Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles.
Cell Metab
; 35(6): 1038-1056.e8, 2023 06 06.
Article
in En
| MEDLINE
| ID: mdl-37060901
ABSTRACT
Even-chain acylcarnitine (AC) metabolites, most of which are generated as byproducts of incomplete fatty acid oxidation (FAO), are viewed as biomarkers of mitochondrial lipid stress attributable to one or more metabolic bottlenecks in the ß-oxidation pathway. The origins and functional implications of FAO bottlenecks remain poorly understood. Here, we combined a sophisticated mitochondrial phenotyping platform with state-of-the-art molecular profiling tools and multiple two-state mouse models of respiratory function to uncover a mechanism that connects AC accumulation to lipid intolerance, metabolic inflexibility, and respiratory inefficiency in skeletal muscle mitochondria. These studies also identified a short-chain carbon circuit at the C4 node of FAO wherein reverse flux of glucose-derived acetyl CoA through medium-chain ketothiolase enhances lipid tolerance and redox stability in heart mitochondria by regenerating free CoA and NAD+. The findings help to explain why diminished FAO capacity, AC accumulation, and metabolic inflexibility are tightly linked to poor health outcomes.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyruvic Acid
/
Mitochondria
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Cell Metab
Journal subject:
METABOLISMO
Year:
2023
Document type:
Article
Affiliation country:
United States