling the complex interplay of cellular metabolism and immune responses, with potential implications for therapeutic development.

Recent Findings

A lot of work is being done around the importance of metabolism on immunological responses, such as neutrophils’ NET functions, macrophage inflammasome activation, T-cell profile, and B-cell response to stimulus. Most of the metabolic reprograms are due to mitochondrial fission and fusion profiles, regulated by genes such as Mtfn1 and Mtfn2. Mitofusin genes’ role is disclosed in this article, as also thoroughly delved into the latest literature that identifies genes related to cellular metabolism.

Summary

Immune cells undergo metabolic reprogramming to support their diverse functions during an effective immune response. This review helps to elucidate the mechanisms of mitochondrial-nuclear crosstalk related to immune cells, focusing on the role of mitochondrial-derived signals, nuclear transcription factors, and their modifications on metabolism. Mitochondria play pivotal roles in immunological responses, such as antiviral responses, cell survival, and immune cell function. The delicate balance between mitochondrial and nucleus processes is crucial for immune cell responsiveness to external stimuli. Understanding these regulatory pathways provides insights into immune cell metabolism and may pave the way for novel therapeutic strategies for immune-related disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Breda CN de S, Davanzo GG, Basso PJ, Saraiva Câmara NO, Moraes-Vieira PMM. Mitochondria as central hub of the immune system. Redox Biol. 2019;26:101255.

  2. Buck MD, O’Sullivan D, Klein Geltink RI, Curtis JD, Chang CH, Sanin DE, et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell. 2016;166(1):63–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  4. Zong WX, Rabinowitz JD, White E. Mitochondria and cancer. Mol Cell. 2016;61(5):667–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Deng X, Wang Q, Cheng M, Chen Y, Yan X, Guo R, et al. Pyruvate dehydrogenase kinase 1 interferes with glucose metabolism reprogramming and mitochondrial quality control to aggravate stress damage in cancer. J Cancer. 2020;11(4):962–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rambold AS, Pearce EL. Mitochondrial dynamics at the interface of immune cell metabolism and function. Trends Immunol. 2018;39(1):6–18.

    Article  CAS  PubMed  Google Scholar 

  7. Drake LE, Springer MZ, Poole LP, Kim CJ, Macleod KF. Expanding perspectives on the significance of mitophagy in cancer. Semin Cancer Biol. 2017;47:110–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Si L, Fu J, Liu W, Hayashi T, Nie Y, Mizuno K, et al. Silibinin inhibits migration and invasion of breast cancer MDA-MB-231 cells through induction of mitochondrial fusion. Mol Cell Biochem. 2020;463(1–2):189–201.

    Article  CAS  PubMed  Google Scholar 

  9. Srinivasan S, Guha M, Kashina A, Avadhani NG. Mitochondrial dysfunction and mitochondrial dynamics-the cancer connection. Biochim Biophys Acta Bioenerg. 2017;1858(8):602–14.

    Article  CAS  PubMed  Google Scholar 

  10. Cai WW, Yu Y, Zong SY, Wei F. Metabolic reprogramming as a key regulator in the pathogenesis of rheumatoid arthritis. Inflamm Res Off J Eur Histamine Res Soc Al. 2020;69(11):1087–101.

    CAS  Google Scholar 

  11. •• Khan S, Basu S, Raj D, Lahiri A. Role of mitochondria in regulating immune response during bacterial infection. Int Rev Cell Mol Biol. 2023;374:159–200. Excellent review of current insights on metabolism’s role on bacterial burden response related to mitochondria.

    Article  CAS  PubMed  Google Scholar 

  12. Rius-Pérez S, Torres-Cuevas I, Millán I, Ortega ÁL, Pérez S. PGC-1α, inflammation, and oxidative stress: an integrative view in metabolism. Oxid Med Cell Longev. 2020;2020:1452696.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Dabrowska A, Venero JL, Iwasawa R, Hankir MK, Rahman S, Boobis A, et al. PGC-1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity. Aging. 2015;7(9):629–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Taherzadeh-Fard E, Saft C, Akkad DA, Wieczorek S, Haghikia A, Chan A, et al. PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease. Mol Neurodegener. 2011;6(1):32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kiyama T, Chen CK, Wang SW, Pan P, Ju Z, Wang J, et al. Essential roles of mitochondrial biogenesis regulator Nrf1 in retinal development and homeostasis. Mol Neurodegener. 2018;13(1):56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Virbasius JV, Scarpulla RC. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci. 1994;91(4):1309–13.

