Increase in mitochondrial mass in human fibroblasts under oxidative stress and during replicative cell senescence.
Abnormal proliferation of mitochondria generally occurs in muscle of aged individuals and patients with mitochondrial myopathy. An increase in the mitochondrial DNA (mtDNA) copy number has also been observed in aging human tissues. However, the molecular mechanism underlying the increase in mitochondrial mass and mtDNA is still unclear. In a previous study, we demonstrated that sublethal levels of oxidative stress caused an increase in mitochondrial mass in human lung cells. In this communication, we report our recent findings that the mitochondrial mass in human lung fibroblasts (MRC-5) in a later proliferation stage is significantly increased compared to that in the early stages of proliferation. The extent of the increase in mitochondrial mass in the senescent cells was similar to that in cells in the early stages of proliferation that had been treated with low concentrations (< or = 180 microM) of hydrogen peroxide (H(2)O(2)). Moreover, we found that the rate of reactive oxygen species (ROS) production was higher in cells in the later proliferation stage compared to cells in the early proliferation stages. A similar phenomenon was also observed in cells in the early proliferation stages under low levels of oxidative stress. On the other hand, the mRNA levels of many nuclear DNA-encoded proteins involved in mitochondrial biogenesis, particularly nuclear respiratory factor-1, were found to increase in cells in later proliferation stages and in cells in early proliferation stages that had been treated with 180 microM H(2)O(2). Interestingly, the increase in mitochondrial mass in the cells under oxidative stress could be repressed by treatment with cycloheximide or m-chlorocarbonyl cyanide phenylhydrazone but not by chloramphenicol. Furthermore, the mitochondrial mass of mtDNA-less rho(o) cells was also significantly increased by exposure to low concentrations (e.g. 180 microM) of H(2)O(2). These results suggest that the increase in mitochondrial mass in replicative senescent cells may result from an increase in ROS production, and that it is dependent on both de novo synthesis of nuclear DNA-encoded proteins and their import into mitochondria, dictated by the membrane potential of mitochondria.
Lee
Hsin-Chen
HC
Department of Biochemistry and Center for Cellular and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, ROC.
Yin
Pen-Hui
PH
Chi
Chin-Wen
CW
Wei
Yau-Huei
YH
D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D005452:Fluoresceins / Q000032:analysis / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism*; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D005452:Fluoresceins; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; C029569:diacetyldichlorofluorescein; D006861:Hydrogen Peroxide