Mitofusin 1 and Optic Atrophy 1 Shift Metabolism to Mitochondrial Respiration During Aging

Overview

Journal Aging Cell

Specialties Cell Biology
Geriatrics

Date 2017 Aug 1

PMID 28758339

Citations 35

Authors

Jyung Mean Son

Ehab H Sarsour

Anurag Kakkerla Balaraju

Jenna Fussell

Amanda L Kalen

Brett A Wagner

Garry R Buettner

Prabhat C Goswami

Affiliations

Soon will be listed here.

Abstract

Replicative and chronological lifespan are two different modes of cellular aging. Chronological lifespan is defined as the duration during which quiescent normal cells retain their capacity to re-enter the proliferative cycle. This study investigated whether changes in metabolism occur during aging of quiescent normal human fibroblasts (NHFs) and the mechanisms that regulate these changes. Bioenergetics measurements were taken in quiescent NHFs from younger (newborn, 3-day, 5-month, and 1-year) and older (58-, 61-, 63-, 68-, and 70-year) healthy donors as well as NHFs from the same individual at different ages (29, 36, and 46 years). Results show significant changes in cellular metabolism during aging of quiescent NHFs: Old NHFs exhibit a significant decrease in glycolytic flux and lactate levels, and increase in oxygen consumption rate (OCR) and ATP levels compared to young NHFs. Results from the Seahorse XF Cell Mito Stress Test show that old NHFs with a lower Bioenergetic Health Index (BHI) are more prone to oxidative stress compared to young NHFs with a higher BHI. The increase in OCR in old NHFs is associated with a shift in mitochondrial dynamics more toward fusion. Genetic knockdown of mitofusin 1 (MFN1) and optic atrophy 1 (OPA1) in old NHFs decreased OCR and shifted metabolism more toward glycolysis. Downregulation of MFN1 and OPA1 also suppressed the radiation-induced increase in doubling time of NHFs. In summary, results show that a metabolic shift from glycolysis in young to mitochondrial respiration in old NHFs occurs during chronological lifespan, and MFN1 and OPA1 regulate this process.

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References

Lee S, Jeong S, Lim W, Kim S, Park Y, Sun X . Mitochondrial fission and fusion mediators, hFis1 and OPA1, modulate cellular senescence. J Biol Chem. 2007; 282(31):22977-83. DOI: 10.1074/jbc.M700679200. View

Jiang H, Hsu J, Yen C, Chao C, Chen R, Pan C . Neural activity and CaMKII protect mitochondria from fragmentation in aging Caenorhabditis elegans neurons. Proc Natl Acad Sci U S A. 2015; 112(28):8768-73. PMC: 4507213. DOI: 10.1073/pnas.1501831112. View

Anand R, Wai T, Baker M, Kladt N, Schauss A, Rugarli E . The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J Cell Biol. 2014; 204(6):919-29. PMC: 3998800. DOI: 10.1083/jcb.201308006. View

Chen H, Vermulst M, Wang Y, Chomyn A, Prolla T, McCaffery J . Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell. 2010; 141(2):280-9. PMC: 2876819. DOI: 10.1016/j.cell.2010.02.026. View

Riera C, Dillin A . Tipping the metabolic scales towards increased longevity in mammals. Nat Cell Biol. 2015; 17(3):196-203. DOI: 10.1038/ncb3107. View

McQuibban G, Lee J, Zheng L, Juusola M, Freeman M . Normal mitochondrial dynamics requires rhomboid-7 and affects Drosophila lifespan and neuronal function. Curr Biol. 2006; 16(10):982-9. DOI: 10.1016/j.cub.2006.03.062. View

Siegel M, Kruse S, Percival J, Goh J, White C, Hopkins H . Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell. 2013; 12(5):763-71. PMC: 3772966. DOI: 10.1111/acel.12102. View

Munro J, Steeghs K, Morrison V, Ireland H, Parkinson E . Human fibroblast replicative senescence can occur in the absence of extensive cell division and short telomeres. Oncogene. 2001; 20(27):3541-52. DOI: 10.1038/sj.onc.1204460. View

Fabrizio P, Longo V . The chronological life span of Saccharomyces cerevisiae. Methods Mol Biol. 2007; 371:89-95. DOI: 10.1007/978-1-59745-361-5_8. View

10.

Civiletto G, Varanita T, Cerutti R, Gorletta T, Barbaro S, Marchet S . Opa1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models. Cell Metab. 2015; 21(6):845-54. PMC: 4457891. DOI: 10.1016/j.cmet.2015.04.016. View

11.

Galloway C, Lee H, Nejjar S, Jhun B, Yu T, Hsu W . Transgenic control of mitochondrial fission induces mitochondrial uncoupling and relieves diabetic oxidative stress. Diabetes. 2012; 61(8):2093-104. PMC: 3402299. DOI: 10.2337/db11-1640. View

12.

Sarsour E, Goswami M, Kalen A, Goswami P . MnSOD activity protects mitochondrial morphology of quiescent fibroblasts from age associated abnormalities. Mitochondrion. 2010; 10(4):342-9. PMC: 2874624. DOI: 10.1016/j.mito.2010.02.004. View

13.

Sarsour E, Agarwal M, Pandita T, Oberley L, Goswami P . Manganese superoxide dismutase protects the proliferative capacity of confluent normal human fibroblasts. J Biol Chem. 2005; 280(18):18033-41. DOI: 10.1074/jbc.M501939200. View

14.

Henderson E, Larson D . Telomeres--what's new at the end?. Curr Opin Genet Dev. 1991; 1(4):538-43. DOI: 10.1016/s0959-437x(05)80205-9. View

15.

Brand M, Nicholls D . Assessing mitochondrial dysfunction in cells. Biochem J. 2011; 435(2):297-312. PMC: 3076726. DOI: 10.1042/BJ20110162. View

16.

Chan D . Fusion and fission: interlinked processes critical for mitochondrial health. Annu Rev Genet. 2012; 46:265-87. DOI: 10.1146/annurev-genet-110410-132529. View

17.

Harris N, Costa V, Maclean M, Mollapour M, Moradas-Ferreira P, Piper P . Mnsod overexpression extends the yeast chronological (G(0)) life span but acts independently of Sir2p histone deacetylase to shorten the replicative life span of dividing cells. Free Radic Biol Med. 2003; 34(12):1599-606. DOI: 10.1016/s0891-5849(03)00210-7. View

18.

Yang C, Chen D, Lee S, Walter L . The dynamin-related protein DRP-1 and the insulin signaling pathway cooperate to modulate Caenorhabditis elegans longevity. Aging Cell. 2011; 10(4):724-8. PMC: 3135752. DOI: 10.1111/j.1474-9726.2011.00711.x. View

19.

Collins J, Huang C, Hughes S, Kornfeld K . The measurement and analysis of age-related changes in Caenorhabditis elegans. WormBook. 2008; :1-21. PMC: 4781475. DOI: 10.1895/wormbook.1.137.1. View

20.

Chacko B, Kramer P, Ravi S, Benavides G, Mitchell T, Dranka B . The Bioenergetic Health Index: a new concept in mitochondrial translational research. Clin Sci (Lond). 2014; 127(6):367-73. PMC: 4202728. DOI: 10.1042/CS20140101. View