An NADH-controlled gatekeeper of ATP synthase

Area of Science:

• Mitochondrial biology
• Cellular metabolism
• Biochemistry

Background:

• Adenosine triphosphate (ATP) is essential for cellular functions, primarily generated via oxidative phosphorylation (OXPHOS) at the inner mitochondrial membrane.
• The precise mechanisms governing substrate supply for ATP synthesis remain incompletely understood.
• Mitochondrial dysfunction is implicated in various diseases, highlighting the need to study ATP production regulation.

Purpose of the Study:

• To elucidate the regulatory mechanisms of ATP synthesis, focusing on substrate supply logistics.
• To identify key proteins involved in controlling ATP production in response to cellular metabolic states.
• To investigate the role of mitochondrial apoptosis-inducing factor 1 (AIFM1) and adenylate kinase 2 (AK2) in ATP homeostasis.

Main Methods:

• Protein-protein interaction studies to identify the AIFM1-AK2 complex.
• NADH dependency assays to assess the influence of cellular redox state.
• Glycolysis modulation experiments to link mitochondrial ATP production to cellular metabolic status.
• Genetic manipulation in Caenorhabditis elegans to study in vivo functional consequences.

Main Results:

• Identified a novel interaction between AIFM1 and AK2, acting as a gatekeeper for ATP synthase.
• Demonstrated that the AIFM1-AK2 interaction is dependent on NADH levels and influenced by glycolysis.
• Showed that disruption of the AIFM1-AK2 association impairs the ability of C. elegans to adapt to metabolic stress and nutrient fluctuations.

Conclusions:

• AIFM1 functions as a cellular NADH sensor, regulating AK2 localization near OXPHOS complexes for local ADP regeneration.
• This AIFM1-AK2 mediated signal relay balances ATP synthase substrate supply with ATP conservation, facilitating cellular adaptation to energy fluctuations.
• The findings have potential implications for understanding and treating AIFM1-related mitochondrial diseases.