BACKGROUND: Pathogenic variants in the NDUFV1 gene disrupt mitochondrial complex I, leading to neuroregression with leukoencephalopathy and basal ganglia involvement on neuroimaging. This study aims to provide a concise review on NDUFV1-related disorders while adding the largest cohort from a single center to the existing literature.
METHODS: We retrospectively collected genetically proven cases of NDUFV1 pathogenic variants from our center over the last decade and explored reported instances in existing literature. Magnetic resonance imaging (MRI) patterns observed in these patients were split into three types-Leigh (putamen, basal ganglia, thalamus, and brainstem involvement), mitochondrial leukodystrophy (ML) (cerebral white matter involvement with cystic cavitations), and mixed (both).
RESULTS: Analysis included 44 children (seven from our center and 37 from literature). The most prevalent comorbidities were hypertonia, ocular abnormalities, feeding issues, and hypotonia at onset. Children with the Leigh-type MRI pattern exhibited significantly higher rates of breathing difficulties, whereas those with a mixed phenotype had a higher prevalence of dystonia. The c.1156C>T variant in exon 8 of the NDUFV1 gene was the most common variant among individuals of Asian ethnicity and is predominantly associated with irritability and dystonia. Seizures and Leigh pattern of MRI of the brain was found to be less commonly associated with this variant. Higher rate of mortality was observed in children with Leigh-type pattern on brain MRI and those who did not receive mitochondrial cocktail.
CONCLUSIONS: MRI phenotyping might help predict outcome. Appropriate and timely treatment with mitochondrial cocktail may reduce the probability of death and may positively impact the long-term outcomes, regardless of the genetic variant or age of onset.

Impaired mitochondrial function and dysregulated energy metabolism have been shown to be involved in the pathological progression of kidney diseases such as acute kidney injury (AKI) and diabetic nephropathy. Hence, improving mitochondrial function is a promising strategy for treating renal dysfunction. NADH: ubiquinone oxidoreductase core subunit V1 (NDUFV1) is an important subunit of mitochondrial complex I. In the present study, we found that NDUFV1 was reduced in kidneys of renal ischemia/reperfusion (I/R) mice. Meanwhile, renal I/R induced kidney dysfunction as evidenced by increases in BUN and serum creatinine, severe injury of proximal renal tubules, oxidative stress, and cell apoptosis. All these detrimental outcomes were attenuated by increased expression of NDUFV1 in kidneys. Moreover, knockdown of Ndufv1 aggravated cell insults induced by H2 O2 in TCMK-1 cells, which further confirmed the renoprotective roles of NDUFV1. Mechanistically, NDUFV1 improved the integrity and function of mitochondria, leading to reduced oxidative stress and cell apoptosis. Overall, our data indicate that NDUFV1 has an ability to maintain mitochondrial homeostasis in AKI, suggesting therapies by targeting mitochondria are useful approaches for dealing with mitochondrial dysfunction associated renal diseases such as AKI.

Mitochondrial respiratory chain disorders (MRC) are amongst the most common group of inborn errors of metabolism. MRC, of which complex I deficiency accounts for approximately a quarter, are very diverse, causing a wide range of clinical problems and can be difficult to diagnose. We report an illustrative MRC case whose diagnosis was elusive. Clinical signs included failure to thrive caused by recurrent vomiting, hypotonia and progressive loss of motor milestones. Initial brain imaging suggested Leigh syndrome but without expected diffusion restriction. Muscle respiratory chain enzymology was unremarkable. Whole-genome sequencing identified a maternally inherited NDUFV1 missense variant [NM_007103.4 (NDUFV1):c.1157G > A; p.(Arg386His)] and a paternally inherited synonymous variant [NM_007103.4 (NDUFV1):c.1080G > A; (p.Ser360=)]. RNA sequencing demonstrated aberrant splicing. This case emphasizes the diagnostic odyssey of a patient in whom a confirmed diagnosis was elusive because of atypical features and normal muscle respiratory chain enzyme (RCE) activities, along with a synonymous variant, which are often filtered out from genomic analyses. It also illustrates the following points: (1) complete resolution of magnetic resonance imaging changes may be part of the picture in mitochondrial disease; (2) analysis for synonymous variants is important for undiagnosed patients; and (3) RNA-seq is a powerful tool to demonstrate pathogenicity of putative splicing variants.

