Journal
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS
Volume 1863, Issue 3, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbabio.2022.148532
Keywords
Mitochondria; Bioenergetics; MDH2; Oxaloacetate; Malate aspartate shuttle; NADH redox homeostasis; Respiratory chain supercomplexes; Respirasomes
Categories
Funding
- AFM-Telethon Trampoline [AFM-19613]
- INCa-Canceropole GSO [2020-EM27]
- ANR [ANR16-CE14-0013, MetaboY HUB-ANR-11-INBS-0010]
- INSERM
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The mitochondrial respiratory chain plays a crucial role in metabolic processes by regenerating NAD+ and ATP. Recent studies have shown that complex I can form functional entities called respirasomes, which facilitate NADH oxidation. However, findings demonstrate that complex II is preferred for electron transfer in heart and liver mitochondria. This unexpected result suggests a new regulatory mechanism for mitochondrial respiration in response to NADH/NAD+ redox stress.
The mitochondrial respiratory chain (RC) enables many metabolic processes by regenerating both mitochondrial and cytosolic NAD+ and ATP. The oxidation by the RC of the NADH metabolically produced in the cytosol involves redox shuttles as the malate-aspartate shuttle (MAS) and is of paramount importance for cell fate. However, the specific metabolic regulations allowing mitochondrial respiration to prioritize NADH oxidation in response to high NADH/NAD+ redox stress have not been elucidated. The recent discovery that complex I (NADH dehydrogenase), and not complex II (Succinate dehydrogenase), can assemble with other respiratory chain complexes to form functional entities called respirasomes, led to the assumption that this supramolecular organization would favour NADH oxidation. Unexpectedly, characterization of heart and liver mitochondria demonstrates that the RC systematically favours electrons provided by the 'respirasome free' complex II. Our results demonstrate that the preferential succinate driven respiration is tightly controlled by OAA levels, and that OAA feedback inhibition of complex II rewires RC fuelling increasing NADH oxidation capacity. This new regulatory mechanism synergistically increases RC's NADH oxidative capacity and rewires MDH2 driven anaplerosis of the TCA, preventing malate production from succinate to favour oxidation of cytosolic malate. This regulatory mechanism synergistically adjusts RC and TCA fuelling in response to extramitochondrial malate produced by the MAS.
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