Functional crosstalk between the carrier translocase machinery and YME1 complex maintains mitochondrial proteostasis and integrity

The TIM22 pathway cargos are essential for sustaining mitochondrial proteostasis as an excess of these proteins leads to proteostatic stress and cell death. Yme1 is an inner membrane metalloprotease that regulates proteostasis with its chaperone-like and proteolytic activities. Although the mitochondrial translocase and protease machinery are critical for organelle health, the functional link between these complexes remains unexplored. The present study unravels a novel genetic connection between the TIM22 complex and YME1 machinery in maintaining mitochondrial proteostasis and quality control. Our genetic analyses indicate that impairment in the TIM22 complex rescues the respiratory growth defects of cells without Yme1. We further demonstrate that Yme1 is essential for the stability of the TIM22 complex and regulating the proteostasis of the TIM22 pathway substrates. Moreover, impairment in the TIM22 complex suppressed the mitochondrial structural and functional defects of Yme1 devoid cells. Notably, the functional dependence between the TIM22 and YME1 complexes remains functionally conserved from yeast to humans. Our findings suggest that excessive levels of the TIM22 pathway substrates could be one of the reasons for the respiratory growth defects of cells lacking Yme1 and compromising the TIM22 complex compensate for the imbalance in mitochondrial proteostasis caused by loss of Yme1.