title: Mitochondrial complex III stabilizes complex I in the absence of NDUFS4 to provide partial activity.
abstract: Mitochondrial complex I (CI) is a multi-subunit enzyme that forms the major entry point of nicotinamide adenine dinucleotide (NADH) electrons into the respiratory chain. Mutations in the NDUFS4 gene, encoding an accessory subunit of this complex, cause a Leigh-like phenotype in humans. To study the nature and penetrance of the CI defect in different tissues, we investigated the role of NDUFS4 in mice with fatal mitochondrial encephalomyopathy, caused by a systemic inactivation of the Ndufs4 gene. We report that the absence of NDUFS4 in different mouse tissues results in decreased activity and stability of CI. This CI instability leads to an increased disconnection of electron influx of the NADH dehydrogenase module from the holo-complex. However, the formation of respiratory supercomplexes still allows formation of active CI in these Ndufs4 knock-out mice. These results reveal the importance of these supramolecular interactions not only for stabilization but also for the assembly of CI, which becomes especially relevant in pathological conditions.
authors.affiliation: Nijmegen Center for Mitochondrial Disorders at the Department of Pediatrics, Radboud University Nijmegen Medical Centre, HB 6500 Nijmegen, The Netherlands.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Calvaruso
authors.forename: Peter
authors.initials: P
authors.lastname: Willems
authors.forename: Mariël
authors.initials: M
authors.lastname: van den Brand
authors.forename: Federica
authors.initials: F
authors.lastname: Valsecchi
authors.forename: Shane
authors.initials: S
authors.lastname: Kruse
authors.forename: Richard
authors.initials: R
authors.lastname: Palmiter
authors.forename: Jan
authors.initials: J
authors.lastname: Smeitink
authors.forename: Leo
authors.initials: L
authors.lastname: Nijtmans
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000737:chemistry / Q000201:enzymology*; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology* / Q000235:genetics; D011485:Protein Binding; D055550:Protein Stability
chemical_list: C534449:Ndufs4 protein, mouse; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III