Cells Engage Endogenous Malonate Synthesis to Drive Mitochondrial Metabolism

Area of Science:

• Biochemistry
• Cellular Metabolism
• Mitochondrial Function

Background:

• Malonate is an endogenous inhibitor of electron transport chain complex II.
• Its cellular source and metabolism are poorly understood, with Acyl-CoA Synthetase Family Member 3 (ACSF3) being the only known enzyme involved in its mitochondrial conversion.
• Previous studies on the link between ACSF3 and mitochondrial fatty acid synthesis (mtFAS) have shown conflicting results.

Purpose of the Study:

• To investigate the role of malonate in mtFAS.
• To clarify the metabolic pathway of malonate, particularly its relationship with ACSF3 and mtFAS.
• To identify the cellular source of malonate and its contribution to mitochondrial function.

Main Methods:

• Development of a novel mass spectrometry approach for stable isotope tracing into mtFAS products.
• Utilizing this method to trace malonate and other nutrients into mtFAS.
• Investigating the role of ACSF3 and ACC1 in malonate metabolism and mtFAS activity.

Main Results:

• Malonate serves as a carbon source for mtFAS, independent of ACSF3.
• Evidence of acetyl-CoA carboxylase 1 (ACC1)-dependent malonate synthesis from glucose was found.
• ACC1 is essential for optimal mtFAS activity and influences oxidative phosphorylation.

Conclusions:

• Malonate is a regulated endogenous intermediate supporting mtFAS activity.
• ACC1 plays a crucial role in malonate synthesis and subsequent mtFAS regulation.
• These findings highlight malonate's importance in mitochondrial oxidative function.