TIMM50, also called TIM50, is an essential component of the TIM23 complex in the mitochondrial inner membrane. It is crucial for importing cytosolic proteins with a mitochondrial targeting presequence into the mitochondrial inner compartment, thus playing a vital role in mitochondrial membrane transportation and influencing key aspects of mitochondrial physiology, such as mitochondrial morphology, OXPHOS assembly, and respiratory capacity [1,2,3].

Mutations in TIMM50 have been found to cause severe mitochondrial dysfunction. In a patient with West syndrome, optic atrophy, neutropenia, cardiomyopathy, Leigh syndrome, and persistent 3-MGA-uria, compound heterozygous mutations in TIMM50 led to reduced TIMM50 protein, severe morphological and ultrastructural mitochondrial defects, decreased levels of OXPHOS complexes and supercomplexes, and reduced maximum respiratory capacity [1]. In an infant patient with rapidly progressive, severe encephalopathy, compound heterozygous pathogenic mutations in TIMM50 caused low levels of TIMM50 and other TIM23 complex components, lower mitochondrial membrane potential, impaired protein import, decreased respiration, and increased ROS production [2]. In a mitochondrial disease patient homozygous for a novel TIMM50 variant, the pathogenic variant reduced the levels and activity of the endogenous TIM23 complex, resulting in a combined OXPHOS defect and changes to mitochondrial ultrastructure [3]. In human fibroblasts and mouse neurons with TIMM50 deficiency, there were declined respiration rates, reduced cellular ATP levels, and defective mitochondrial trafficking in neuronal processes, along with increased electrical activity in mouse neuronal cells, potentially contributing to the patients' epileptic phenotype [4,5]. Downregulation of TIMM50 was also found to be sufficient for triggering senescence through impaired mitochondrial function, while overexpression significantly slowed senescence onset [6].

In conclusion, TIMM50 is essential for mitochondrial function, as demonstrated by various loss-of-function studies. Mutations or downregulation of TIMM50 are associated with severe mitochondrial dysfunction, neurological phenotypes, and cellular senescence. These findings highlight the importance of TIMM50 in maintaining normal mitochondrial function and its potential implications in related diseases.