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

In Mpv17 -/- murine muscle, a compensatory rise in mitochondrial transcripts initially offsets uniform mtDNA depletion, but by six months mtDNA deletions emerge and deletion-harboring fibers expand with supra-physiological mtDNA.

• Why it matters: mtDNA depletion and multiple deletions often coexist in mitochondrial disease, neurodegeneration, and aging, yet the sequence linking depletion to focal deletion accumulation is unresolved.
• What they did: Longitudinal bulk and in situ analyses tracked mitochondrial transcripts, deletion emergence, and respiratory-deficient fibers in Mpv17 -/- muscle, with parallel validation in human mitochondrial myopathy.
• The result: Depletion reprograms mtDNA and RNA metabolism, coinciding with elevated Hsp60 and an Hsp60-high fiber state that is linked to clonal expansion of deleted mtDNA.

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