Mitochondrial complex I deficiency (MCID) is the most common biochemical defect identified in childhood with mitochondrial diseases, mainly including Leigh syndrome, encephalopathy, macrocephaly with progressive leukodystrophy, hypertrophic cardiomyopathy and myopathy.
To identify genetic cause in a patient with early onset autosomal recessive MCID.
Trio whole-exome sequencing was performed and phenotype-related data analyses were conducted. All candidate mutations were confirmed by Sanger sequencing.
Here we report a child of Leigh syndrome presented with global developmental delay, progressive muscular hypotonia and myocardial damage. A missense mutation c.118C > T (p.Arg40Trp) and a previously reported mutation c.1157G > A (p.Arg386His) in NDUFV1 have been identified as compound heterozygous in the patient. The mutation p.Arg386His is closely associated with the impairment of 4Fe-4S domain and this mutation has been reported pathogenic. The c.118C > T mutation has not been reported in ClinVar and HGMD database. In silico protein analyses showed that p.Arg40 is highly conserved in a wide range of species, and the amino acid substitution p.Trp40 largely decreases the stability of NDUFV1. In addition, the mutation has not been detected in the Asian populations and it was predicted to be deleterious by numerous prediction tools.
This research expands the mutation spectrum of NDUFV1 and substantially provides an early and accurate diagnosis basis of MCID, which would benefit subsequently effective genetic counseling and prenatal diagnosis for future reproduction of the family.

The FoxQ1 is an oncogenic transcription factor that is overexpressed in basal-like and luminal-type human breast cancers when compared to the normal mammary tissue. The FoxQ1 is implicated in mammary tumor progression. However, the mechanism by which FoxQ1 promotes mammary tumorigenesis is not fully understood. In this study, we present experimental evidence for a novel function of FoxQ1 in the regulation of complex I activity of the electron transport chain. The RNA-seq data from FoxQ1 overexpressing basal-like SUM159 cells revealed a statistically significant increase in the expression of complex I subunits NDUFS1 and NDUFS2 when compared to the empty vector (EV) transfected control cells. Consistent with these results, the basal and ATP-linked oxygen consumption rates were significantly increased by FoxQ1 overexpression in SUM159 and luminal-type MCF-7 cells. The FoxQ1 overexpression in both cell lines resulted in increased intracellular levels of pyruvate, lactate, and ATP that was associated with overexpression of pyruvate dehydrogenase and pyruvate carboxylase proteins. Activity and assembly of complex I were significantly enhanced by FoxQ1 overexpression in SUM159 and MCF-7 cells that correlated with increased mRNA and/or protein levels of complex I subunits NDUFS1, NDUFS2, NDUFV1, and NDUFV2. The chromatin immunoprecipitation assay revealed the recruitment of FoxQ1 at the promoters of both NDUFS1 and NDUFV1. The cell proliferation of SUM159 and MCF-7 cells was increased significantly by overexpression of NDUFS1 as well as NDUFV1 proteins. In conclusion, we propose that increased complex I-linked oxidative phosphorylation is partly responsible for oncogenic role of FoxQ1 at least in human breast cancer cells.

Mitochondrial homeostasis plays essential role for the proper functioning of the kidney. NADH-ubiquinone oxidoreductase core subunit V1 (NDUFV1) is an enzyme in the complex I of electron transport chain (ETC) in mitochondria. In the present study, we examined the effects of NDUFV1 on renal function in unilateral ureteral obstruction (UUO) model mice. Our data showed that increased expression of NDUFV1 improves kidney function as evidenced by the decreases in blood urea nitrogen and serum creatinine in UUO mice. Moreover, NDUFV1 also maintains renal structures and alleviates renal fibrosis induced by UUO surgery. Mechanistically, NDUFV1 mitigates the increased oxidative stress in the kidney in UUO model mice. Meanwhile, increased expression of NDUFV1 in the kidney improves the integrity of the complex I and potentiates the complex I activity. Overall, these results indicate that the ETC complex I plays a beneficial role against renal dysfunction induced by acute kidney injury such as UUO. Therefore, NDUFV1 might be a druggable target for developing agents for dealing with disabled mitochondria-associated renal diseases.

OBJECTIVE: To investigate the pathogenic gene in a child with optic atrophy and analyze the influence of this gene mutation on protein structure.
OBJECTIVE: We collected the clinical record of the 13-year-old girl and her relatives. The child received examinations of the visual acuity, visual field, fundus, OCT, visual-evoked potential (VEP) and the nerve system, underwent brain MRI and was followed up for 1 year. Genomic DNA was extracted from the peripheral blood of the child and her parents for next-generation sequencing of the whole exon. The pathogenic gene mutation was identified and the resultant changes in the protein structure was analyzed.
OBJECTIVE: The patient presented with impaired vision and optic nerve atrophy in both eyes with low amplitude of VEP, but did not show dystonia or pyramidal tract symptom. Brain MRI detected no leukodystrophy. Genetic analysis suggested a heterozygous c.53_54delTG mutation in exon 1 in the NDUFV1 gene of complex I, which caused a frameshift starting with the codon valine 18, thus changing the amino acid to an Alanine residue and creating a premature stop codon at position 20 of the new reading frame (p.Val18AlafsX20). A heterozygous for c.1162+4A>C: IVS8 + 4A>C in intron 8 was also found. Protein structure analysis showed the missing of important structure of NDUFV1 subunit in complex I.
OBJECTIVE: We identified a novel NDUFV1 mutation in a child with optic nerve atrophy. This finding may provide further insight into the genotype-phenotype correlations for NDUFV1 gene.

