Novel MTND1 mutations cause isolated exercise intolerance, complex I deficiency and increased assembly factor expression

Abstract

Complex I (CI) is the largest of the five multi-subunit complexes constituting the human oxidative phosphorylation (OXPHOS) system. Seven of its catalytic core subunits are encoded by mitochondrial DNA (ND (NADH dehydrogenase)1–6, ND4L (NADH dehydrogenase subunit 4L)), with mutations in all seven having been reported in association with isolated CI deficiency. We investigated two unrelated adult patients presenting with marked exercise intolerance, persistent lactic acidaemia and severe muscle-restricted isolated CI deficiency associated with sub-sarcolemmal mitochondrial accumulation. Screening of the mitochondrial genome detected novel mutations in the MTND1 (NADH dehydrogenase subunit 1) gene, encoding subunit of CI [Patient 1, m.3365T>C predicting p.(Leu20Pro); Patient 2, m.4175G>A predicting p.(Trp290*)] at high levels of mitochondrial DNA heteroplasmy in skeletal muscle. We evaluated the effect of these novel MTND1 mutations on complex assembly showing that CI assembly, although markedly reduced, was viable in the absence of detectable ND1 signal. Real-time PCR and Western blotting showed overexpression of different CI assembly factor transcripts and proteins in patient tissue. Together, our data indicate that the mechanism underlying the expression of the biochemical defect may involve a compensatory response to the novel MTND1 gene mutations, promoting assembly factor up-regulation and stabilization of respiratory chain super-complexes, resulting in partial rescue of the clinical phenotype.

A novel immunofluorescent assay to investigate oxidative phosphorylation deficiency in mitochondrial myopathy: understanding mechanisms and improving diagnosis

“…We have shown that specific genotypes present similar patterns of mitochondrial deficiency, consistent with the known biochemical defect. For example, patients harbouring compound heterozygous LRPPRC mutations showed isolated COX deficiency 44 45 46 , whilst the patient carrying the m.4175G > A MT-ND1 mutation showed isolated complex I deficiency 47 48 49 50 .…”

Benign mitochondrial myopathy with exercise intolerance in a large multigeneration family due to a homoplasmic m.3250T>C mutation in MTTL1

“…Isolated mitochondrial myopathies have characteristically presented as sporadic cases due to heteroplasmic mutations in protein-coding genes of mtDNA [14,15] in mt-tRNA genes [5][6][7][8], and recently also with mutations in nuclear genes causing autosomal recessive disorders such as ISCU and FDX1L [16,17]. In the era of next-generation sequencing, it is important to realize that many mtDNA mutations are somatic and can only be detected in DNA isolated from muscle [14,[18][19][20][21].…”

Distinct role of Arabidopsis mitochondrial P-type pentatricopeptide repeat protein-modulating editing protein, PPME, in nad1 RNA editing

“…Recently, a 4175G>A mutation in human MTND1 , a homolog of plant NAD1 , has been identified that causes defective complex I assembly. 60 It converts the codon from being translated as Trp to a stop codon, which halts translation and may cause complex I disassembly. These authors have suggested that the conserved Trp residue plays an important role in human mitochondrial complex I functionality.…”