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Preservation of mitochondrial membrane potential is necessary for lifespan extension from dietary restriction

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Abstract

Dietary restriction (DR) increases lifespan in many organisms, but its underlying mechanisms are not fully understood. Mitochondria play a central role in metabolic regulation and are known to undergo changes in structure and function in response to DR. Mitochondrial membrane potential (Δψm) is the driving force for ATP production and mitochondrial outputs that integrate many cellular signals. One such signal regulated by Δψm is nutrient-status sensing. Here, we tested the hypothesis that DR promotes longevity through preserved Δψm during adulthood. Using the nematode Caenorhabditis elegans, we find that Δψm declines with age relatively early in the lifespan, and this decline is attenuated by DR. Pharmacologic depletion of Δψm blocked the longevity and health benefits of DR. Genetic perturbation of Δψm and mitochondrial ATP availability similarly prevented lifespan extension from DR. Taken together, this study provides further evidence that appropriate regulation of Δψm is a critical factor for health and longevity in response to DR.

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Data Availability

All data are presented in the manuscript and supplementary materials. Raw data files for lifespans are included in the supplementary materials, and other raw data can be made available upon request.

References

  1. Anderson RM, Shanmuganayagam D, Weindruch R. Caloric restriction and aging: studies in mice and monkeys. Toxicol Pathol. 2009;37(1):47–51.

    Article  PubMed  Google Scholar 

  2. Kapahi P, Kaeberlein M, Hansen M. Dietary restriction and lifespan: Lessons from invertebrate models. Ageing Res Rev. 2017;39:3–14.

    Article  PubMed  Google Scholar 

  3. Lee MB, et al. Antiaging diets: Separating fact from fiction. Science. 2021. 374(6570): p. eabe7365.

  4. Longo VD, Anderson RM. Nutrition, longevity and disease: From molecular mechanisms to interventions. Cell. 2022;185(9):1455–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kaeberlein TL, et al. Lifespan extension in Caenorhabditis elegans by complete removal of food. Aging Cell. 2006;5(6):487–94.

    Article  CAS  PubMed  Google Scholar 

  6. Sutphin GL, Kaeberlein M. Dietary restriction by bacterial deprivation increases life span in wild-derived nematodes. Exp Gerontol. 2008;43(3):130–5.

    Article  CAS  PubMed  Google Scholar 

  7. Greer EL, Brunet A. Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans. Aging Cell. 2009;8(2): p. 113–27.

  8. Lakowski B, Hekimi S. The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 1998;95(22):13091–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Brys K, et al. Disruption of insulin signalling preserves bioenergetic competence of mitochondria in ageing Caenorhabditis elegans. BMC Biol. 2010;8:91.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hagopian K, et al. Long-term calorie restriction reduces proton leak and hydrogen peroxide production in liver mitochondria. Am J Physiol Endocrinol Metab. 2005;288(4):E674–84.

    Article  CAS  PubMed  Google Scholar 

  11. Bevilacqua L, et al. Effects of short- and medium-term calorie restriction on muscle mitochondrial proton leak and reactive oxygen species production. Am J Physiol Endocrinol Metab. 2004;286(5):E852–61.

    Article  CAS  PubMed  Google Scholar 

  12. Anderson RM, Weindruch R. Metabolic reprogramming in dietary restriction. Interdiscip Top Gerontol. 2007;35:18–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hughes AL, Gottschling DE. An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast. Nature. 2012;492(7428):261–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Berry BJ, et al. Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan. Nature Aging. 2022. In Press.

  15. Ames BN, Shigenaga MK, Hagen TM. Mitochondrial decay in aging. Biochim Biophys Acta. 1995;1271(1):165–70.

    Article  PubMed  Google Scholar 

  16. Sugrue MM, Tatton WG. Mitochondrial membrane potential in aging cells. Biol Signals Recept. 2001;10(3–4):176–88.

    Article  CAS  PubMed  Google Scholar 

  17. Bayliak MM, et al. Middle age as a turning point in mouse cerebral cortex energy and redox metabolism: Modulation by every-other-day fasting. Exp Gerontol. 2021;145:111182.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang H, et al. Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte. Elife. 2020;9.

