Mitochondrial fission and fusion mediators, hFis1 and OPA1, modulate cellular senescence.
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 beta-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 beta-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.
Lee
Seungmin
S
Department of Biochemistry, Ajou University School of Medicine, Ajou University, 5 Wonchon-dong, Yeongtong-gu, Suwon 443-721, Korea.
Jeong
Seon-Yong
SY
Lim
Won-Chung
WC
Kim
Sujeong
S
Park
Yong-Yea
YY
Sun
Xuejun
X
Youle
Richard J
RJ
Cho
Hyeseong
H
D049109:Cell Proliferation; D016922:Cellular Senescence; D004249:DNA Damage; D053938:DNA Fragmentation; D020558:GTP Phosphohydrolases / Q000502:physiology*; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins; D008928:Mitochondria; D024101:Mitochondrial Proteins / Q000502:physiology*; D008954:Models, Biological; D010641:Phenotype; D034622:RNA Interference; D017382:Reactive Oxygen Species; D013997:Time Factors
C476525:FIS1 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human