Abstract
SummaryMitophagy 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.
Highlights
Mitochondrial dysfunction is an integral component of degenerative diseases, from neurodegeneration to disorders of sensory or endocrine organs, heart and skeletal muscle, as well as normal aging (Suomalainen and Battersby, 2018)
Why dysfunctional mitochondria are not destined to be recycled in the affected fibers, why pathogenic mitochondrial DNA (mtDNA) variants accumulate in muscle cells, why nuclei centralize in muscle disease, and the mechanisms that contribute to progression of mitochondrial pathogenesis and muscle fatigue in aging remain unknown
Total levels of mitophagy are increased in muscle with mitochondrial dysfunction In order to assess in vivo mitophagy in mitochondrial myopathy, we established and applied the associated viral (AAV) vector carrying mito-QC (AAV-mito-QC) to the Deletor and wild-type (WT) littermate mice at 24 months of age (Figure 1A) and harvested skeletal and cardiac muscle 3 weeks post-injection
Summary
Mitochondrial dysfunction is an integral component of degenerative diseases, from neurodegeneration to disorders of sensory or endocrine organs, heart and skeletal muscle, as well as normal aging (Suomalainen and Battersby, 2018). Up to 30% of muscle fibers in nonagenarians were found to be deficient for the mitochondrial respiratory chain (RC) activities (Bua et al, 2006) associated with the progressive accumulation of pathogenic mitochondrial DNA (mtDNA) variants. Such RC-deficient fibers, some with abundant ultrastructurally abnormal mitochondria (raggedred fibers; RRFs), are hallmarks of mitochondrial muscle disease and typically harbor high amounts of pathogenic mtDNA variants. Why dysfunctional mitochondria are not destined to be recycled in the affected fibers, why pathogenic mtDNA variants accumulate in muscle cells, why nuclei centralize in muscle disease, and the mechanisms that contribute to progression of mitochondrial pathogenesis and muscle fatigue in aging remain unknown
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