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.
"However, contradictory results regarding the morphology of mitochondria in senescent cells has been reported. The formation of giant mitochondria caused by a reduction in hFis1 expression was reported in mammalian cells , . A reduction in the ratio of mitochondria to total cell volume in senescent cells was observed by Rafelski et al. . "
[Show abstract][Hide abstract] ABSTRACT: Mitochondria form a reticulum network dynamically fuse and divide in the cell. The balance between mitochondria fusion and fission is correlated to the shape, activity and integrity of these pivotal organelles. Resveratrol is a polyphenol antioxidant that can extend life span in yeast and worm. This study examined mitochondria dynamics in replicative senescent yeast cells as well as the effects of resveratrol on mitochondria fusion and fission. Collecting cells by biotin-streptavidin sorting method revealed that majority of the replicative senescent cells bear fragmented mitochondrial network, indicating mitochondria dynamics favors fission. Resveratrol treatment resulted in a reduction in the ratio of senescent yeast cells with fragmented mitochondria. The readjustment of mitochondria dynamics induced by resveratrol likely derives from altered expression profiles of fusion and fission genes. Our results demonstrate that resveratrol serves not only as an antioxidant, but also a compound that can mitigate mitochondria fragmentation in replicative senescent yeast cells.
PLoS ONE 08/2014; 9(8):e104345. DOI:10.1371/journal.pone.0104345 · 3.23 Impact Factor
"One study has shown that the inhibition of mitochondrial fission can induce sustained mitochondrial elongation and changes in senescence-associated phenotype . It was also shown that these changes could be suppressed via the reconstitution of mitochondria, suggesting that the mutual opposition of mitochondrial fusion and fission is required for normal cell growth (Lee et al., 2007). Also, the induction of mitochondrial fusion by silencing the fission protein Drp1 causes a decrease in cellular TG accumulation , while the induction of mitochondrial fission by silencing the fusion proteins Mfn2 and OPA1 causes an increase in this parameter (Kita et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: Adipogenesis and lipid accumulation during aging have a great impact on the aging process and the pathogenesis of chronic, age-related diseases. However, little is known about the age-related molecular changes in lipid accumulation and the mechanisms underlying them. Here, using 5-month- and 25-month-old rats (young and old, respectively), we found that epididymal fat is the only tissue to accumulate during aging. By testing tissues rich with mitochondria in old and young animals, we found that the old animals had elevated levels of triglycerides in their muscle, heart and liver tissues but not in their kidneys, while, the mRNA level of fatty acid synthase remained unchanged among four tissues. Regarding lipid degradation, we determined that the activities of mitochondrial ETC. complexes changed in aged rats (Muscle: decreased complex I and V activity; Heart: decreased complex I acitivity; Liver: increased complex I and III activity; Kidney: decreased complex I and increased complex II activity). While, changes in mitochondrial content were not observed in muscle, heart nor liver tissue except increased complex IV and V subunits in aged kidneys. Furthermore, decreased mitochondrial fusion marker Mfn2, decreased PGC-1α level were observed in the aged muscle, heart and liver but remained unchanged in the kidneys. Down-regulation of Mfn2 with siRNA in 293 T cells induced significant mitochondrial dysfunction including decreased oxygen consumption, decreased ATP production, and increased ROS production, followed by increased triglycerides content suggesting a contributing role of decreased mitochondrial fusion to lipid deposit. Meanwhile, judging from autophagy marker p62/SQSTM1 and LC3-II, autophagy was suppressed in the aged muscle, heart and liver but remained unchanged in the kidneys. Taken together, these data suggest that reduction in PGC-1α expression, disruption of mitochondrial dynamics and autophagy might contribute to lipid accumulation during aging.
"In our cell model, slow growth was not associated with apoptotic cell death but with cellular senescence, as demonstrated by increased SA-βgal activity and cell cycle arrest at the G1 phase. We have also found that frataxin deficiency is associated with mitochondrial elongation and, interestingly, morphodynamic changes of mitochondria closely link to the cell cycle (Lee et al., 2013) and mitochondrial elongation concretely triggers cellular senescence (Lee et al., 2007). "
[Show abstract][Hide abstract] ABSTRACT: Friedreich ataxia is considered a neurodegenerative disorder involving both the peripheral and central nervous systems. Dorsal root ganglia (DRG) are the major target tissue structures. This neuropathy is caused by mutations in the FXN gene that encodes frataxin. Here, we investigated the mitochondrial and cell consequences of frataxin depletion in a cellular model based on frataxin silencing in SH-SY5Y human neuroblastoma cells, a cell line that has been used widely as in vitro models for studies on neurological diseases. We showed that the reduction of frataxin induced mitochondrial dysfunction due to a bioenergetic deficit and abnormal Ca(2+) homeostasis in the mitochondria that were associated with oxidative and endoplasmic reticulum stresses. The depletion of frataxin did not cause cell death but increased autophagy, which may have a cytoprotective effect against cellular insults such as oxidative stress. Frataxin silencing provoked slow cell growth associated with cellular senescence, as demonstrated by increased SA-βgal activity and cell cycle arrest at the G1 phase. We postulate that cellular senescence might be related to a hypoplastic defect in the DRG during neurodevelopment, as suggested by necropsy studies.
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