| Autor: |
Takayuki Mito, Amy E. Vincent, Julie Faitg, Robert W. Taylor, Nahid A. Khan, Thomas G. McWilliams, Anu Suomalainen |
| Přispěvatelé: |
STEMM - Stem Cells and Metabolism Research Program, University of Helsinki, Department of Anatomy, Faculty of Medicine, HUSLAB, Doctoral Programme Brain & Mind, Doctoral Programme in Integrative Life Science, Doctoral Programme in Clinical Research, Doctoral Programme in Biomedicine, Department of Neurosciences, Medicum, Anu Wartiovaara / Principal Investigator |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Popis: |
Mitophagy is a quality control mechanism that eliminates damaged mitochondria, yet its significance in mammalian pathophysiology and aging has remained unclear. Here, we report that mitophagy contributes to mitochondrial dysfunction in skeletal muscle of aged mice and human patients. The early disease stage is characterized by muscle fibers with central nuclei, with enhanced mitophagy around these nuclei. However, progressive mitochondrial dysfunction halts mitophagy and disrupts lysosomal homeostasis. Interestingly, activated or halted mitophagy occur in a mosaic manner even in adjacent muscle fibers, indicating cell-autonomous regulation. Rapamycin restores mitochondrial turnover, indicating mTOR-dependence of mitochondrial recycling in advanced disease stage. Our evidence suggests that (1) mitophagy is a hallmark of age-related mitochondrial pathology in mammalian muscle, (2) mosaic halting of mitophagy is a mechanism explaining mosaic respiratory chain deficiency and accumulation of pathogenic mtDNA variants in adult-onset mitochondrial diseases and normal aging, and (3) augmenting mitophagy is a promising therapeutic approach for muscle mitochondrial dysfunction. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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