MtDNA‐maintenance defects: syndromes and genes

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

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“…POLG and TWNK, DNA2, MGME1 ), dNTP supply (e.g. TP, RRM2B, TK2, DGUOK ), and proteins regulating mitochondrial dynamics ( OPA1 and MFN2 )2.…”

Section: Introductionmentioning

confidence: 99%

Subcellular origin of mitochondrial DNA deletions in human skeletal muscle

Vincent

Rosa

Pabis

et al. 2018

Annals of Neurology

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“…Many prevalent and rare neurodegenerative disorders have been associated with mitochondrial deficiencies, which affect central as well as peripheral parts of the nervous system (Nunnari & Suomalainen, 2012;Kawamata & Manfredi, 2017;Viscomi & Zeviani, 2017;Nissanka & Moraes, 2018). Mitochondria are central metabolic organelles and therefore of pivotal importance for neuronal survival.…”

Section: Introductionmentioning

confidence: 99%

Loss of the mitochondrial i ‐ AAA protease YME 1L leads to ocular dysfunction and spinal axonopathy

et al. 2018

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Disturbances in the morphology and function of mitochondria cause neurological diseases, which can affect the central and peripheral nervous system. The i‐AAA protease YME1L ensures mitochondrial proteostasis and regulates mitochondrial dynamics by processing of the dynamin‐like GTPase OPA1. Mutations in YME1L cause a multi‐systemic mitochondriopathy associated with neurological dysfunction and mitochondrial fragmentation but pathogenic mechanisms remained enigmatic. Here, we report on striking cell‐type‐specific defects in mice lacking YME1L in the nervous system. YME1L‐deficient mice manifest ocular dysfunction with microphthalmia and cataracts and develop deficiencies in locomotor activity due to specific degeneration of spinal cord axons, which relay proprioceptive signals from the hind limbs to the cerebellum. Mitochondrial fragmentation occurs throughout the nervous system and does not correlate with the degenerative phenotype. Deletion of Oma1 restores tubular mitochondria but deteriorates axonal degeneration in the absence of YME1L, demonstrating that impaired mitochondrial proteostasis rather than mitochondrial fragmentation causes the observed neurological defects.

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“…1). This class of mitochondrial diseases expanded rapidly and still expands [112], as the first gene associated with multiple mtDNA deletions was the adenine nucleotide translocator‐1/ANT1 ( SLC25A4 ) [113], rapidly followed by the simultaneous identification of the helicase Twinkle/PEO1 ( TWNK ) [114] and the mitochondrial polymerase gamma ( POLG ) [115], fulfilling the prediction that all genes building the mtDNA replisome would be candidates for mtDNA maintenance disorders [116]. Interestingly, the first gene identified for mtDNA depletion was thymidine phosphorylase ( TYMP ) associated with the adult form of mitochondrial neurogastrointetinal encephalomyopathy (MNGIE), a severe disorder dominated by gastrointestinal pseudo‐obstructions and dysmotility [117].…”

Section: Mitochondrial Diseases Due To Altered Mtdna Secondary To Defmentioning

confidence: 99%

“…A third category of genes unexpectedly implicated in mtDNA maintenance includes key factors that regulate mitochondrial dynamics, such as optic atrophy 1 gene ( OPA1 ) [121,122] and mitofusin 2 ( MFN2 ) [123,124], both necessary to fuse, respectively, the inner and the outer mitochondrial membranes. To complete the landscape of mtDNA maintenance diseases, there are further genes for which the function is yet unclear, as recently reviewed [112].…”

Section: Mitochondrial Diseases Due To Altered Mtdna Secondary To Defmentioning

confidence: 99%

Mitochondrial diseases in adults

et al. 2020

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Mitochondrial medicine is a field that expanded exponentially in the last 30 years. Individually rare, mitochondrial diseases as a whole are probably the most frequent genetic disorder in adults. The complexity of their genotype–phenotype correlation, in terms of penetrance and clinical expressivity, natural history and diagnostic algorithm derives from the dual genetic determination. In fact, in addition to the about 1.500 genes encoding mitochondrial proteins that reside in the nuclear genome (nDNA), we have the 13 proteins encoded by the mitochondrial genome (mtDNA), for which 22 specific tRNAs and 2 rRNAs are also needed. Thus, besides Mendelian genetics, we need to consider all peculiarities of how mtDNA is inherited, maintained and expressed to fully understand the pathogenic mechanisms of these disorders. Yet, from the initial restriction to the narrow field of oxidative phosphorylation dysfunction, the landscape of mitochondrial functions impinging on cellular homeostasis, driving life and death, is impressively enlarged. Finally, from the clinical standpoint, starting from the neuromuscular field, where brain and skeletal muscle were the primary targets of mitochondrial dysfunction as energy‐dependent tissues, after three decades virtually any subspecialty of medicine is now involved. We will summarize the key clinical pictures and pathogenic mechanisms of mitochondrial diseases in adults.

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MtDNA‐maintenance defects: syndromes and genes

Cited by 151 publications

References 109 publications

Subcellular origin of mitochondrial DNA deletions in human skeletal muscle

Subcellular origin of mitochondrial DNA deletions in human skeletal muscle

Loss of the mitochondrial i ‐ AAA protease YME 1L leads to ocular dysfunction and spinal axonopathy

Mitochondrial diseases in adults

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