Pathological Mutations of the Human NDUFS4 Gene of the 18-kDa (AQDQ) Subunit of Complex I Affect the Expression of the Protein and the Assembly and Function of the Complex

Scacco, Salvatore; Petruzzella, Vittoria; Budde, Sandy; Vergari, Rosaria; Tamborra, Rosanna; Panelli, Damiano; Heuvel, Lambert P. van den; Smeitink, Jan A.M.; Papa, Sergio

doi:10.1074/jbc.m307615200

Cited by 121 publications

(105 citation statements)

References 37 publications

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“…The evidence from the patients with mutations in NDUFV1 (51 kDa) and NDUFS4 (18 kDa) indicates that the 830-kDa subcomplex is minimally missing these 2 subunits in both cases (our unpublished results). An approximately 800-kDa subcomplex has previously been reported in patients with NDUFS4 mutations who also fail to assemble the holoenzyme complex (26)(27)(28), and it almost certainly represents the same subcomplex we identify here. A recent paper reporting a patient with a homozygous nonsense mutation in NDUFS6 (13-kDa subunit) described the accumulation of a 750-kDa subcomplex in patient fibroblasts, but the estimated size of the subcomplex was based on a holoenzyme molecular weight of 900 kDa.…”

Section: Figurementioning

confidence: 52%

A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy

Ogilvie

Kennaway²,

Shoubridge³

2005

Journal of Clinical Investigation

259

222

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NADH:ubiquinone oxidoreductase (complex I) deficiency is a common cause of mitochondrial oxidative phosphorylation disease. It is associated with a wide range of clinical phenotypes in infants, including Leigh syndrome, cardiomyopathy, and encephalomyopathy. In at least half of patients, enzyme deficiency results from a failure to assemble the holoenzyme complex; however, the molecular chaperones required for assembly of the mammalian enzyme remain unknown. Using whole genome subtraction of yeasts with and without a complex I to generate candidate assembly factors, we identified a paralogue (B17.2L) of the B17.2 structural subunit. We found a null mutation in B17.2L in a patient with a progressive encephalopathy and showed that the associated complex I assembly defect could be completely rescued by retroviral expression of B17.2L in patient fibroblasts. An anti-B17.2L antibody did not associate with the holoenzyme complex but specifically recognized an 830-kDa subassembly in several patients with complex I assembly defects and coimmunoprecipitated a subset of complex I structural subunits from normal human heart mitochondria. These results demonstrate that B17.2L is a bona fide molecular chaperone that is essential for the assembly of complex I and for the normal function of the nervous system.

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Section: Figurementioning

confidence: 52%

A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy

Ogilvie

Kennaway²,

Shoubridge³

2005

Journal of Clinical Investigation

259

222

View full text Add to dashboard Cite

show abstract

“…NDUFS4 is a nuclear-encoded subunit, which, once phosphorylated by cAMP/protein kinase A (PKA) in the cytosol on its C-terminal end of the protein (37), promotes import and maturation of the precursor protein, which then incorporates into the core complex of complex I and enables its proper activity. Pathological mutations in the human NDUFS4 gene result in the disappearance of the protein encoded by the gene, failure of the final step of complex I assembly, and suppression of the NADH ubiquinone oxidoreductase activity (38). Complex I dysfunction is frequently associated with abnormalities of inflammation and cardiac dysfunction (39,40).…”

Section: Discussionmentioning

confidence: 99%

Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension

Plecitá–Hlavatá

Tauber

et al. 2016

Am J Respir Cell Mol Biol

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Remodeling of the distal pulmonary artery wall is a characteristic feature of pulmonary hypertension (PH). In hypoxic PH, the most substantial pathologic changes occur in the adventitia. Here, there is marked fibroblast proliferation and profound macrophage accumulation. These PH fibroblasts (PH-Fibs) maintain a hyperproliferative, apoptotic-resistant, and proinflammatory phenotype in ex vivo culture. Considering that a similar phenotype is observed in cancer cells, where it has been associated, at least in part, with specific alterations in mitochondrial metabolism, we sought to define the state of mitochondrial metabolism in PH-Fibs. In PH-Fibs, pyruvate dehydrogenase was markedly inhibited, resulting in metabolism of pyruvate to lactate, thus consistent with a Warburg-like phenotype. In addition, mitochondrial bioenergetics were suppressed and mitochondrial fragmentation was increased in PH-Fibs. Most importantly, complex I activity was substantially decreased, which was associated with down-regulation of the accessory subunit nicotinamide adenine dinucleotide reduced dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4). Owing to less-efficient ATP synthesis, mitochondria were hyperpolarized and mitochondrial superoxide production was increased. This pro-oxidative status was further augmented by simultaneous induction of cytosolic nicotinamide adenine dinucleotide phosphate reduced oxidase 4. Although acute and chronic exposure to hypoxia of adventitial fibroblasts from healthy control vessels induced increased glycolysis, it did not induce complex I deficiency as observed in PH-Fibs. This suggests that hypoxia alone is insufficient to induce NDUFS4 down-regulation and constitutive abnormalities in complex I. In conclusion, our study provides evidence that, in the pathogenesis of vascular remodeling in PH, alterations in fibroblast mitochondrial metabolism drive distinct changes in cellular behavior, which potentially occur independently of hypoxia.

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“…Patients with defects in cytochrome b not only lose complex III, but also show decreased amounts of complex I, while maintaining normal enzymatic activity of the complex (15). Conversely, the disruption of complex I function caused by nonsense mutations in NDUFS4, a subunit of this large multimeric complex, leads to the partial loss of complex III activity in skin fibroblast cultures obtained from Leigh-like patients (18,19). However, defects in the complex I subunit ND5 did not cause a loss of complex III in the I-III supercomplex (20).…”

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confidence: 99%

Complex I Function Is Defective in Complex IV-deficient Caenorhabditis elegans

Suthammarak

Yang

Morgan

et al. 2009

Journal of Biological Chemistry

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Cytochrome c oxidase (COX) is hypothesized to be an important regulator of oxidative phosphorylation. However, no animal phenotypes have been described due to genetic defects in nuclear-encoded subunits of COX. We knocked down predicted homologues of COX IV and COX Va in the nematode Caenorhabditis elegans. Animals treated with W09C5.8 (COX IV) or Y37D8A.14 (COX Va) RNA interference had shortened lifespans and severe defects in mitochondrial respiratory chain function. Amount and activity of complex IV, as well as supercomplexes that included complex IV, were decreased in COXdeficient worms. The formation of supercomplex I:III was not dependent on COX. We found that COX deficiencies decreased intrinsic complex I enzymatic activity, as well as complex I-III enzymatic activity. However, overall amounts of complex I were not decreased in these animals. Surprisingly, intrinsic complex I enzymatic activity is dependent on the presence of complex IV, despite no overall decrease in the amount of complex I. Presumably the association of complex I with complex IV within the supercomplex I:III:IV enhances electron flow through complex I. Our results indicate that reduction of a single subunit within the electron transport chain can affect multiple enzymatic steps of electron transfer, including movement within a different protein complex. Patients presenting with multiple defects of electron transport may, in fact, harbor a single genetic defect.

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Pathological Mutations of the Human NDUFS4 Gene of the 18-kDa (AQDQ) Subunit of Complex I Affect the Expression of the Protein and the Assembly and Function of the Complex

Cited by 121 publications

References 37 publications

A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy

A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy

Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension

Complex I Function Is Defective in Complex IV-deficient Caenorhabditis elegans

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