  17. Guaragnella N, Coyne LP, Chen XJ, Giannattasio S. Mitochondria–cytosol–nucleus crosstalk: learning from Saccharomyces cerevisiae. FEMS Yeast Res. 2018;18(8):foy088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rigon M, Townley AR, Campanella M. Mitochondria ensure immune surveillance by retro-communication with the nucleus. Cell Metab. 2021;33(5):853–5.

    Article  CAS  PubMed  Google Scholar 

  19. Moretton A, Morel F, Macao B, Lachaume P, Ishak L, Lefebvre M, et al. Selective mitochondrial DNA degradation following double-strand breaks. PLoS One. 2017;12(4):e0176795.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Madsen PM, Pinto M, Patel S, McCarthy S, Gao H, Taherian M, et al. Mitochondrial DNA double-strand breaks in oligodendrocytes cause demyelination, axonal injury, and CNS inflammation. J Neurosci. 2017;37(42):10185–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. •• Tigano M, Vargas DC, Tremblay-Belzile S, Fu Y, Sfeir A. Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance. Nature. 2021;591(7850):477–81. Excellent overview of retrograde signaling pathway related to instabilities in the mitochondrial genome.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  PubMed  Google Scholar 

  23. West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 2015;520(7548):553–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Horwitz MA. Formation of a novel phagosome by the Legionnaires’ disease bacterium (Legionella pneumophila) in human monocytes. J Exp Med. 1983;158(4):1319–31.

    Article  CAS  PubMed  Google Scholar 

  25. Chong A, Lima CA, Allan DS, Nasrallah GK, Garduño RA. The purified and recombinant Legionella pneumophila chaperonin alters mitochondrial trafficking and microfilament organization. Infect Immun. 2009;77(11):4724–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pinegin B, Vorobjeva N, Pashenkov M, Chernyak B. The role of mitochondrial ROS in antibacterial immunity. J Cell Physiol. 2018;233(5):3745–54.

    Article  CAS  PubMed  Google Scholar 

  27. Shekhova E. Mitochondrial reactive oxygen species as major effectors of antimicrobial immunity. PLOS Pathog. 2020;16(5):e1008470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bauernfeind F, Bartok E, Rieger A, Franchi L, Núñez G, Hornung V. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J Immunol Baltim Md 1950. 2011;187(2):613–7.

    CAS  Google Scholar 

  29. Muñoz-Planillo R, Kuffa P, Martínez-Colón G, Smith BL, Rajendiran TM, Núñez G. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity. 2013;38(6):1142–53.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Kelley N, Jeltema D, Duan Y, He Y. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int J Mol Sci. 2019;20(13):3328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Desai R, East DA, Hardy L, Faccenda D, Rigon M, Crosby J, et al. Mitochondria form contact sites with the nucleus to couple prosurvival retrograde response. Sci Adv. 2020;6(51):eabc9955.

    Article  CAS  PubMed  Google Scholar 

  32. •• Steinert EM, Vasan K, Chandel NS. Mitochondrial metabolism regulation of T cell–mediated immunity. Annu Rev Immunol. 2021;39(1):395–416. Excellent overview of metabolism’s role in T-cell response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Campbell SL, Wellen KE. Metabolic signaling to the nucleus in cancer. Mol Cell. 2018;71(3):398–408.

    Article  CAS  PubMed  Google Scholar 

  34. Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell. 2012;148(6):1145–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, et al. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell. 2013;155(1):160–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang L, Ishihara T, Ibayashi Y, Tatsushima K, Setoyama D, Hanada Y, et al. Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration. Diabetologia. 2015;58(10):2371–80.

    Article  CAS  PubMed  Google Scholar 

  38. Mehta MM, Weinberg SE, Chandel NS. Mitochondrial control of immunity: beyond ATP. Nat Rev Immunol. 2017;17(10):608–20.

    Article  CAS  PubMed  Google Scholar 

  39. Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity. 2013;38(4):633–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang Y, Li N, Zhang X, Horng T. Mitochondrial metabolism regulates macrophage biology. J Biol Chem. 2021;297(1):100904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tur J, Vico T, Lloberas J, Zorzano A, Celada A. Chapter one - macrophages and mitochondria: a critical interplay between metabolism, signaling, and the functional activity. In: Alt FW, editor. Advances in Immunology. Academic Press; 2017. p. 1–36.

