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Subcellular origin of mitochondrial DNA deletions in human skeletal muscle
Author(s) -
Vincent Amy E.,
Rosa Hannah S.,
Pabis Kamil,
Lawless Conor,
Chen Chun,
Grünewald Anne,
Rygiel Karolina A.,
Rocha Mariana C.,
Reeve Amy K.,
Falkous Gavin,
Perissi Valentina,
White Kathryn,
Davey Tracey,
Petrof Basil J.,
Sayer Avan A.,
Cooper Cyrus,
Deehan David,
Taylor Robert W.,
Turnbull Doug M.,
Picard Martin
Publication year - 2018
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25288
Subject(s) - mitochondrial dna , biology , respiratory chain , mitochondrial biogenesis , mitochondrion , mitochondrial myopathy , mitochondrial respiratory chain , skeletal muscle , myopathy , mitochondrial disease , human mitochondrial genetics , genetics , microbiology and biotechnology , gene , anatomy
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