Mitochondria harbor respiratory complexes that perform oxidative phosphorylation. Complex I is the first enzyme of the respiratory chain that oxidizes NADH. A dysfunction in complex I can result in higher cellular levels of NADH, which in turn strengthens the interaction between apoptosis-inducing factor 1 (AIFM1) and Mitochondrial intermembrane space import and assembly protein 40 (MIA40) in the mitochondrial intermembrane space. We investigated whether MIA40 modulates the activity of AIFM1 upon increased NADH/NAD+ balance. We found that in model cells characterized by an increase in NADH the AIFM1-MIA40 interaction is strengthened and these cells demonstrate resistance to AIFM1-induced cell death. Either silencing of MIA40, rescue of complex I, or depletion of NADH through the expression of yeast NADH-ubiquinone oxidoreductase-2 sensitized NDUFA13-KO cells to AIFM1-induced cell death. These findings indicate that the complex of MIA40 and AIFM1 suppresses AIFM1-induced cell death in a NADH-dependent manner. This study identifies an effector complex involved in regulating the programmed cell death that accommodates the metabolic changes in the cell and provides a molecular explanation for AIFM1-mediated chemoresistance of cancer cells.

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Journal Article

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Mussulini BHM, Maruszczak KK, Draczkowski P, Borrero-Landazabal MA, Ayyamperumal S, Wnorowski A, Wasilewski M, Chacinska A

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