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This study investigates the cellular origins and metabolic fate of malonate, a molecule traditionally characterized as an inhibitor of mitochondrial complex II. Using a novel stable isotope tracing approach combined with mass spectrometry, the researchers demonstrate that malonate serves as a carbon source for mitochondrial fatty acid synthesis (mtFAS), and that this incorporation occurs independently of the enzyme ACSF3, which was previously assumed to be the primary mediator of this process. Additionally, the study provides evidence that the enzyme ACC1 synthesizes malonate from glucose and is required for optimal mtFAS activity, with downstream consequences for oxidative phosphorylation.
Why it matters
Understanding how cells regulate mitochondrial metabolism through endogenous malonate synthesis may open new avenues for research into metabolic diseases, cancer biology, and conditions involving mitochondrial dysfunction, where oxidative phosphorylation is impaired.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Malonate is often described as an endogenous inhibitor of complex II of the electron transport chain. However, the cellular source of malonate is unclear, and current knowledge concerning its metabolism is limited to the action of a single enzyme, Acyl-CoA Synthetase Family Member 3 (ACSF3), which converts malonate to malonyl-CoA in the mitochondrial matrix. One potential route of malonate metabolism downstream of ACSF3 is its consumption by the mitochondrial fatty acid synthesis (mtFAS) pathway. However, studies examining the link between ACSF3 and mtFAS have yielded conflicting results. We developed a novel mass spectrometry approach to perform stable isotope tracing into products of mtFAS, and found that while malonate is in fact a carbon source for mtFAS, ACSF3 is not required for malonate incorporation into mtFAS products. Using this method to trace other nutrients into mtFAS, we also found evidence of acetyl-CoA carboxylase 1 (ACC1)-dependent malonate synthesis from glucose. We further show that ACC1 is required for optimal mtFAS activity, with downstream effects on oxidative phosphorylation. Together these findings establish the malonate as a regulated endogenous intermediate that supports mtFAS activity and mitochondrial oxidative function.
Source: Cells Engage Endogenous Malonate Synthesis to Drive Mitochondrial Metabolism