Leigh syndrome (LS) is most frequently characterized by the presence of focal, bilateral, and symmetric brain lesions Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare condition, characterized by progressive pyramidal, cerebellar, and dorsal column dysfunction. We describe a case with infantile-onset neurodegeneration, psychomotor retardation, irritability, hypotonia, and nystagmus. Brain MRI demonstrated signal abnormalities in the deep cerebral white matter, corticospinal and dorsal column tracts, and pyramids, which resemble the MRI pattern of a severe form of LBSL, and involvement of basal ganglia and thalamus that resemble the radiological features of LS. We identified biallelic loss-of-function mutations, one novel (c.756delC, p.Thr253Glnfs*44) and another reported (c.1156C > T, p.Arg386Cys), in NDUFV1 (NADH:Ubiquinone Oxidoreductase Core Subunit V1) by exome sequencing. Biochemical and functional analyses revealed lactic acidosis, complex I (CI) assembly and enzyme deficiency, and a loss of NDUFV1 protein. Complementation assays restored the NDUFV1 protein, CI assembly, and CI enzyme levels. The clinical and radiological features of this case are compatible with the phenotype of LS and LBSL associated with NDUFV1 mutations.

Aims: REDOX signaling from reactive oxygen species (ROS) generated by the mitochondria (mitochondrial reactive oxygen species [mtROS]) has been implicated in cancer growth and survival. Here, we investigated the effect of 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione (AOL), a recently characterized member of the new class of mtROS suppressors (S1QELs), on human lung adenocarcinoma proteome reprogramming, bioenergetics, and growth. Results: AOL reduced steady-state cellular ROS levels in human lung cancer cells without altering the catalytic activity of complex I. AOL treatment induced dose-dependent inhibition of lung cancer cell proliferation and triggered a reduction in tumor growth in vivo. Molecular investigations demonstrated that AOL reprogrammed the proteome of human lung cancer cells. In particular, AOL suppressed the determinants of the Warburg effect and increased the expression of the complex I subunit NDUFV1 which was also identified as AOL binding site using molecular modeling computer simulations. Comparison of the molecular changes induced by AOL and MitoTEMPO, an mtROS scavenger that is not an S1QEL, identified a core component of 217 proteins commonly altered by the two treatments, as well as drug-specific targets. Innovation: This study provides proof-of-concept data on the anticancer effect of AOL on mouse orthotopic human lung tumors. A unique dataset on proteomic reprogramming by AOL and MitoTEMPO is also provided. Lastly, our study revealed the repression of NDUFV1 by S1QEL AOL. Conclusion: Our findings demonstrate the preclinical anticancer properties of S1QEL AOL and delineate its mode of action on REDOX and cancer signaling.

Leigh syndrome is a subacute necrotising encephalomyopathy proven by post-mortem analysis of brain tissue showing spongiform lesions with vacuolation of the neuropil followed by demyelination, gliosis and capillary proliferation caused by mutations in one of over 75 different genes, including nuclear- and mitochondrial-encoded genes, most of which are associated with mitochondrial respiratory chain function. In this study, we report a patient with suspected Leigh syndrome presenting with seizures, ptosis, scoliosis, dystonia, symmetrical putaminal abnormalities and a lactate peak on brain MRS, but showing normal MRC enzymology in muscle and liver, thereby complicating the diagnosis. Whole exome sequencing uncovered compound heterozygous mutations in NADH dehydrogenase (ubiquinone) flavoprotein 1 gene (NDUFV1), c.1162+4A>C (NM_007103.3), resulting in skipping of exon 8, and c.640G>A, causing the amino acid substitution p.Glu214Lys, both of which have previously been reported in a patient with complex I deficiency. Patient fibroblasts showed a significant reduction in NDUFV1 protein expression, decreased complex CI and complex IV assembly and consequential reductions in the enzymatic activities of both complexes by 38% and 67%, respectively. The pathogenic effect of these variations was further confirmed by immunoblot analysis of subunits for MRC enzyme complexes in patient muscle, liver and fibroblast where we observed 90%, 60% and 95% reduction in complex CI, respectively. Together these studies highlight the importance of a comprehensive, multipronged approach to the laboratory evaluation of patients with suspected Leigh syndrome.