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

Abstract

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.

Carbon Dots as Potential Therapeutic Agents for Treating Non-Alcoholic Fatty Liver Disease and Associated Inflammatory Bone Loss

“…To further elucidate the role of PPARα in lipid metabolism regulation, we examined the expression of the PPARα target gene, carnitine palmitoyl transferase 1 (CPT1) . CPT1, a rate-regulating enzyme of the CPT system, resides on the mitochondrial outer membrane and facilitates the attachment of fatty acid acyl groups to carnitine . In agreement with previous findings, the hepatic expression of CPT1 of mice in the HFD group was significantly lower compared with that in the NCD group (Figure d) .…”

“…43 CPT1, a rate-regulating enzyme of the CPT system, resides on the mitochondrial outer membrane and facilitates the attachment of fatty acid acyl groups to carnitine. 44 In agreement with previous findings, the hepatic expression of CPT1 of mice in the HFD group was significantly lower compared with that in the NCD group (Figure 4d). 45 However, the CPT1 mRNA expression of mice in the group of HFD + MCDs tended to be increased.…”

Fuel oxidation under the control of mitochondrial shape and dynamics

“…Erin L Seifert * & György Hajn oczky ** How mitochondrial shape and substratespecific metabolism are related has been a difficult question to address. Here, new work by Ngo et al (2023) reports that mitochondrial shape-long versus fragmented-determines the activity of b-oxidation of long-chain fatty acids, supporting a novel role for mitochondrial fission products as b-oxidation hubs.…”

“…This raised the possibility that CPT1 could integrate information about mitochondrial shape. Building on previous studies showing a lower sensitivity of CPT1 to its endogenous inhibitor, malonyl-CoA, in a curved versus a planar lipid bilayer (Frigini et al, 2020), Ngo et al (2023) reasoned that mitochondrial elongation results in fewer regions of high curvature within the mitochondrial network. Testing the sensitivity of malonyl-CoA inhibition of CPT1, they found that genetic approaches or excess nutrients that elongate or fragment mitochondria, respectively, increased or lessened malonyl-CoA's inhibition of boxidation.…”

A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling

“…Mitochondrial tubular versus spherical morphology may also impact mitochondrial metabolic tasks; with tubular mitochondria favoring enzymatic activities in the matrix, and spherical mitochondria improving bioenergetic efficiency. Shirihai and colleagues recently demonstrated that mitochondrial fragmentation, such as observed in PP hepatocytes, increases fatty acid oxidation 39 . We further demonstrated a correlation between hepatic mitochondrial structure and function; pharmacological modulation of major nutrient signaling pathways resulted in a remodeled mitochondrial structure and its corresponding function (Fig 7).…”