CHCHD4, also known as MIA40, is a central component of the mitochondrial disulfide relay system (DRS) [2,3,5]. It is essential and evolutionarily conserved, playing a crucial role in the import and oxidative folding of proteins in the mitochondrial intermembrane space. This process is vital for mitochondrial functions such as respiration, bioenergetic and biosynthetic pathways, as well as cellular signalling and transcriptional networks. Thus, CHCHD4 is key for maintaining normal cellular physiology, and its dysfunction is associated with various diseases including mitochondrial disease and cancer [2].

In cancer, integrated analysis of genome-wide Nuclease technology and SILAC proteomic screening data shows that CHCHD4 regulates a shortlist of common essential genes/proteins, including subunits of complex I (DRS substrates) and those involved in key metabolic pathways, which are essential for tumour cell growth [1]. In skeletal muscle, exercise-induced down-regulation of CHCHD4 decreases the import of TRIAP1 into mitochondria, promoting the formation of oxidative slow-twitch fibers [4]. In hypoxic pulmonary hypertension, elevation of CHCHD4 alleviates vascular remodeling and pulmonary artery resistance by orchestrating mitochondrial oxidative phosphorylation [6]. In lung adenocarcinoma, the USF1-CHCHD4 axis promotes tumour progression, potentially via activating the MYC pathway [7].

In conclusion, CHCHD4 is essential for normal mitochondrial function and cellular physiology. Model-based research, especially in the context of cancer, skeletal muscle adaptation, hypoxic pulmonary hypertension, and lung adenocarcinoma, has revealed its significance in various biological processes and disease conditions. These findings enhance our understanding of the molecular mechanisms underlying these diseases and may offer potential therapeutic targets.