A stress-adapted fiber state promotes clonal expansion of deleted mitochondrial DNA

Mitochondrial DNA (mtDNA) depletion and multiple deletions frequently coexist in mitochondrial disease, neurodegeneration, and aging, yet how the two relate and why deletions accumulate focally remain unresolved. Here, longitudinal bulk and in situ analyses of Mpv17^-/- murine muscle reveal that a compensatory rise in mitochondrial transcripts per mtDNA initially offsets severe, uniform mtDNA depletion, preserving the respiratory chain. However, this response carries a delayed cost: by six months transcripts decline, mtDNA deletions emerge, and respiratory-deficient fibers appear. Paradoxically, fibers harboring deletions accumulate supra-physiological amounts of mtDNA, despite prior depletion. This expansion is invariably accompanied by elevated Hsp60, and the same holds in human mitochondrial myopathy. We propose that depletion reprograms mitochondrial DNA and RNA metabolism, inadvertently promoting deletion formation and creating an Hsp60-high fiber state permissive for clonal expansion. Therefore, depletion and multiple deletions can be sequential phases of a common degenerative process, relevant also to aging and neurodegeneration.