Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Abstract

Mitochondria are small cellular constituents that generate cellular energy (ATP) by oxidative phosphorylation (OXPHOS). Dysfunction of these organelles is linked to a heterogeneous group of multisystemic disorders, including diabetes, cancer, ageing-related pathologies and rare mitochondrial diseases (MDs). With respect to the latter, mutations in subunit-encoding genes and assembly factors of the first OXPHOS complex (CI) induce isolated CI deficiency and Leigh syndrome (LS). This syndrome is an early-onset, often fatal, encephalopathy with a variable clinical presentation and poor prognosis due to the lack of effective intervention strategies. Mutations in the nuclear DNA (nDNA)-encoded NDUFS4 gene, encoding the NADH: Ubiquinone oxidoreductase subunit S4 (NDUFS4) of CI induce “mitochondrial complex I deficiency, nuclear type 1” (MC1DN1) and LS in pediatric patients. A variety of (tissue-specific) Ndufs4 knockout mouse models were developed to study the LS pathomechanism and intervention testing. Here, we review and discuss the role of CI and NDUFS4 mutations in human MD, and review how the analysis of Ndufs4 knockout mouse models has generated new insights into the MC1ND1/LS pathomechanism and its therapeutic targeting.

Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice

“…We would speculate that our results are most comparable to the widely used Ndufs4 hemizygous mice, which show a normal body weight, normal longevity, and a relative lack of phenotype 42 . We did not see a statistically significant decrease in complex I activity in our mice.…”

“…By contrast, NADH:ubiquinone oxidoreductase subunit S4 ( Ndufs4 ) encodes an 18 kDa accessory subunit of complex I that does not directly participate in electron transfer. Ndufs4 is instead thought to be an assembly factor that interacts with subunits of the matrix-facing N-module and the membrane associated Q-module of complex I which contributes to the stability of the fully assembled complex I 42 , (Fig. S1 ).…”

“…There is an extensive literature on mice with deletion and mutation of the complex I subunit Ndufs4 which is a model used primarily for studying primary mitochondrial disease 42 . There are several different versions of the Ndufs4 deficient mouse that have been reported, although the majority make use of an exon-2 floxed allele for tissue specific deletion or a null allele that was generated with deletion of exon two resulting in a frame shift 41 .…”

“…Contrasting these paradoxical life extending results, vertebrate models with genetically altered expression of ETC components have generally demonstrated detrimental effects on lifespan and healthspan with few exceptions 35 – 40 . Most studies on the effect of genetic alteration of complex I in mice have used mutation or deletion of the accessory subunit gene Ndufs4 which is associated with phenotypes resembling human mitochondrial diseases such as Leigh syndrome and Leber Hereditary Optic Neuropathy 41 , 42 . Notably, loss of Ndufs4 results in approximately 50% loss of mitochondrial complex I function 41 .…”

Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective

“…The constitutive Ndufs4 KO mouse model appeared healthy at birth, but starting from 40 days of age, it develops progressive encephalopathy, growth retardation, ataxia, hypotonia, and lethargy, ultimately leading to death at ~7 weeks. Notably, CI activity was reduced, recapitulating the pathophysiology observed in LS patients [110].…”