    Google Scholar 

  42. Park S, Won JH, Hwang I, Hong S, Lee HK, Yu JW. Defective mitochondrial fission augments NLRP3 inflammasome activation. Sci Rep. 2015;22(5):15489.

    Article  Google Scholar 

  43. Gao Z, Li Y, Wang F, Huang T, Fan K, Zhang Y, et al. Mitochondrial dynamics controls anti-tumour innate immunity by regulating CHIP-IRF1 axis stability. Nat Commun. 2017;8(1):1805.

    Article  PubMed  PubMed Central  Google Scholar 

  44. • Batista-Gonzalez A, Vidal R, Criollo A, Carreño LJ. New insights on the role of lipid metabolism in the metabolic reprogramming of macrophages. Front Immunol. 2020;10. Excellent review of current knowledge of metabolism and macrophage function and activation.

  45. Nathan C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol. 2006;6(3):173–82.

    Article  CAS  PubMed  Google Scholar 

  46. Riffelmacher T, Clarke A, Richter FC, Stranks A, Pandey S, Danielli S, et al. Autophagy-dependent generation of free fatty acids is critical for normal neutrophil differentiation. Immunity. 2017;47(3):466-480.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dahlgren C, Karlsson A, Bylund J. Intracellular neutrophil oxidants: from laboratory curiosity to clinical reality. J Immunol. 2019;202(11):3127–34.

    Article  CAS  PubMed  Google Scholar 

  48. •• Stojkov D, Gigon L, Peng S, Lukowski R, Ruth P, Karaulov A, et al. Physiological and pathophysiological roles of metabolic pathways for NET formation and other neutrophil functions. Front Immunol. 2022;13. Excellent paper bringing together new literature on neutrophil profile and its function dependence on metabolic changes.

  49. Kuijpers TW, Maianski NA, Tool ATJ, Smit GPA, Rake JP, Roos D, et al. Apoptotic neutrophils in the circulation of patients with glycogen storage disease type 1b (GSD1b). Blood. 2003;101(12):5021–4.

    Article  CAS  PubMed  Google Scholar 

  50. Everts B, Amiel E, van der Windt GJW, Freitas TC, Chott R, Yarasheski KE, et al. Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood. 2012;120(7):1422–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Thwe PM, Pelgrom LR, Cooper R, Beauchamp S, Reisz JA, D’Alessandro A, et al. Cell-intrinsic glycogen metabolism supports early glycolytic reprogramming required for dendritic cell immune responses. Cell Metab. 2017;26(3):558-567.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Palmieri F. The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch. 2004;447(5):689–709.

    Article  CAS  PubMed  Google Scholar 

  53. Pearce EJ, Everts B. Dendritic cell metabolism. Nat Rev Immunol. 2015;15(1):18–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zaccagnino P, Saltarella M, Maiorano S, Gaballo A, Santoro G, Nico B, et al. An active mitochondrial biogenesis occurs during dendritic cell differentiation. Int J Biochem Cell Biol. 2012;44(11):1962–9.

    Article  CAS  PubMed  Google Scholar 

  55. Del Prete A, Zaccagnino P, Di Paola M, Saltarella M, Oliveros Celis C, Nico B, et al. Role of mitochondria and reactive oxygen species in dendritic cell differentiation and functions. Free Radic Biol Med. 2008;44(7):1443–51.

    Article  PubMed  Google Scholar 

  56. D’Souza AD, Parikh N, Kaech SM, Shadel GS. Convergence of multiple signaling pathways is required to coordinately up-regulate mtDNA and mitochondrial biogenesis during T cell activation. Mitochondrion. 2007;7(6):374–85.

    Article  PubMed  PubMed Central  Google Scholar 

  57. O’Sullivan D, van der Windt GJW, Huang SCC, Curtis JD, Chang CH, Buck MD, et al. Memory CD8+ T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity. 2014;41(1):75–88.

    Article  PubMed  PubMed Central  Google Scholar 

  58. van der Windt GJW, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68–78.

