CHCHD4, also known as MIA40, is a central component of the mitochondrial disulfide relay system (DRS) within the mitochondrial intermembrane space (IMS) [2,5]. It is evolutionarily conserved and essential for the proper functioning of mitochondria, which are pivotal for normal cellular physiology, participating in processes like respiration, bioenergetics, and cellular signaling [2]. The DRS, of which CHCHD4 is a key part, is involved in the oxidation-dependent import of nuclear-encoded mitochondrial proteins into the IMS [2,5].

In cancer research, CHCHD4 has been shown to be a critical regulator of tumour cell growth. Genome-wide Nuclease technology and SILAC proteomic screening data analysis identified a set of common essential genes/proteins regulated by CHCHD4, including subunits of complex I and those involved in key metabolic pathways, highlighting its importance in tumour cell growth [1]. In skeletal muscle, exercise-induced downregulation of CHCHD4 decreases the import of TRIAP1 into mitochondria, promoting the formation of oxidative slow-twitch fibers, which are beneficial for metabolism [3]. In hypoxic pulmonary hypertension, elevation of CHCHD4 orchestrates mitochondrial oxidative phosphorylation and antagonizes abnormal pulmonary artery smooth muscle cell growth and migration, suggesting its potential as a therapeutic target [4]. In auditory neuropathy spectrum disorder, an AIFM1 variant impairs the interaction between AIF and CHCHD4, leading to mitochondrial dysfunction and caspase-independent apoptosis [6].

In summary, CHCHD4 is crucial for mitochondrial function and protein import. Model-based research, especially in disease-related studies such as cancer, muscle adaptation, pulmonary hypertension, and auditory neuropathy, has revealed its diverse roles in regulating cellular processes. These findings contribute to understanding the mechanisms of these diseases and may offer potential therapeutic strategies targeting CHCHD4.