Mosaic dysfunction of mitophagy in mitochondrial muscle disease

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Mito , T , Vincent , A E , Faitg , J , Taylor , R W , Khan , N A , McWilliams , T G & Suomalainen , A 2022 , ' Mosaic dysfunction of mitophagy in mitochondrial muscle disease ' , Cell Metabolism , vol. 34 , no. 2 , pp. 197-+ .

Title: Mosaic dysfunction of mitophagy in mitochondrial muscle disease
Author: Mito, Takayuki; Vincent, Amy E.; Faitg, Julie; Taylor, Robert W.; Khan, Nahid A.; McWilliams, Thomas G.; Suomalainen, Anu
Contributor organization: STEMM - Stem Cells and Metabolism Research Program
University of Helsinki
Department of Anatomy
Faculty of Medicine
Doctoral Programme Brain & Mind
Doctoral Programme in Integrative Life Science
Doctoral Programme in Clinical Research
Doctoral Programme in Biomedicine
Department of Neurosciences
Anu Wartiovaara / Principal Investigator
Date: 2022-02-01
Language: eng
Number of pages: 17
Belongs to series: Cell Metabolism
ISSN: 1550-4131
Abstract: 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.
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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