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.

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…This in turn leads to the accumulation of a defective supercomplex I+III 2 intermediate that partially lacks the complex I N catalytic module, thus explaining the severe reduction in complex I activity detected in the complex IV mutant cells. A similar assembly phenotype has been recently described in a NDUFS4 knock-out mice (Calvaruso et al, 2011). The same argument would serve to explain why failures in the insertion of the complex III subunits cytochrome b or RISP may lead to combined complex I and complex III deficiencies in human tissues (Lamantea et al, 2002;Acín-Perez et al, 2004;Fernandez-Vizarra et al, 2007;Moran et al, 2010a).…”

Novel Insights into the Role of Neurospora crassa NDUFAF2, an Evolutionarily Conserved Mitochondrial Complex I Assembly Factor

“…A similar interaction of the human NDUFAF2 with an 830-kDa intermediate that accumulates in patients' mitochondria deficient in some nuclear complex I genes, namely, NDUFV1 (20,21), NDUFS1 (21), NDUFS4 (21), and NDUFS6 (22), was previously described. We suggest that intermediate a is the equivalent of this 830-kDa subcomplex, which also lacks the N module (19,49,50).…”

“…Mitochondria from patients and mice deficient in NDUFS4 were described as devoid of complex I activity, with accumulation of the 830-kDa intermediate associated with the NDUFAF2 assembly factor (20,21,49,50). However, it was recently reported that the absence of NDUFS4 results in increased instability of complex I leading to the accumulation of two subcomplexes, the N module and the 830-kDa intermediate, which has been found to be associated with two assembly factors (49,50). Furthermore, complex I activity was detected in different tissues of homozygous ndufs4 mutant mice, consistent with our results from nuo21 mutant.…”

Subcomplexes of Ancestral Respiratory Complex I Subunits Rapidly Turn Over in Vivo as Productive Assembly Intermediates in Arabidopsis*

“…This proposal is supported by evidence from mice that knockout of complex III (43) or complex IV (44) subunits decreases the content of complex I, suggesting that supercomplex formation stabilizes complex I. It has also been proposed in human mitochondria that supercomplex formation is required for assembly of complex I as well as for its stabilization (45). In addition, structural stabilization of labile membrane protein complexes is proposed as a major function of supercomplex formation in Paracoccus denitrificans (46).…”