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J. Biol. Chem., Vol. 282, Issue 31, 22977-22983, August 3, 2007

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Mitochondrial Fission and Fusion Mediators, hFis1 and OPA1, Modulate Cellular Senescence^*

Seungmin Lee¹, Seon-Yong Jeong^¶1, Won-Chung Lim, Sujeong Kim, Yong-Yea Park, Xuejun Sun^||, Richard J. Youle^**, and Hyeseong Cho²

From the Department of Biochemistry and ^¶Department of Medical Genetics, Ajou University School of Medicine and Graduate School of Molecular Science and Technology, Ajou University, 5 Wonchon-dong, Yeongtong-gu, Suwon 443-721, Korea, ^||Molecular Imaging Facility, Cross Cancer Institute, Edmonton T6G 1Z2, Alberta, Canada, and^**Biochemistry Section, SNB, NINDS, National Institutes of Health, Bethesda, Maryland 20892

The number and morphology of mitochondria within a cell are precisely regulated by the mitochondrial fission and fusion machinery. The human protein, hFis1, participates in mitochondrial fission by recruiting the Drp1 into the mitochondria. Using short hairpin RNA, we reduced the expression levels of hFis1 in mammalian cells. Cells lacking hFis1 showed sustained elongation of mitochondria and underwent significant cellular morphological changes, including enlargement, flattening, and increased cellular granularity. In these cells, staining for acidic senescence-associated -galactosidase activity was elevated, and the rate of cell proliferation was greatly reduced, indicating that cells lacking hFis1 undergo senescence-associated phenotypic changes. Reintroduction of the hFis1 gene into hFis1-depleted cells restored mitochondrial fragmentation and suppressed senescence-associated -galactosidase activity. Moreover, depletion of both hFis1 and OPA1, a critical component of mitochondrial fusion, resulted in extensive mitochondrial fragmentation and markedly rescued cells from senescence-associated phenotypic changes. Intriguingly, sustained elongation of mitochondria was associated with decreased mitochondrial membrane potential, increased reactive oxygen species production, and DNA damage. The data indicate that sustained mitochondrial elongation induces senescence-associated phenotypic changes that can be neutralized by mitochondrial fragmentation. Thus, one of the key functions of mitochondrial fission might be prevention of the sustained extensive mitochondrial elongation that triggers cellular senescence.

Received for publication, January 24, 2007 , and in revised form, May 9, 2007.

^* This work was supported by grants from Korea Science and Engineering Foundation through Chronic Inflammatory Disease Research Center R13-2003-019 and the Korea Research Foundation Grant KRF EP0030, Republic of Korea. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biochemistry, Ajou University School of Medicine, 5 Wonchon-dong, Yeongtong-gu, Suwon 443-721, Korea. Tel.: 82-31-219-5052; Fax: 82-31-219-5059; E-mail: hscho{at}ajou.ac.kr.

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