Loss of the cardiac-enriched mitochondrial transporter SLC25A34 promotes heart failure by attenuating fatty acid oxidation

Abstract

Heart failure is characterized by profound structural and metabolic remodeling. Members of the solute carrier family 25 (SLC25), as inner mitochondrial membrane proteins, play critical roles in mitochondrial dysfunction during heart failure; however, the role of cardiac-enriched SLC25 family members remains incompletely understood. In this study, we identify solute carrier family 25 member 34 (SLC25A34) as a previously unrecognized mitochondrial regulator of cardiac energy metabolism in heart failure. SLC25A34 is highly enriched in the heart and predominantly expressed in adult cardiomyocytes. Its expression progressively increases during postnatal cardiac development, is closely associated with fatty acid-based energy utilization, and is inducible by palmitate. In contrast, SLC25A34 expression is markedly reduced in failing human hearts and multiple mouse models of heart failure. Mechanistically, oxidative stress during heart failure suppresses SLC25A34 expression in cardiomyocytes. Genetic deletion of Slc25a34 exacerbates cardiac dysfunction and adverse remodeling following transverse aortic constriction, without significantly affecting cardiac hypertrophy. Integrated biochemical, transcriptomic, and functional analyses demonstrate that loss of SLC25A34 suppresses the AMPK–CPT1B axis, thereby impairing fatty acid oxidation, leading to reduced ATP production, lipid droplet accumulation, and disrupted redox homeostasis. Conversely, adeno-associated virus-mediated cardiac-specific overexpression of Slc25a34 significantly mitigates heart failure progression. Collectively, these findings establish SLC25A34 as a key mitochondrial regulator linking fatty acid metabolism, energy sensing, and redox homeostasis and suggest that targeting SLC25A34 may represent a novel therapeutic strategy for heart failure.