Loss of Miro1 drives cardiac and mitochondrial dysfunction exacerbated by metabolic stress.

Abstract

Cardiac mitochondrial remodelling is a hallmark of type 2 diabetes-linked heart failure (T2DM-HF). We previously reported that mitochondrial morphological changes occur in early-stage disease and identified down-regulation of the mitochondrial protein Miro1 (Rhot1). Neuronal Miro1 regulates mitochondrial movement but the role of cardiac Miro1 remains poorly understood. Therefore, we generated a cardiac-specific Miro1 knockout (Miro1cko) mouse model to investigate how cardiomyocyte-Miro1 deficiency affects cardiac and mitochondrial structure-function. Miro1cko mice compared to controls develop mild diastolic and systolic dysfunction and electrical abnormalities, cellular hypertrophy and fibrosis. Miro1cko leads to aberrant mitochondrial respiration and elevated H₂O₂ production, consistent with electron microscopy showing disrupted cristae morphology, with putative links to Myosin19 down-regulation. Three-dimensional electron microscopy identified mitochondrial remodelling with interfibrillar mitochondria (IFM) ~50% smaller with an increased surface complexity. Since fusion-fission protein expression was unchanged these data identify Miro1 as a regulator of mitochondrial morphology. Mitochondrial density increases (34% Miro1cko; 30% control), with abnormal IFM clustering, which we suggest is associated with impaired mitophagy since PINK1 and Parkin are down-regulated (~80% and ~ 60% respectively) and imaging flow cytometry of isolated primary cardiomyocytes identified an ~2-fold reduction to mitochondrial clearance indicative of blunted mitophagy. Heterozygous knockout mice, which display a milder cardiac phenotype, rapidly developed HF symptoms when given a high fat diet with L-NAME. In conclusion, loss of Miro1 drives multiple aberrant mitochondrial remodelling events culminating in cardiac dysfunction and predisposes towards accelerated metabolic-HF development. Loss of Miro1 may represent a critical mechanistic link in T2DM-HF pathogenesis and therefore a potential therapeutic target.