    Article  PubMed  Google Scholar 

  59. Buck MD, O’Sullivan D, Klein Geltink RI, Curtis JD, Chang CH, Sanin DE, et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell. 2016;166(1):63–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35(6):871–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Vaeth M, Maus M, Klein-Hessling S, Freinkman E, Yang J, Eckstein M, et al. Store-operated Ca2+ entry controls clonal expansion of T cells through metabolic reprogramming. Immunity. 2017;47(4):664-679.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Li M, Lazorchak AS, Ouyang X, Zhang H, Liu H, Arojo OA, et al. Sin1/mTORC2 regulate B cell growth and metabolism by activating mTORC1 and Myc. Cell Mol Immunol. 2019;16(9):757–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Stein M, Dütting S, Mougiakakos D, Bösl M, Fritsch K, Reimer D, et al. A defined metabolic state in pre B cells governs B-cell development and is counterbalanced by Swiprosin-2/EFhd1. Cell Death Differ. 2017;24(7):1239–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Nutt SL, Hodgkin PD, Tarlinton DM, Corcoran LM. The generation of antibody-secreting plasma cells. Nat Rev Immunol. 2015;15(3):160–71.

    Article  CAS  PubMed  Google Scholar 

  65. Jellusova J, Cato MH, Apgar JR, Ramezani-Rad P, Leung CR, Chen C, et al. Gsk3 is a metabolic checkpoint regulator in B cells. Nat Immunol. 2017;18(3):303–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jang KJ, Mano H, Aoki K, Hayashi T, Muto A, Nambu Y, et al. Mitochondrial function provides instructive signals for activation-induced B-cell fates. Nat Commun. 2015;10(6):6750.

    Article  Google Scholar 

  67. • Jing Y, Luo L, Chen Y, Westerberg LS, Zhou P, Xu Z, et al. SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism. Signal Transduct Target Ther. 2021;6(1):1–13. Excellent paper that exemplifies the importance of metabolism studies for new insights into new diseases, such as COVID-19.

    Google Scholar 

  68. Shen B, Yi X, Sun Y, Bi X, Du J, Zhang C, et al. Proteomic and metabolomic characterization of COVID-19 patient sera. Cell. 2020;182(1):59-72.e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wu D, Shu T, Yang X, Song JX, Zhang M, Yao C, et al. Plasma metabolomic and lipidomic alterations associated with COVID-19. Natl Sci Rev. 2020;7(7):1157–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Caro-Maldonado A, Wang R, Nichols AG, Kuraoka M, Milasta S, Sun LD, et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J Immunol. 2014;192(8):3626–36.

    Article  CAS  PubMed  Google Scholar 

  71. Dufort FJ, Gumina MR, Ta NL, Tao Y, Heyse SA, Scott DA, et al. Glucose-dependent de novo lipogenesis in B lymphocytes: a requirement for ATP-citrate lyase in lipopolysaccharide-induced differentiation*. J Biol Chem. 2014;289(10):7011–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Stathopoulou C, Nikoleri D, Bertsias G. Immunometabolism: an overview and therapeutic prospects in autoimmune diseases. Immunotherapy. 2019;11(9):813–29.

    Article  CAS  PubMed  Google Scholar 

  73. Fulda S, Galluzzi L, Kroemer G. Targeting mitochondria for cancer therapy. Nat Rev Drug Discov. 2010;9(6):447–64.

    Article  CAS  PubMed  Google Scholar 

  74. Bhatti GK, Gupta A, Pahwa P, Khullar N, Singh S, Navik U, et al. Targeting mitochondrial bioenergetics as a promising therapeutic strategy in metabolic and neurodegenerative diseases. Biomed J. 2022;45(5):733–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Villena JA. New insights into PGC-1 coactivators: redefining their role in the regulation of mitochondrial function and beyond. FEBS J. 2015;282(4):647–72.

    Article  CAS  PubMed  Google Scholar 

  76. Liang H, Ward WF. PGC-1α: a key regulator of energy metabolism. Adv Physiol Educ. 2006;30(4):145–51.

    Article  PubMed  Google Scholar 

  77. Rowe GC, Jiang A, Arany Z, Kelly DP. PGC-1 coactivators in cardiac development and disease. Circ Res. 2010;107(7):825–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Cheng CF, Ku HC, Lin H. PGC-1α as a pivotal factor in lipid and metabolic regulation. Int J Mol Sci. 2018;19(11):3447.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Besseiche A, Riveline JP, Gautier JF, Bréant B, Blondeau B. Metabolic roles of PGC-1α and its implications for type 2 diabetes. Diabetes Metab. 2015;41(5):347–57.

    Article  CAS  PubMed  Google Scholar 

  80. Yaribeygi H, Farrokhi FR, Butler AE, Sahebkar A. Insulin resistance: review of the underlying molecular mechanisms. J Cell Physiol. 2019;234(6):8152–61.

