Molecular base of biochemical complex I deficiency

Hoefs, Saskia J.G.; Rodenburg, Richard J.; Smeitink, Jan A.M.; Heuvel, Lambert P. van den

doi:10.1016/j.mito.2012.07.106

Cited by 36 publications

(35 citation statements)

References 155 publications

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“…In plants, an additional two subunits of the peripheral arm are also mitochondrially encoded, which are NADH dehydrogenase 7 and 9 (Nad7 and Nad9), homologs of the 49-kD and 30-kD subunits in bovine, respectively. The complex is assembled in a modular way with the help of at least 10 assembly factors Hoefs et al, 2012;Mimaki et al, 2012). Complex I in plants follows a similar assembly pattern, except that it builds on the assembly of the plant-specific carbonic anhydrase module as an early step Li et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…The majority of human OXPHOS disorders are a result of complex I deficiency, caused by mutations in one of the 44 structural subunits, in one of the assembly factors, or in mitochondrial gene expression (Tucker et al, 2011;Hoefs et al, 2012). Some cases of complex I deficiency in humans are caused by mutation of a specific mitochondrial tRNA (Calvo et al, 2010;Swalwell et al, 2011), whereas a growing number of nuclear mutants are being described that affect splicing or editing of the mitochondrial nad transcripts in plants (Colas de FrancsSmall and Small, 2013).…”

Section: Introductionmentioning

confidence: 99%

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The Evolutionarily Conserved Iron-Sulfur Protein INDH Is Required for Complex I Assembly and Mitochondrial Translation in Arabidopsis

et al. 2013

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The assembly of respiratory complexes is a multistep process, requiring coordinate expression of mitochondrial and nuclear genes and cofactor biosynthesis. We functionally characterized the iron-sulfur protein required for NADH dehydrogenase (INDH) in the model plant Arabidopsis thaliana. An indh knockout mutant lacked complex I but had low levels of a 650-kD assembly intermediate, similar to mutations in the homologous NUBPL (nucleotide binding protein-like) in Homo sapiens. However, heterozygous indh/+ mutants displayed unusual phenotypes during gametogenesis and resembled mutants in mitochondrial translation more than mutants in complex I. Gradually increased expression of INDH in indh knockout plants revealed a significant delay in reassembly of complex I, suggesting an indirect role for INDH in the assembly process. Depletion of INDH protein was associated with decreased 35 S-Met labeling of translation products in isolated mitochondria, whereas the steady state levels of several mitochondrial transcripts were increased. Mitochondrially encoded proteins were differentially affected, with near normal levels of cytochrome c oxidase subunit2 and Nad7 but little Nad6 protein in the indh mutant. These data suggest that INDH has a primary role in mitochondrial translation that underlies its role in complex I assembly.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Evolutionarily Conserved Iron-Sulfur Protein INDH Is Required for Complex I Assembly and Mitochondrial Translation in Arabidopsis

et al. 2013

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“…The mutational spectrum is highly heterogeneous and disease-causing mutations have been found in both nDNA and mtDNA genes. Disease-causing mutations in nDNA-encoded genes have been reported in twelve CI core and accessory subunits, in eight assembly factors and also in an uncharacterized protein (Hoefs et al, 2012). Clinical phenotypes that have been associated with CI deficiency include fatal infantile lactic acidosis, leukoencephalopathy, Leigh syndrome, hepatopathy with renal tubulopathy, neonatal cardiomyopathy and MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) (DiMauro and Emmanuele, 2013;Fassone and Rahman, 2012).…”

Section: Introductionmentioning

confidence: 99%

Broad phenotypic variability in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1

et al. 2015

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“…Given this complexity and the critical role of CI in the ETC, it is not surprising that numerous mitochondrial diseases, such as Leigh's syndrome, result from mutations in mitochondrial DNA (mtDNA)-or nuclear-DNA-encoded CI subunits, as well as assembly factors (12). Thus far, at least 33 genes encoding either CI subunits or assembly factors have been associated with genetic defects in CI deficiency (13).…”

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confidence: 99%

TIMMDC1/C3orf1 Functions as a Membrane-Embedded Mitochondrial Complex I Assembly Factor through Association with the MCIA Complex

Guarani

Paulo

Zhai

et al. 2014

Molecular and Cellular Biology

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Complex I (CI) of the electron transport chain, a large membrane-embedded NADH dehydrogenase, couples electron transfer to the release of protons into the mitochondrial inner membrane space to promote ATP production through ATP synthase. In addition to being a central conduit for ATP production, CI activity has been linked to neurodegenerative disorders, including Parkinson's disease. CI is built in a stepwise fashion through the actions of several assembly factors. We employed interaction proteomics to interrogate the molecular associations of 15 core subunits and assembly factors previously linked to human CI deficiency, resulting in a network of 101 proteins and 335 interactions (edges). TIMMDC1, a predicted 4-pass membrane protein, reciprocally associated with multiple members of the MCIA CI assembly factor complex and core CI subunits and was localized in the mitochondrial inner membrane, and its depletion resulted in reduced CI activity and cellular respiration. Quantitative proteomics demonstrated a role for TIMMDC1 in assembly of membrane-embedded and soluble arms of the complex. This study defines a new membrane-embedded CI assembly factor and provides a resource for further analysis of CI biology.

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Molecular base of biochemical complex I deficiency

Cited by 36 publications

References 155 publications

The Evolutionarily Conserved Iron-Sulfur Protein INDH Is Required for Complex I Assembly and Mitochondrial Translation in Arabidopsis

The Evolutionarily Conserved Iron-Sulfur Protein INDH Is Required for Complex I Assembly and Mitochondrial Translation in Arabidopsis

Broad phenotypic variability in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1

TIMMDC1/C3orf1 Functions as a Membrane-Embedded Mitochondrial Complex I Assembly Factor through Association with the MCIA Complex

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