An NADH-controlled gatekeeper of ATP synthase

Abstract

ATP fuels crucial cellular processes and is obtained mostly by oxidative phosphorylation (OXPHOS) at the inner mitochondrial membrane. While significant progress has been made in mechanistic understanding of ATP production, critical aspects surrounding its substrate supply logistics are poorly understood. We identify an interaction between mitochondrial apoptosis-inducing factor 1 (AIFM1) and adenylate kinase 2 (AK2) as gatekeeper of ATP synthase. This interaction is NADH-dependent and influenced by glycolysis, linking it to the cells metabolic state. Genetic interference with AIFM1/AK2 association impedes the ability of Caenorhabditis elegans animals to handle altered metabolic rates and nutrient availability. Together, the results imply AIFM1 as a cellular NADH sensor, placing AK2 next to the OXPHOS complexes for local ADP regeneration as the substrate for ATP synthesis. This metabolic signal relay balances ATP synthase substrate supply against ATP conservation, enabling cells to adapt to fluctuating energy availability, with possible implications for AIFM1-related mitochondrial diseases. HighlightsO_LIDiscovery of AIFM1/AK2 interaction as a gatekeeper of mitochondrial ATP synthase C_LIO_LIAIFM1/AK2 interaction is NADH-dependent and linked to the cells metabolic state C_LIO_LIDisrupting AIFM1/AK2 impairs metabolic adaptation in Caenorhabditis elegans C_LIO_LIAIFM1 as NADH sensor, influencing ATP synthesis with mitochondrial disease implications C_LI