Ndufaf5-KO Mouse

Ndufaf5, also known as C20orf7, is a mitochondrial complex I (CI) assembly factor. It belongs to the family of seven-β-strand S-adenosylmethionine-dependent methyltransferases and catalyzes the introduction of a hydroxyl group into Arg-73 in the NDUFS7 subunit of human complex I at an early stage in the assembly of complex I [2,4]. Mitochondrial complex I is crucial for the mitochondrial respiratory chain, thus Ndufaf5 is of great importance in maintaining normal mitochondrial function.

Mutations in Ndufaf5 have been linked to Leigh syndrome, a severe neurological disorder. In a study of patients with biallelic Ndufaf5 mutations, the onset age had a bimodal distribution. The early-onset group presented with psychomotor delay, seizure, respiratory failure, and hyponatremia, while the late-onset group had normal development initially but then showed slowly progressive dystonia [1]. Additionally, prenatal manifestations such as brain cysts, corpus callosal malformations, non-immune hydrops fetalis, and growth restriction have been associated with biallelic Ndufaf5 variants [3]. A case report also showed that compound heterozygous mutations in Ndufaf5 could lead to early infant death due to Leigh syndrome [5]. In the Dictyostelium model, disruption of Ndufaf5 leads to CI deficiency, growth and development defects, and an increase in autophagy, suggesting novel AMPK-independent pathways responsible for Ndufaf5 cytopathology [2].

In conclusion, Ndufaf5 is essential for the assembly of mitochondrial complex I. Studies, including those using genetic models like the Dictyostelium model, have revealed its role in normal development and disease, particularly in Leigh syndrome. Understanding Ndufaf5 provides insights into the mechanisms of mitochondrial respiratory chain-related disorders and potential therapeutic strategies.