  19. Brenner S. The genetics of Caenorhabditis elegans. Genetics. 1974;77(1):71–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Weir HJ, et al. Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. Cell Metab. 2017;26(6):884-896.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Macedo F, et al. Lifespan-extending interventions enhance lipid-supported mitochondrial respiration in Caenorhabditis elegans. FASEB J. 2020;34(8):9972–81.

    Article  CAS  PubMed  Google Scholar 

  22. Sutphin GL, Kaeberlein M. Measuring Caenorhabditis elegans life span on solid media. J Vis Exp. 2009(27).

  23. Berry BJ, et al. Optogenetic control of mitochondrial protonmotive force to impact cellular stress resistance. EMBO Rep. 2020;21(4):e49113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sawin ER, Ranganathan R, Horvitz HR. C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway. Neuron. 2000;26(3): p. 619–31.

  25. Tsalik EL, Hobert O. Functional mapping of neurons that control locomotory behavior in Caenorhabditis elegans. J Neurobiol. 2003;56(2):178–97.

    Article  PubMed  Google Scholar 

  26. Kwon YJ, et al. High-throughput BioSorter quantification of relative mitochondrial content and membrane potential in living Caenorhabditis elegans. Mitochondrion. 2018;40:42–50.

    Article  CAS  PubMed  Google Scholar 

  27. Dingley S, et al. Mitochondrial respiratory chain dysfunction variably increases oxidant stress in Caenorhabditis elegans. Mitochondrion. 2010;10(2):125–36.

    Article  CAS  PubMed  Google Scholar 

  28. Aspernig H, et al. Mitochondrial Perturbations Couple mTORC2 to Autophagy in C. elegans. Cell Rep. 2019;29(6): p. 1399–1409.e5.

  29. Shpilka T, et al. UPR mt scales mitochondrial network expansion with protein synthesis via mitochondrial import in Caenorhabditis elegans. Nat Commun. 2021;12(1):479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Perry SW, et al. Mitochondrial membrane potential probes and the proton gradient: a practical usage guide. Biotechniques. 2011;50(2):98–115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nisoli E, et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science. 2005;310(5746):314–7.

    Article  CAS  PubMed  Google Scholar 

  32. Guarente L. Mitochondria–a nexus for aging, calorie restriction, and sirtuins? Cell. 2008;132(2):171–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lanza IR, et al. Chronic caloric restriction preserves mitochondrial function in senescence without increasing mitochondrial biogenesis. Cell Metab. 2012;16(6):777–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rhoads TW, et al. Molecular and Functional Networks Linked to Sarcopenia Prevention by Caloric Restriction in Rhesus Monkeys. Cell Syst. 2020;10(2):156-168.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hancock CR, et al. Does calorie restriction induce mitochondrial biogenesis? A reevaluation FASEB J. 2011;25(2):785–91.

    Article  CAS  PubMed  Google Scholar 

  36. Bruss MD, et al. Calorie restriction increases fatty acid synthesis and whole body fat oxidation rates. Am J Physiol Endocrinol Metab. 2010;298(1):E108–16.

    Article  CAS  PubMed  Google Scholar 

  37. Cho I, Hwang GJ, Cho JH. Uncoupling Protein, UCP-4 May Be Involved in Neuronal Defects During Aging and Resistance to Pathogens in Caenorhabditis elegans. Mol Cells. 2016;39(9):680–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Berry BJ, et al. Use the Protonmotive Force: Mitochondrial Uncoupling and Reactive Oxygen Species. J Mol Biol. 2018;430(21):3873–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Iser WB, et al. Examination of the requirement for ucp-4, a putative homolog of mammalian uncoupling proteins, for stress tolerance and longevity in C. elegans. Mech Ageing Dev. 2005;126(10): p. 1090–6.

  40. Pfeiffer M, et al. Caenorhabditis elegans UCP4 protein controls complex II-mediated oxidative phosphorylation through succinate transport. J Biol Chem. 2011;286(43):37712–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bertholet AM, et al. H + transport is an integral function of the mitochondrial ADP/ATP carrier. Nature. 2019;571(7766):515–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chevrollier A, et al. Adenine nucleotide translocase 2 is a key mitochondrial protein in cancer metabolism. Biochim Biophys Acta. 2011;1807(6):562–7.

