Ndufs4, encoding the NADH:ubiquinone oxidoreductase subunit S4, is a subunit of mitochondrial complex I. Mitochondrial complex I is crucial in oxidative phosphorylation, the process generating cellular energy (ATP). Dysfunction in this complex is linked to various disorders. Ndufs4-related research often uses knockout mouse models to understand its role in disease mechanisms [1].

In Leigh syndrome, mutations in Ndufs4 gene can lead to 'mitochondrial complex I deficiency, nuclear type 1' and Leigh syndrome in paediatric patients. Ndufs4 knockout mouse models help study the pathomechanism of Leigh syndrome [1]. In diabetic kidney disease, podocyte-specific overexpression of Ndufs4 in mice improves cristae morphology, mitochondrial dynamics, and albuminuria, indicating its role in regulating cristae remodeling and mitochondrial function in kidney podocytes [2,5]. Ndufs4 ablation in mouse hippocampus decreases mitochondrial respiration and synaptophysin expression, suggesting its involvement in neuroplasticity [3]. Also, Ndufs4 deficiency in mice accelerates permanent low-frequency threshold shifts after moderate noise exposure, showing its role in cochlear function [4]. Myeloid-specific deletion of Ndufs4 in mice reproduces a pro-inflammatory metabolic profile in macrophages, affecting post-myocardial infarction recovery [6].

In conclusion, Ndufs4 is essential for mitochondrial complex I function and thus for energy production. Studies using Ndufs4 knockout mouse models have provided insights into its role in diseases such as Leigh syndrome, diabetic kidney disease, neurodegenerative-related processes, cochlear function, and post-myocardial infarction recovery, highlighting its significance in understanding disease mechanisms and potential therapeutic targets.