Respiratory chain complex I deficiency

Kirby, Denise M.; Crawford, Megan R.; Cleary, Maureen; Dahl, Hans Henrik M.; Dennett, Xenia; Thorburn, David R.

doi:10.1212/wnl.52.6.1255

Cited by 257 publications

(215 citation statements)

References 32 publications

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“…1 A number of mitochondrial DNA (mtDNA) mutations have recently been reported in association with a specific complex I deficiency in several of these patients. These have included mutations in the tRNA Leu(UUR) gene, 3 and a G14459A transition in the ND6 gene that has previously been characterised in patients with Lebers hereditary optic neuropathy (LHON) and dystonia. 4 The association of this mutation with Leigh disease therefore raises the possibility that mutations in other mtDNA-encoded structural complex I genes may play a role in the pathogenesis of this disorder.…”

Section: Introductionmentioning

confidence: 99%

Leigh disease associated with a novel mitochondrial DNA ND5 mutation

et al. 2002

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Leigh disease is a genetically heterogeneous, neurodegenerative disorder of childhood that is caused by defects of either the nuclear or mitochondrial genome. Here, we report the molecular genetic findings in a patient with neuropathological hallmarks of Leigh disease and complex I deficiency. Direct sequencing of the seven mitochondrial DNA (mtDNA)-encoded complex I (ND) genes revealed a novel missense mutation (T12706C) in the mitochondrial ND5 gene. The mutation is predicted to change an invariant amino acid in a highly conserved transmembrane helix of the mature polypeptide and was heteroplasmic in both skeletal muscle and cultured skin fibroblasts. The association of the T12706C ND5 mutation with a specific biochemical defect involving complex I is highly suggestive of a pathogenic role for this mutation.

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Section: Introductionmentioning

confidence: 99%

Leigh disease associated with a novel mitochondrial DNA ND5 mutation

et al. 2002

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“…The heart, being highly energy dependent, is particularly vulnerable to OXPHOS defects, with cardiac involvement recognized in about a third of children and up to 80% of adults with OXPHOS disorders (3,4). Complex I (CI) deficiency is the most common OXPHOS disorder and has a wide range of clinical presentations, including neurodegeneration, muscle weakness, cardiac failure, liver failure, and early death, often in childhood (5,6). As identified by Cochrane review, "there is currently no clear evidence supporting the use of any intervention in OXPHOS disorders" (7).…”

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confidence: 99%

Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy

Pepe

Grubb

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondrial complex I (CI) deficiency is the most common mitochondrial enzyme defect in humans. Treatment of mitochondrial disorders is currently inadequate, emphasizing the need for experimental models. In humans, mutations in the NDUFS6 gene, encoding a CI subunit, cause severe CI deficiency and neonatal death. In this study, we generated a CI-deficient mouse model by knockdown of the Ndufs6 gene using a gene-trap embryonic stem cell line. Ndufs6 gt/gt mice have essentially complete knockout of the Ndufs6 subunit in heart, resulting in marked CI deficiency. Small amounts of wild-type Ndufs6 mRNA are present in other tissues, apparently due to tissue-specific mRNA splicing, resulting in milder CI defects. Ndufs6 gt/gt mice are born healthy, attain normal weight and maturity, and are fertile. However, after 4 mo in males and 8 mo in females, Ndufs6 gt/gt mice are at increased risk of cardiac failure and death. Before overt heart failure, Ndufs6 gt/gt hearts show decreased ATP synthesis, accumulation of hydroxyacylcarnitine, but not reactive oxygen species (ROS). Ndufs6 gt/gt mice develop biventricular enlargement by 1 mo, most pronounced in males, with scattered fibrosis and abnormal mitochondrial but normal myofibrillar ultrastructure. Ndufs6 gt/gt isolated working heart preparations show markedly reduced left ventricular systolic function, cardiac output, and functional work capacity. This reduced energetic and functional capacity is consistent with a known susceptibility of individuals with mitochondrial cardiomyopathy to metabolic crises precipitated by stresses. This model of CI deficiency will facilitate studies of pathogenesis, modifier genes, and testing of therapeutic approaches. mouse model | mitochondrial diseases M itochondria generate the majority of energy required for cellular function and survival. Defects in mitochondrial oxidative phosphorylation (OXPHOS) cause a wide range of diseases, collectively affecting ∼1/5,000 births (1). OXPHOS dysfunction was first identified in neuromuscular disorders but symptoms can potentially affect any organ, with any age of onset and any mode of inheritance (2). The heart, being highly energy dependent, is particularly vulnerable to OXPHOS defects, with cardiac involvement recognized in about a third of children and up to 80% of adults with OXPHOS disorders (3, 4). Complex I (CI) deficiency is the most common OXPHOS disorder and has a wide range of clinical presentations, including neurodegeneration, muscle weakness, cardiac failure, liver failure, and early death, often in childhood (5, 6). As identified by Cochrane review, "there is currently no clear evidence supporting the use of any intervention in OXPHOS disorders" (7). Thus, there is an urgent need for suitable animal models to study pathogenic mechanisms and novel therapeutic approaches. Such models can also shed light on the wide range of common, complex diseases to which mitochondrial dysfunction contributes (8).Despite the high prevalence of OXPHOS disorders, relatively few genetic models have been...

