Subcellular origin of mitochondrial DNA deletions in human skeletal muscle

Amy E. Vincent, Hannah S. Rosa, Kamil Pabis, Conor Lawless, Chun Chen, Anne Grünewald, Karolina A. Rygiel, Mariana C. Rocha, Amy K. Reeve, Gavin Falkous, Valentina Perissi, Kathryn White, Tracey Davey, Basil J. Petrof, Avan A. Sayer, Cyrus Cooper, David Deehan, Robert W. Taylor, Doug M. Turnbull*, Martin Picard

*Corresponding author for this work
12 Citations (Scopus)


Objective: In patients with mitochondrial DNA (mtDNA) maintenance disorders and with aging, mtDNA deletions sporadically form and clonally expand within individual muscle fibers, causing respiratory chain deficiency. This study aimed to identify the sub-cellular origin and potential mechanisms underlying this process. Methods: Serial skeletal muscle cryosections from patients with multiple mtDNA deletions were subjected to subcellular immunofluorescent, histochemical, and genetic analysis. Results: We report respiratory chain–deficient perinuclear foci containing mtDNA deletions, which show local elevations of both mitochondrial mass and mtDNA copy number. These subcellular foci of respiratory chain deficiency are associated with a local increase in mitochondrial biogenesis and unfolded protein response signaling pathways. We also find that the commonly reported segmental pattern of mitochondrial deficiency is consistent with the three-dimensional organization of the human skeletal muscle mitochondrial network. Interpretation: We propose that mtDNA deletions first exceed the biochemical threshold causing biochemical deficiency in focal regions adjacent to the myonuclei, and induce mitochondrial biogenesis before spreading across the muscle fiber. These subcellular resolution data provide new insights into the possible origin of mitochondrial respiratory chain deficiency in mitochondrial myopathy. Ann Neurol 2018;84:289–301.

Original languageEnglish
JournalAnnals of Neurology
Issue number2
Pages (from-to)289-301
Number of pages13
Publication statusPublished - 08.2018

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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