Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl‐CoA.

Changes in mitochondrial morphology are associated with nutrient utilization, but the precise causalities and the underlying mechanisms remain unknown. Here, using cellular models representing a wide variety of mitochondrial shapes, we show a strong linear correlation between mitochondrial fragmentation and increased fatty acid oxidation (FAO) rates. Forced mitochondrial elongation following MFN2 over‐expression or DRP1 depletion diminishes FAO, while forced fragmentation upon knockdown or knockout of MFN2 augments FAO as evident from respirometry and metabolic tracing. Remarkably, the genetic induction of fragmentation phenocopies distinct cell type‐specific biological functions of enhanced FAO. These include stimulation of gluconeogenesis in hepatocytes, induction of insulin secretion in islet β‐cells exposed to fatty acids, and survival of FAO‐dependent lymphoma subtypes. We find that fragmentation increases long‐chain but not short‐chain FAO, identifying carnitine O‐palmitoyltransferase 1 (CPT1) as the downstream effector of mitochondrial morphology in regulation of FAO. Mechanistically, we determined that fragmentation reduces malonyl‐CoA inhibition of CPT1, while elongation increases CPT1 sensitivity to malonyl‐CoA inhibition. Overall, these findings underscore a physiologic role for fragmentation as a mechanism whereby cellular fuel preference and FAO capacity are determined. Synopsis: Metabolic fuel preference is associated with mitochondrial architecture, yet the mechanisms that connect shape and function remain unknown. This study demonstrates selective coupling between mitochondrial architecture and fatty acid (FA) utilization, uncovering an unexpected connection between mitochondrial fusion and fission, and fuel choice.Long‐chain FA oxidation capacity increases upon mitochondrial fragmentation and decreases upon mitochondrial elongation.Activity of CPT1, a rate‐limiting enzyme in fatty acid oxidation, is inhibited by the elongation of mitochondria, but enhanced by their fragmentation.Mitochondrial fragmentation reduces CPT1's sensitivity to its endogenous inhibitor, malonyl‐CoA, which is a product of pyruvate metabolism and the first metabolite in FA synthesis.Fragmentation‐induced FA utilization has cell type‐specific functional consequences, causing increased hepatic gluconeogenesis, induction of insulin secretion at non‐stimulatory glucose levels, and enhanced survival of OXPHOS‐dependent lymphoma cells. [ABSTRACT FROM AUTHOR]