Detection of "deleted" mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome.

Mita, Shuji; Schmidt, Beny; Schon, Eric A.; DiMauro, Salvatore; Bonilla, Eduardo

doi:10.1073/pnas.86.23.9509

Cited by 182 publications

(98 citation statements)

References 28 publications

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“…COX‐deficient muscle fibers in patients with single, large‐scale mtDNA deletions have been consistently shown to accumulate high levels of mtDNA deletions 27, 35, 36. Accordingly, we have shown that deletion level increases with higher degrees of OXPHOS deficiency across a total of 673 fibers from 6 patients.…”

Section: Discussionmentioning

confidence: 54%

Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

Rocha

Rosa

Grady

et al. 2018

Annals of Neurology

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ObjectiveSingle, large‐scale deletions in mitochondrial DNA (mtDNA) are a common cause of mitochondrial disease. This study aimed to investigate the relationship between the genetic defect and molecular phenotype to improve understanding of pathogenic mechanisms associated with single, large‐scale mtDNA deletions in skeletal muscle.MethodsWe investigated 23 muscle biopsies taken from adult patients (6 males/17 females with a mean age of 43 years) with characterized single, large‐scale mtDNA deletions. Mitochondrial respiratory chain deficiency in skeletal muscle biopsies was quantified by immunoreactivity levels for complex I and complex IV proteins. Single muscle fibers with varying degrees of deficiency were selected from 6 patient biopsies for determination of mtDNA deletion level and copy number by quantitative polymerase chain reaction.ResultsWe have defined 3 “classes” of single, large‐scale deletion with distinct patterns of mitochondrial deficiency, determined by the size and location of the deletion. Single fiber analyses showed that fibers with greater respiratory chain deficiency harbored higher levels of mtDNA deletion with an increase in total mtDNA copy number. For the first time, we have demonstrated that threshold levels for complex I and complex IV deficiency differ based on deletion class.InterpretationCombining genetic and immunofluorescent assays, we conclude that thresholds for complex I and complex IV deficiency are modulated by the deletion of complex‐specific protein‐encoding genes. Furthermore, removal of mt‐tRNA genes impacts specific complexes only at high deletion levels, when complex‐specific protein‐encoding genes remain. These novel findings provide valuable insight into the pathogenic mechanisms associated with these mutations. Ann Neurol 2018;83:115–130

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Section: Discussionmentioning

confidence: 54%

Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

Rocha

Rosa

Grady

et al. 2018

Annals of Neurology

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“…Muscle biopsies from patients with KSS or CPEO show ragged-red fibers and cytochrome oxidase-negative fibers [58,59]. Clinical signs vary widely in different syndromes but include muscle weakness, heart block, retinopathy, deafness, diabetes, short stature and dementia [2,60].…”

Section: Discussionmentioning

confidence: 99%

“…Because deletions erase essential parts of the mitochondrial protein synthetic machinery (i.e. tRNAs) [58,61] as well as essential components of the respiratory chain complexes that produce energy and other metabolites for the cell (Figure 5), we expected a strong 'nuclear response' to the 'mitochondrial stimulus'.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Alemi

Prigione

Wong

et al. 2007

Free Radical Biology and Medicine

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Deletions within the mitochondrial DNA (mtDNA) cause Kearns Sayre Syndrome (KSS) and Chronic Progressive External Opthalmoplegia (CPEO). The clinical signs of KSS include muscle weakness, heart block, pigmentary retinopathy, ataxia, deafness, short stature, and dementia. The identical deletions occur and rise exponentially as humans age, particularly in substantia nigra. Deletions at >30% concentration cause deficits in basic bioenergetic parameters, including membrane potential and ATP synthesis, but it is poorly understood how these alterations cause the pathologies observed in patients. To better understand the consequences of mtDNA deletions, we microarrayed 6 cell types containing mtDNA deletions from KSS and CPEO patients. There was a prominent inhibition of transcripts encoding ubiquitin-mediated proteasome activity, and a prominent induction of transcripts involved in the AMP kinase pathway, macroautophagy, and amino acid degradation. In mutant cells, we confirmed a decrease in proteasome biochemical activity, significantly lower concentration of several amino acids, and induction of an autophagic transcript. An interpretation consistent with the data is that mtDNA deletions increase protein damage, inhibit the ubiquitin-proteasome system, decrease amino acid salvage, and activate autophagy. This provides a novel pathophysiological mechanism for these diseases, and suggests potential therapeutic strategies.

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“…Although no severe biochemical deficiency could be demonstrated, the cell-line appeared to be more sensitive to doxycycline than control cell-lines (Spelbrink et al 1994). Since different cells in a single culture generally contain different percentages of mutant mtDNA (Mita et al 1989;Matthews et al 1995), this meant that treatment with low concentrations of DC could, in principle, be used to select against those cells in culture harbouring the highest percentages of del-mtDNA, and thereby reduce the average percentage of del-mtDNA in culture. Previous findings had already indicated that the addition of low concentrations of DC resulted in a stronger inhibition of growth in cells with a high level of del-mtDNA compared to control lymphoblasts (Spelbrink et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Preferential amplification and phenotypic selection in a population of deleted and wild-type mitochondrial DNA in cultured cells

et al. 1997

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Detection of "deleted" mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome.

Abstract: Using in situ hybridization and immunocy-

Cited by 182 publications

References 28 publications

Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Preferential amplification and phenotypic selection in a population of deleted and wild-type mitochondrial DNA in cultured cells

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