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“…Moreover, there is a recognizable profile of artefactual enzyme loss at longer time intervals, with complex II being the most labile (Thorburn et al 2004). Samples were processed routinely for measurement of complex I, II, III, II+III, IV, and citrate synthase activities as previously described (Kirby et al 1999). Each MRC complex activity was expressed as a ratio relative to citrate synthase and complex II (Kirby et al 1999).…”

Section: Methodsmentioning

confidence: 99%

“…Samples were processed routinely for measurement of complex I, II, III, II+III, IV, and citrate synthase activities as previously described (Kirby et al 1999). Each MRC complex activity was expressed as a ratio relative to citrate synthase and complex II (Kirby et al 1999). Our diagnostic criteria specified that if one or more MRC ratios were less than 20% of control mean, it was regarded as 'diagnostic', and that ratios of 20-30% of control mean were 'probable' (Bernier et al 2002).…”

Section: Methodsmentioning

confidence: 99%

Decreased activities of mitochondrial respiratory chain complexes in non‐mitochondrial respiratory chain diseases

Hui

Kirby

Thorburn

et al. 2006

Develop Med Child Neuro

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The aim of this study was to illustrate the difficulties in establishing a diagnosis of mitochondrial respiratory chain (MRC) disorders based on clinical grounds in combination with intermediate activities of the MRC enzyme complexes. We reviewed retrospectively all medical and laboratory records of patients initially considered likely to have MRC disorders on clinical grounds, and subsequently diagnosed with other disorders (n=20; 11 males, 9 females). Data were retrieved from hospital records, referral letters, and results of enzymatic analysis at a reference laboratory. Clinical symptoms included developmental delay, epilepsy, hypotonia, movement disorder, spastic quadriplegia, tetany, microcephaly, visual problems, carpopedal spasms, dysmorphism, hearing loss, muscle weakness and rhabdomyolysis, and fulminant hepatitis. Blood and cerebrospinal fluid lactate levels were elevated in 13/20 and 9/20 respectively. One or more MRC complex activities (expressed as ratios relative to citrate synthase and/or complex II activity) were less than 50% of control mean activity in 11/20 patients (including patients with deficiencies of pyruvate dehydrogenase complex, pantothenate kinase, holocarboxylase synthetase, long-chain hydroxy acyl-CoA dehydrogenase, molybdenum co-factor, and neonatal haemochromatosis). One patient had a pattern suggestive of mitochondrial proliferation. We conclude that intermediate results of MRC enzymes should be interpreted with caution and clinicians should be actively looking for other underlying diagnoses.

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Respiratory chain complex I deficiency

Abstract: Heterogeneous clinical features, tissue specificity, and absence of lactic acidosis or abnormal mitochondrial morphology in many patients have resulted in underdiagnosis of respiratory chain complex I deficiency.

Cited by 257 publications

References 32 publications

Leigh disease associated with a novel mitochondrial DNA ND5 mutation

Leigh disease associated with a novel mitochondrial DNA ND5 mutation

Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy

Decreased activities of mitochondrial respiratory chain complexes in non‐mitochondrial respiratory chain diseases

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