Temporal inhibition of the electron transport chain attenuates stress‐induced cellular senescence by prolonged disturbance of proteostasis in human fibroblasts
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- Yasuhiro Takenaka
- Department of Bioregulatory Science, Graduate School of Medicine Nippon Medical School Tokyo Japan
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- Ikuo Inoue
- Department of Diabetes and Endocrinology Saitama Medical University Japan
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- Masataka Hirasaki
- Department of Clinical Cancer Genomics, International Medical Center Saitama Medical University Japan
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- Masaaki Ikeda
- Department of Physiology Saitama Medical University Japan
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- Yoshihiko Kakinuma
- Department of Bioregulatory Science, Graduate School of Medicine Nippon Medical School Tokyo Japan
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説明
<jats:p>We previously developed a stress‐induced premature senescence (SIPS) model in which normal human fibroblast MRC‐5 cells were treated with either the proteasome inhibitor MG132 or the vacuolar‐type ATPase inhibitor bafilomycin A1 (BAFA1). To clarify the involvement of mitochondrial function in our SIPS model, MRC‐5 cells were treated with MG132 or BAFA1 along with an inhibitor targeting either the electron transport chain complex I or complex III, or with a mitochondrial uncoupler. SIPS induced by MG132 or BAFA1 was significantly attenuated by short‐term co‐treatment with the complex III inhibitor, antimycin A (AA), but not the complex I inhibitor, rotenone or the mitochondrial uncoupler, carbonyl cyanide 3‐chlorophenylhydrazone. By co‐treatment with AA, mitochondrial and intracellular reactive oxygen species levels, accumulation of protein aggregates and mitochondrial unfolded protein responses (UPR<jats:sup>mt</jats:sup>) were remarkably suppressed. Furthermore, AA co‐treatment suppressed the hyperpolarization of the mitochondrial membrane and the induction of mitophagy observed in MG132‐treated cells and enhanced mitochondrial biogenesis. These findings provide evidence that the temporal inhibition of mitochondrial respiration exerts protective effects against the progression of premature senescence caused by impaired proteostasis.</jats:p>
収録刊行物
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- The FEBS Journal
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The FEBS Journal 290 (15), 3843-3857, 2023-04-14
Wiley