TIM22 Complex-NADH dehydrogenase crosstalk maintains mitochondrial health by modulating cell death

Programmed cell death is essential for organismal development. When dysregulated, it leads to neurodegenerative diseases and cancer. Although apoptotic pathways are well studied, the role of mitochondrial import translocases in regulating cell death remains unclear. Our study reveals a unique apoptotic pathway controlled by the TIM22 complex, an inner mitochondrial membrane translocase. This pathway involves a multiprotein complex formed by Tim22 and Nde1, a part of the respiratory electron transport chain. Under stress, the cytosol-exposed Nde1 isoform, a pro-apoptotic factor, is stabilised by the TIM22 complex, which includes the Tim18 subunit and Tim22’s transmembrane segments. Notably, impairing the TIM22 complex and deleting Nde1 suppresses apoptosis and restores mitochondrial health. Beyond its role in import, our study uncovers a moonlighting function of the TIM22 complex in regulating mitochondria-dependent apoptotic cell death.