The Change of Mitochondrial Fusion and Fission in human Skeletal Muscle with Aging

  • Cho, Hyung-Jun (Department of Orthopaedic Surgery, Kyung Hee University Hospital) ;
  • Park, Soo-Yeon (Graduate School of Education, Yong In University)
  • Received : 2012.04.17
  • Accepted : 2012.06.08
  • Published : 2012.06.30

Abstract

A gradual change of molecules that are related in fission and fusion is occurred during aging process. Although aging effects on mitochondrial fusion and fission are investigated, it is still unclear that the extent of the change in mitochondria fusion and fission periodically. In this study we investigated the changes of mitochondrial proteins involved in fusion (Mfn2, Opa1) and fission (Drp1, Fis1) in the human gracilis muscle ranging from 10 to 50 years of age (n=40). The gracilis muscle showed a significant increase in muscle apoptotic changes in the age of 50s compared with 10s by using in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL). The expression levels of Drp1 and Fis1 (P<0.01, P<0.05) mRNA were significantly elevated and the Mfn2 and Opa1 (P<0.01, P<0.05) levels were decreased from older individuals. The ratio of fission and fusion was altered and the level of increment of fission gene was greater than fusion gene decrement in the age of 50s. These findings suggest that changes of mitochondrial fusion and fission proteins related with aging might contribute to aged muscle apoptosis.

