NDUFAF4 variants are associated with Leigh syndrome and cause a specific mitochondrial complex I assembly defect

Baertling, Fabian; Sánchez‐Caballero, Laura; Brand, Mariël A.M. van den; Wintjes, Liesbeth T.; Brink, Maaike; Brandt, Frans A. van den; Wilson, Callum; Rodenburg, Richard J.; Nijtmans, Leo

doi:10.1038/ejhg.2017.133

Cited by 31 publications

(18 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Given the profound disruption of CI activity observed in ECSIT-deleted macrophages ( Figure 3 ), we performed BN-PAGE followed by western blotting to examine CI and the ECSIT-containing assembly complexes. Consistent with previous reports, we found that the levels of NDUFAF1 in the ECSIT-associated subcomplexes (≈400 kDa and 700 kDa) in mitochondrial preparations were significantly decreased ( Figure 4A ), suggesting that function of the MCIA complex might be impaired ( Baertling et al, 2017 ; Guerrero-Castillo et al, 2017 ). However, in contrast to previous reports, we found that other components of CI, NDUFS3 and ND6, were substantially diminished in ECSIT KO cells and importantly, did not accumulate in detectable assembly intermediates ( Figure 4A ).…”

Section: Resultssupporting

confidence: 92%

An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages

et al. 2018

View full text Add to dashboard Cite

SUMMARY ECSIT is a mitochondrial complex I (CI)-associated protein that has been shown to regulate the production of mitochondrial reactive oxygen species (mROS) following engagement of Toll-like receptors (TLRs). We have generated an Ecsit conditional knockout (CKO) mouse strain to study the in vivo role of ECSIT. ECSIT deletion results in profound alteration of macrophage metabolism, leading to a striking shift to reliance on glycolysis, complete disruption of CI activity, and loss of the CI holoenzyme and multiple subassemblies. An increase in constitutive mROS production in ECSIT-deleted macrophages prevents further TLR-induced mROS production. Surprisingly, ECSIT-deleted cells accumulate damaged mitochondria because of defective mitophagy. ECSIT associates with the mitophagy regulator PINK1 and exhibits Parkin-dependent ubiquitination. However, upon ECSIT deletion, we observed increased mitochondrial Parkin without the expected increase in mitophagy. Taken together, these results demonstrate a key role of ECSIT in CI function, mROS production, and mitophagy-dependent mitochondrial quality control.

show abstract

Section: Resultssupporting

confidence: 92%

An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Baertling F. et al described a patient with NDUFAF4 missense variants c.194 T > C (p.Leu65Pro) displaying an early-onset with neurodevelopmental regression, hypotonia, failure to thrive and irritability [25]. Biochemical profile showed hyperlactacidemia in plasma and cerebral spinal fluid (CSF).…”

Section: Oxphos Defectsmentioning

confidence: 99%

Molecular basis of Leigh syndrome: a current look

Baldo

Vilarinho

2020

Orphanet J Rare Dis

View full text Add to dashboard Cite

Leigh Syndrome (OMIM 256000) is a heterogeneous neurologic disorder due to damage in mitochondrial energy production that usually starts in early childhood. The first description given by Leigh pointed out neurological symptoms in children under 2 years and premature death. Following cases brought some hypothesis to explain the cause due to similarity to other neurological diseases and led to further investigation for metabolic diseases. Biochemical evaluation and specific metabolic profile suggested impairment in energy production (OXPHOS) in mitochondria. As direct approach to involved tissues is not always possible or safe, molecular analysis is a great cost-effective option and, besides biochemical results, is required to confirm the underlying cause of this syndrome face to clinical suspicion. The Next Generation Sequencing (NGS) advance represented a breakthrough in molecular biology allowing simultaneous gene analysis giving short-time results and increasing the variants underlying this syndrome, counting over 75 monogenic causes related so far. NGS provided confirmation of emerging cases and brought up diagnosis in atypical presentations as late-onset cases, which turned Leigh into a heterogeneous syndrome with variable outcomes. This review highlights clinical presentation in both classic and atypical phenotypes, the investigation pathway throughout confirmation emphasizing the underlying genetic heterogeneity and increasing number of genes assigned to this syndrome as well as available treatment.

show abstract

“…Homologues of the complex are present in all domains of life and contribute to the generation of the proton motive force essential to drive energyconsuming processes (Friedrich, 2014). A dysfunction or incomplete assembly of the human complex is associated with the onset of neurodegenerative diseases such as Parkinson's syndrome (Lin and Beal 2006;Rhein et al, 2009;Baertling et al, 2017). In patients with Friedreich's ataxia, non-functional Fe/S proteins and local iron accumulation have been observed that are caused by a mutation of the gene encoding frataxin (Bidichandani and Delatycki, 1998;Isaya, 2014).…”

Section: Introductionmentioning

confidence: 99%

Iron‐sulfur cluster carrier proteins involved in the assembly of Escherichia coli NADH:ubiquinone oxidoreductase (complex I)

Burschel

Decovic

Nuber

et al. 2018

Molecular Microbiology

View full text Add to dashboard Cite

Summary The NADH:ubiquinone oxidoreductase (respiratory complex I) is the main entry point for electrons into the Escherichia coli aerobic respiratory chain. With its sophisticated setup of 13 different subunits and 10 cofactors, it is anticipated that various chaperones are needed for its proper maturation. However, very little is known about the assembly of E. coli complex I, especially concerning the incorporation of the iron‐sulfur clusters. To identify iron‐sulfur cluster carrier proteins possibly involved in the process, we generated knockout strains of NfuA, BolA, YajL, Mrp, GrxD and IbaG that have been reported either to be involved in the maturation of mitochondrial complex I or to exert influence on the clusters of bacterial complex. We determined the NADH and succinate oxidase activities of membranes from the mutant strains to monitor the specificity of the individual mutations for complex I. The deletion of NfuA, BolA and Mrp led to a decreased stability and partially disturbed assembly of the complex as determined by sucrose gradient centrifugation and native PAGE. EPR spectroscopy of cytoplasmic membranes revealed that the BolA deletion results in the loss of the binuclear Fe/S cluster N1b.

show abstract

NDUFAF4 variants are associated with Leigh syndrome and cause a specific mitochondrial complex I assembly defect

Cited by 31 publications

References 13 publications

An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages

An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages

Molecular basis of Leigh syndrome: a current look

Iron‐sulfur cluster carrier proteins involved in the assembly of Escherichia coli NADH:ubiquinone oxidoreductase (complex I)

Contact Info

Product

Resources

About