    Article  CAS  PubMed  Google Scholar 

  81. Wu H, Deng X, Shi Y, Su Y, Wei J, Duan H. PGC-1α, glucose metabolism and type 2 diabetes mellitus. J Endocrinol. 2016;229(3):R99-115.

    Article  CAS  PubMed  Google Scholar 

  82. Corona JC, Duchen MR. PPARγ and PGC-1α as therapeutic targets in Parkinson’s. Neurochem Res. 2015;40(2):308–16.

    Article  CAS  PubMed  Google Scholar 

  83. Summermatter S, Shui G, Maag D, Santos G, Wenk MR, Handschin C. PGC-1α improves glucose homeostasis in skeletal muscle in an activity-dependent manner. Diabetes. 2013;62(1):85–95.

    Article  CAS  PubMed  Google Scholar 

  84. Summermatter S, Santos G, Pérez-Schindler J, Handschin C. Skeletal muscle PGC-1α controls whole-body lactate homeostasis through estrogen-related receptor α-dependent activation of LDH B and repression of LDH A. Proc Natl Acad Sci. 2013;110(21):8738–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kang C, Ji LL. Role of PGC-1α in muscle function and aging. J Sport Health Sci. 2013;2(2):81–6.

    Article  Google Scholar 

  86. Eisele PS, Furrer R, Beer M, Handschin C. The PGC-1 coactivators promote an anti-inflammatory environment in skeletal muscle in vivo. Biochem Biophys Res Commun. 2015;464(3):692–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Dinulovic I, Furrer R, Di Fulvio S, Ferry A, Beer M, Handschin C. PGC-1α modulates necrosis, inflammatory response, and fibrotic tissue formation in injured skeletal muscle. Skelet Muscle. 2016;6(1):38.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Yuan D, Xiao D, Gao Q, Zeng L. PGC-1α activation: a therapeutic target for type 2 diabetes? Eat Weight Disord - Stud Anorex Bulim Obes. 2019;24(3):385–95.

    Article  Google Scholar 

  89. • Panes JD, Wendt A, Ramirez-Molina O, Castro PA, Fuentealba J. Deciphering the role of PGC-1α in neurological disorders: from mitochondrial dysfunction to synaptic failure. Neural Regen Res. 2022;17(2):237–45. Excellent paper on PGC-1α connection to metabolism and diseases.

    Article  CAS  PubMed  Google Scholar 

  90. Esteves AR, Arduíno DM, Swerdlow RH, Oliveira CR, Cardoso SM. Dysfunctional mitochondria uphold calpain activation: contribution to Parkinson’s disease pathology. Neurobiol Dis. 2010;37(3):723–30.

    Article  CAS  PubMed  Google Scholar 

  91. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primer. 2017;23(3):17013.

    Article  Google Scholar 

  92. Villapol S. Roles of peroxisome proliferator-activated receptor gamma on brain and peripheral inflammation. Cell Mol Neurobiol. 2018;38(1):121–32.

    Article  CAS  PubMed  Google Scholar 

  93. •• Faghfouri AH, Khajebishak Y, Payahoo L, Faghfuri E, Alivand M. PPAR-gamma agonists: potential modulators of autophagy in obesity. Eur J Pharmacol. 2021;5(912):174562. Excellent paper due to the different techniques used and the innovative results obtained.

    Article  Google Scholar 

  94. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006;127(2):397–408.

    Article  CAS  PubMed  Google Scholar 

  95. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 1999;98(1):115–24.

    Article  CAS  PubMed  Google Scholar 

  96. Dinkova-Kostova AT, Abramov AY. The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med. 2015;88(Pt B):179–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci. 2016;73(17):3221–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Dorn GW, Vega RB, Kelly DP. Mitochondrial biogenesis and dynamics in the developing and diseased heart. Genes Dev. 2015;29(19):1981–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Poznyak AV, Ivanova EA, Sobenin IA, Yet SF, Orekhov AN. The role of mitochondria in cardiovascular diseases. Biology. 2020;9(6):137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Cui M, Atmanli A, Morales MG, Tan W, Chen K, Xiao X, et al. Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance. Nat Commun. 2021;12(1):5270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Chong H, Wei Z, Na M, Sun G, Zheng S, Zhu X, et al. The PGC-1α/NRF1/miR-378a axis protects vascular smooth muscle cells from FFA-induced proliferation, migration and inflammation in atherosclerosis. Atherosclerosis. 2020;297:136–45.