Keywords

References

  1. Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A, Rodriquez M, Kellner U, Leo-Kottler B, Auburger G, Bhattacharya SS, Wissinger B. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet. 2000. 26: 211-215. https://doi.org/10.1038/79944
  2. Bach D, Naon D, Pich S, Soriano FX, Vega N, Rieusset J, Laville M, Guilet C, Boirie Y, Wallerg-Henriksson H, Manco M, Calvani M, Castagneto M, Palcin M, Mingrone G, Zierath JR, Vidal H, Zorzano A. Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6. Diabetes. 2005. 54: 2685-2693. https://doi.org/10.2337/diabetes.54.9.2685
  3. Bossy-Wetzel E, Barsoum MJ, Godzik A, Schwarzenbacher R, Lipton SA. Mitochondrial fission in apoptosis, neuro-degeneration and aging. Curr Opin Cell Biol. 2003. 15: 706-716. https://doi.org/10.1016/j.ceb.2003.10.015
  4. Chen H, Chan DC. Mitochondiral dynamics in mammals. Curr Top Dev Biol. 2004. 59: 119-144.
  5. Chen H, McCaffery JM, Chan DC. Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell. 2007. 130: 548-562. https://doi.org/10.1016/j.cell.2007.06.026
  6. Chen H, Vermulst M, Wang YE, Chomyn A, Prolla TA, McCaffery JM, Chan DC. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell. 2010. 141: 280-289. https://doi.org/10.1016/j.cell.2010.02.026
  7. Chen L, Gong Q, Stice JP, Knowlton AA. Mitochondrial OPA1, apoptosis, and heart failure. Cardiovasc Res. 2009. 84: 91-99. https://doi.org/10.1093/cvr/cvp181
  8. Crane JD, Devries MC, Safdar A, Hamadeh MJ, Tarnopolsky MA. The effect of aging on human skeletal muscle mitochondrial and intramyocellular lipid ultrastructure. J Gerontol A Biol Sci Med Sci. 2010. 65: 119-128.
  9. Dimmer KS, Scorrano L. Constructinf mitochondria: what for?. Physiology. 2006. 21: 233-241. https://doi.org/10.1152/physiol.00010.2006
  10. Ding H, Jiang N, Liu H, Liu X, Liu D, Zhoa F, Wen L, Liu S, Ji LL, Zgang Y. Response of mitochondrial fusion and fission protein gene expression to exercise in rat skeletal muscle. Biochim Biophys Acta. 2009. 1800: 250-256.
  11. Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ. The role of dynaminrelated protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell. 2001. 1: 515-525. https://doi.org/10.1016/S1534-5807(01)00055-7
  12. Hales KG, Fuller MT. Developmentally regulated mitochondrial fusion mediated by a conserved, novel, predicted GTPase. Cell. 1997. 90: 121-129. https://doi.org/10.1016/S0092-8674(00)80319-0
  13. Jendrach M, Pohl S, Voth M, Kowald A, Hammerstein P, Bereiter-Hahn J. Morpho-dynamic changes of mitochondria during ageing of human endothelial cells. Mech Ageing Dev. 2005. 126: 813-821. https://doi.org/10.1016/j.mad.2005.03.002
  14. Kelley DE, He J, Menshikova EV, Ritov, VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes. 2002. 51: 2944-2950. https://doi.org/10.2337/diabetes.51.10.2944
  15. Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E. Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci. 2008. 9: 505-518. https://doi.org/10.1038/nrn2417
  16. Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell. 2004. 15: 5001-5011. https://doi.org/10.1091/mbc.E04-04-0294
  17. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006. 443: 787-795. https://doi.org/10.1038/nature05292
  18. Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet. 1989. 1: 642-645.
  19. Lopez-Lluch G, Irusta PM, Navas P, de Cabo R. Mitochondrial biogenesis and healthy aging. Exp Gerontol. 2008. 43: 813-819. https://doi.org/10.1016/j.exger.2008.06.014
  20. Ono T, Isobe K, Nakada K, Hayashi JI. Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria. Nat Genet. 2001. 28: 272-275. https://doi.org/10.1038/90116
  21. Romanello V, Guadagnin E, Gomes L, Rodaer I, Sandri C, Petersen Y, Milan G, Masiero E, Piccolo PD, Roretz M, Scorrano L, Rudolf R, Sandri M. Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J. 2010. 29: 1774-1785. https://doi.org/10.1038/emboj.2010.60
  22. Santel A, Frank S, Gaume B, Herrler M, Youle RJ, Fuller MT. Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells. J Cell Sci. 2003. 116: 2763-2774. https://doi.org/10.1242/jcs.00479
  23. Santel A, Fuller MT. Control of mitochondrial morphology by a human mitofusin. J Cell Sci. 2001. 114: 867-874.
  24. Seo AY, Joseph AM, Dutta D, Hwang JC, Aris J, Leewenburg C. New insights into the role of mitochondria in aging: mitochondrial dynamics and more. J Cell Sci. 2010. 123: 2533-2542. https://doi.org/10.1242/jcs.070490
  25. Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM. A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol. 1998. 143: 351-358. https://doi.org/10.1083/jcb.143.2.351
  26. Smirnova E, Griparic L, Shurland DL, wan der Bliek AM. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell. 2001. 12: 2245-2256. https://doi.org/10.1091/mbc.12.8.2245
  27. Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM. A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol. 1998. 143: 351-358. https://doi.org/10.1083/jcb.143.2.351
  28. Smirnova E, Griparic L, Shurland DL, wan der Bliek AM. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell. 2001. 12: 2245-2256. https://doi.org/10.1091/mbc.12.8.2245
  29. Suen DF, Norris KL, Youle RJ. Mitochondrial dynamics and apoptosis. Genes Dev. 2008. 22: 1577-1590. https://doi.org/10.1101/gad.1658508
  30. Terman A, Kurz T, Navratil M, Arriaga EA, Brunk UT. Mitochondrial turnover and aging of long-lived postmitotic cells: the mitochondrial-lysosomal axis theory of aging. Antioxid Redox Signal. 2010. 12: 503-535. https://doi.org/10.1089/ars.2009.2598
  31. Toledo FG, Watkins S, Kelley DE. Changes induced by physical activity and weight loss in the morphology of intermyofibrillar mitochondria in obese men and women. J Clin Endocrinol Metab. 2006. 91: 3224-3227. https://doi.org/10.1210/jc.2006-0002
  32. Wasilewski M, Scorrano L. The changing shape of mitochondrial apoptosis. Trends Endocrinol Metab. 2009. 20: 287-294. https://doi.org/10.1016/j.tem.2009.03.007
  33. Zorzano A. Regulation of mitofusin-2 expression in skeletal muscle. Appl Physiol Nutr Metab. 2009. 34: 433-439. https://doi.org/10.1139/H09-049