Effect of IGF-1 on the balance between autophagy of dysfunctional mitochondria and apoptosis.
Mutations in mitochondrial DNA (mtDNA) cause excessive production of mitochondrial reactive oxygen species (ROS) and shorten animal life span. We examined the mechanisms responsible for removal of mitochondria with deleterious mtDNA mutations by autophagy. Incubation of primary cells and cell lines in the absence of serum promotes autophagy of mitochondria with deleterious mtDNA mutations but spares their normal counterparts. The effect of serum withdrawal on the autophagy of dysfunctional mitochondria is prevented by the addition of IGF-1. As a result of the elimination of mitochondria with deleterious mutations, excessive ROS production, characteristic of dysfunctional mitochondria, is greatly reduced. Mitochondrial autophagy shares a common mechanism with mitochondrial-induced cell apoptosis, including mitochondrial transition pore formation and increased ROS production.
Gu
Yiping
Y
Division of Immunology and Allergy, Departments of Pediatrics and Immunology, Infection, Immunity, Injury and Repair Program, Research Institute, The University of Toronto, Ont., Canada M5G 1X8.
Wang
Chunjie
C
Cohen
Amos
A
D017209:Apoptosis; D001343:Autophagy; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004272:DNA, Mitochondrial / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D017241:MELAS Syndrome / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology*; D009154:Mutation; D012516:Osteosarcoma; D016877:Oxidants / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D044967:Serum / Q000378:metabolism; D013997:Time Factors
D016895:Culture Media, Serum-Free; D004272:DNA, Mitochondrial; D016877:Oxidants; D017382:Reactive Oxygen Species; D007334:Insulin-Like Growth Factor I; D006861:Hydrogen Peroxide