Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA
Jennifer Ngo1,2,3,4, Dong Wook Choi5,6, Illana A Stanley5
1Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, Molecular Biology Institute, UCLA, CA, Los Angeles, USA.
The EMBO Journal
|March 14, 2023
Summary
Mitochondrial fragmentation boosts fatty acid oxidation (FAO) by reducing malonyl-CoA inhibition of CPT1. This morphological change enhances cellular fuel preference and FAO capacity.
Area of Science:
- Cell Biology
- Metabolic Regulation
- Mitochondrial Dynamics
Background:
- Mitochondrial morphology changes are linked to nutrient use, but mechanisms are unclear.
- Understanding how mitochondrial shape affects metabolism is crucial for cellular function.
Purpose of the Study:
- To investigate the causal relationship between mitochondrial morphology and fatty acid oxidation (FAO).
- To elucidate the molecular mechanisms linking mitochondrial fragmentation to enhanced FAO.
Main Methods:
- Utilized cellular models with diverse mitochondrial shapes.
- Employed genetic manipulation (MFN2 over-expression/knockdown, DRP1 depletion) to alter mitochondrial morphology.
- Assessed FAO rates using respirometry and metabolic tracing.
- Investigated the role of carnitine O-palmitoyltransferase 1 (CPT1) and malonyl-CoA inhibition.
Main Results:
- Demonstrated a strong linear correlation between mitochondrial fragmentation and increased FAO rates.
- Showed that mitochondrial elongation reduced FAO, while fragmentation augmented it.
- Observed cell type-specific functions of enhanced FAO due to fragmentation, including gluconeogenesis, insulin secretion, and lymphoma cell survival.
- Identified CPT1 as a downstream effector, with fragmentation decreasing malonyl-CoA inhibition of CPT1.
Conclusions:
- Mitochondrial fragmentation directly enhances FAO capacity.
- Fragmentation reduces malonyl-CoA inhibition of CPT1, increasing FAO.
- Mitochondrial morphology plays a key physiologic role in determining cellular fuel preference and FAO capacity.
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