    Article  CAS  PubMed  Google Scholar 

  102. Dreger H, Westphal K, Weller A, Baumann G, Stangl V, Meiners S, et al. Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for proteasome inhibitor-mediated cardioprotection. Cardiovasc Res. 2009;83(2):354–61.

    Article  CAS  PubMed  Google Scholar 

  103. Wei Y, Zhang J, Yan X, Peng X, Xu S, Chang H, et al. Remarkable protective effects of Nrf2-mediated antioxidant enzymes and tissue specificity in different skeletal muscles of Daurian ground squirrels over the torpor-arousal cycle. Front Physiol. 2019;10.

  104. Ahmed SMU, Luo L, Namani A, Wang XJ, Tang X. Nrf2 signaling pathway: pivotal roles in inflammation. Biochim Biophys Acta Mol Basis Dis. 2017;1863(2):585–97.

    Article  CAS  PubMed  Google Scholar 

  105. Alonso-Piñeiro JA, Gonzalez-Rovira A, Sánchez-Gomar I, Moreno JA, Durán-Ruiz MC. Nrf2 and Heme oxygenase-1 involvement in atherosclerosis related oxidative stress. Antioxid Basel Switz. 2021;10(9):1463.

    Article  Google Scholar 

  106. Bayeva M, Gheorghiade M, Ardehali H. Mitochondria as a therapeutic target in heart failure. J Am Coll Cardiol. 2013;61(6):599–610.

    Article  CAS  PubMed  Google Scholar 

  107. Huss JM, Imahashi K, Dufour CR, Weinheimer CJ, Courtois M, Kovacs A, et al. The nuclear receptor ERRα is required for the bioenergetic and functional adaptation to cardiac pressure overload. Cell Metab. 2007;6(1):25–37.

    Article  CAS  PubMed  Google Scholar 

  108. Gao W, Wu MH, Wang N, Ying MZ, Zhang YY, Hua J, Chuan L, Wang YJ. Mitochondrial transcription factor A contributes to cisplatin resistance in patients with estrogen receptor-positive breast cancer. Mol Med Rep. 2016;14:5304–10.

    Article  CAS  PubMed  Google Scholar 

  109. Golubickaite I, Ugenskiene R, Cepaite J, Ziliene E, Inciura A, Poskiene L, et al. Mitochondria-related TFAM gene variants and their effects on patients with cervical cancer. Biomed Rep. 2021;15(6):106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Peng H, Yang M, Chen Z-y, Chen P, Guan C-x, Xiang X-d, et al. Expression and methylation of mitochondrial transcription factor A in chronic obstructive pulmonary disease patients with lung cancer. Plos One. 2013;8(12):e82739.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Hsieh YT, Tu HF, Yang MH, Chen YF, Lan XY, Huang CL, et al. Mitochondrial genome and its regulator TFAM modulates head and neck tumourigenesis through intracellular metabolic reprogramming and activation of oncogenic effectors. Cell Death Dis. 2021;12(11):1–11.

    Article  Google Scholar 

  112. Jiang X, Wang J. Down-regulation of TFAM increases the sensitivity of tumour cells to radiation via p53/TIGAR signalling pathway. J Cell Mol Med. 2019;23(7):4545–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP- grants n° 2017/05264–7, 2015/21644–9) and by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Brasil (CAPES) – Financial Code 001.

Author information

Authors and Affiliations

  1. Nephrology Division, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil

    Mariana Abrantes do Amaral & Niels Olsen Saraiva Câmara

  2. Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, Avenida Professor Lineu Prestes, 1730 Cidade Universitária, São Paulo, São Paulo, 05508-000, Brazil

    Barbara Nunes Padovani, Lais Cavalieri Paredes, Mariana Tominaga Pereira & Niels Olsen Saraiva Câmara

  3. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, NY, USA

    Juliana Moreira Mendonça-Gomes

Authors
  1. Mariana Abrantes do Amaral
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Barbara Nunes Padovani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lais Cavalieri Paredes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juliana Moreira Mendonça-Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mariana Tominaga Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Niels Olsen Saraiva Câmara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Niels Olsen Saraiva Câmara.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

do Amaral, M.A., Padovani, B.N., Paredes, L.C. et al. Mitochondrial Metabolic Programming and Crosstalk to Nucleus. Curr. Tissue Microenviron. Rep. 4, 65–76 (2023). https://doi.org/10.1007/s43152-023-00048-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43152-023-00048-9

Keywords

Search

Navigation