    Article  CAS  PubMed  Google Scholar 

  43. Farina F, et al. Differential expression pattern of the four mitochondrial adenine nucleotide transporter ant genes and their roles during the development of Caenorhabditis elegans. Dev Dyn. 2008;237(6):1668–81.

    Article  CAS  PubMed  Google Scholar 

  44. Chinopoulos C. Mitochondrial consumption of cytosolic ATP: not so fast. FEBS Lett. 2011;585(9):1255–9.

    Article  CAS  PubMed  Google Scholar 

  45. García-Aguilar A, Cuezva JM. A Review of the Inhibition of the Mitochondrial ATP Synthase by IF1. Front Physiol. 2018;9:1322.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Fernández-Cárdenas LP, et al. Caenorhabditis elegans ATPase inhibitor factor 1 (IF1) MAI-2 preserves the mitochondrial membrane potential (Δψm) and is important to induce germ cell apoptosis. PLoS One. 2017;12(8):e0181984.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Teofilović A, et al. Late-Onset Calorie Restriction Improves Lipid Metabolism and Aggravates Inflammation in the Liver of Old Wistar Rats. Front Nutr. 2022;9:899255.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Baumeier C, et al. Caloric restriction and intermittent fasting alter hepatic lipid droplet proteome and diacylglycerol species and prevent diabetes in NZO mice. Biochim Biophys Acta. 2015;1851(5):566–76.

    Article  CAS  PubMed  Google Scholar 

  49. Rhoads TW, et al. Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys. Cell Metab. 2018;27(3):677-688.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ricquier D. Bouillaud F. The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem J. 2000;345 Pt 2(Pt 2): p. 161–79.

  51. Fisler JS, Warden CH. Uncoupling proteins, dietary fat and the metabolic syndrome. Nutr Metab (Lond). 2006;3:38.

    Article  PubMed  Google Scholar 

  52. Nedergaard J, Cannon B. The “novel” “uncoupling” proteins UCP2 and UCP3: what do they really do? Pros and cons for suggested functions. Exp Physiol. 2003;88(1):65–84.

    Article  CAS  PubMed  Google Scholar 

  53. Wanders D, et al. UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivity. FASEB J. 2015;29(6):2603–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hill CM, et al. Low protein-induced increases in FGF21 drive UCP1-dependent metabolic but not thermoregulatory endpoints. Sci Rep. 2017;7(1):8209.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Roshanravan B, et al. In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trial. PLoS ONE. 2021;16(7):e0253849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gore E, et al. The Multifaceted ATPase Inhibitory Factor 1 (IF1) in Energy Metabolism Reprogramming and Mitochondrial Dysfunction: A New Player in Age-Associated Disorders? Antioxid Redox Signal. 2022;37(4–6):370–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Martínez-Reyes I, et al. TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions. Mol Cell. 2016;61(2):199–209.

    Article  PubMed  Google Scholar 

  58. Berry BJ, Kaeberlein M. An energetics perspective on geroscience: mitochondrial protonmotive force and aging. Geroscience. 2021;43(4):1591–604.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Angeli S, et al. The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging. Elife. 2021. 10.

  60. Ye X, et al. A pharmacological network for lifespan extension in Caenorhabditis elegans. Aging Cell. 2014;13(2):206–15.

    Article  CAS  PubMed  Google Scholar 

  61. Zhou B, et al. Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension. Cell. 2019;177(2):299-314.e16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

BJB is supported by the Biological Mechanisms for Healthy Aging (BMHA) Training Grant NIH T32AG066574. This work was supported by P30AG013280 to MK. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). The authors thank the laboratory of Rosa E. Navarro González for providing strain RN70 harboring the mai-2 mutation.

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathology, University of Washington Medical Center, 1959 NE Pacific St., Seattle, WA, 98195, USA

    Brandon J. Berry, Evan Mjelde, Fatima Carreno, Kathryn Gilham, Emily J. Hanson, Emily Na & Matt Kaeberlein

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  1. Brandon J. Berry
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  2. Evan Mjelde
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  3. Fatima Carreno
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Correspondence to Brandon J. Berry or Matt Kaeberlein.

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Berry, B.J., Mjelde, E., Carreno, F. et al. Preservation of mitochondrial membrane potential is necessary for lifespan extension from dietary restriction. GeroScience 45, 1573–1581 (2023). https://doi.org/10.1007/s11357-023-00766-w

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