Abstract
ObjectiveIn 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.MethodsSerial skeletal muscle cryosections from patients with multiple mtDNA deletions were subjected to subcellular immunofluorescent, histochemical, and genetic analysis.ResultsWe 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.InterpretationWe 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
Highlights
ObjectiveIn 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
Focal Regions of Deficiency Are Restricted to the Subsarcolemmal Space When surveying c oxidase (COX)/succinate dehydrogenase (SDH) histochemistry, we consistently found that focal regions of deficiency are localized in the subsarcolemmal space
Model Based on our observations, we propose the following model. mitochondrial DNA (mtDNA) deletions that arise in the perinuclear region preferentially accumulate under the influence of mitochondrial biogenesis, reaching critical mass and causing the first visible signs of focal mitochondrial respiratory chain deficiency
Summary
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. 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. Skeletal muscle fibers have a highly organized cytoarchitecture, where spatially restricted mitochondrial subpopulations exist.[13,14] Subsarcolemmal (SS) mitochondria are located at the periphery of the muscle fiber adjacent to the sarcolemma membrane, a subset of which are perinuclear; whereas intermyofibrillar (IMF) mitochondria are located between the myofibrils at the Z-band This raises the question of how clonal expansion proceeds through these highly organized and spatially restricted mitochondrial populations. Increasing our understanding of this phenomenon will provide insight into the origins of mtDNA deletions and respiratory chain deficiency, with potential diagnostic and prognostic implications
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
