Mitochondrial proteostasis is impaired in mouse heart failure

In 15-month-old male and female mice, researchers modeled heart failure with preserved ejection fraction (HFpEF) using a high-fat diet combined with chronic nitric oxide synthase inhibition. The animals developed diastolic dysfunction and reduced cardiac reserve while maintaining preserved ejection fraction. High-resolution respirometry showed significantly reduced mitochondrial respiratory capacity in left ventricular muscle fibers. Proteomic profiling of isolated cardiomyocyte mitochondria revealed broad suppression of proteins supporting oxidative phosphorylation, carbohydrate metabolism, and the citric acid cycle. Regulators of mitochondrial biogenesis were preserved. However, mitochondrial chaperones and proteases involved in quality control were reduced, accompanied by an accumulation of ubiquitinated mitochondrial proteins. The findings suggest that defective mitochondrial proteostasis, rather than impaired biogenesis, may contribute to reduced cardiac reserve.