Key result
OPA1 overexpression preserves LV systolic function despite increasing cardiac fibrosis in diet-induced obese mice.
Why the study?
Although increasing OPA1 expression has been proposed to improve mitochondrial performance, the consequences of sustained OPA1-driven oxidative activation in the lipid-exposed cardiovascular system remained incompletely defined.
Does systemic OPA1 overexpression alter cardiac structure, tissue metabolism, and cardiomyocyte bioenergetics in mice fed a high-fat diet?
Does systemic OPA1 overexpression alter cardiac structure, tissue metabolism, and cardiomyocyte bioenergetics in mice fed a high-fat diet?
Systemic OPA1 overexpression during high-fat diet feeding enhances cardiomyocyte respiratory capacity under lipid-rich conditions but leads to myocardial triglyceride accumulation and early fibrotic remodeling despite preserved systolic function.
INTRODUCTION: Optic atrophy 1 (OPA1) is a mitochondrial inner-membrane GTPase that coordinates mitochondrial fusion, cristae organization, and respiratory efficiency. Beyond mitochondrial bioenergetics, OPA1 contributes to cardiovascular homeostasis, including the maintenance of vascular cell function and phenotype. Although increasing OPA1 expression has been proposed to improve mitochondrial performance, the consequences of sustained OPA1-driven oxidative activation in the lipid-exposed cardiovascular system remain incompletely defined. Here, we investigated cardiac structure, tissue metabolism, and cardiomyocyte bioenergetics in mice with systemic OPA1 overexpression maintained on a high-fat diet (HFD). METHODS: OPA1-overexpressing mice were fed high-fat diet for 20 weeks, followed by indirect calorimetry and echocardiographic analysis. Tissues were used for OMICs investigation and metabolic analysis. RESULTS: OPA1-overexpressing mice displayed preserved global left-ventricular systolic function and ventricular volumes but presented reduced anterior and lateral wall thickness. Histological analysis further revealed a decrease in cardiomyocyte cross-sectional area accompanied by increased myocardial collagen deposition. Cardiac triglyceride content was elevated, whereas cholesterol content was unchanged. In neonatal cardiomyocytes, OPA1 overexpression resulted in increased oxygen consumption, with the strongest response observed in cells co-incubated with very-low-density lipoprotein. Under this lipid-rich condition, ATP-linked respiration, maximal respiration, and spare respiratory capacity were increased. DISCUSSION: Collectively, these findings indicate that systemic OPA1 overexpression was associated with myocardial lipid accumulation and early fibrotic remodeling during HFD feeding, despite preserved systolic function. In vitro, OPA1 overexpression increased cardiomyocyte respiratory capacity under lipid-rich conditions. These data identify a context-dependent effect of OPA1 in which enhanced respiratory capacity may become maladaptive when lipid supply exceeds coordinated oxidative and storage capacity.
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Dalt et al. (2026) studied High-fat diet-induced cardiovascular metabolic and structural remodeling. Systemic OPA1 overexpression on a high-fat diet was evaluated on Cardiac structure, left-ventricular function, tissue metabolism, and cardiomyocyte bioenergetics. Systemic OPA1 overexpression in mice fed a 20-week high-fat diet preserved left-ventricular systolic function while increasing cardiac triglycerides, fibrosis, and cardiomyocyte respiration.
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