Role of Miro1, the mitochondrial Rho GTPase, in cardiomyocyte function and heart homeostasis

Abstract

Introduction

Mitochondria, which are mainly abundant in cardiomyocytes and whose dysfunction has been widely observed in cardiovascular disease, are increasingly being considered as potential therapeutic targets. The function of mitochondria is closely linked to their ability to move along microtubules to adapt their distribution, morphology and dynamics in response to the demands of the cell. The outer mitochondrial membrane protein Miro1 is a key regulator of mitochondrial motility by promoting the anchorage of mitochondria to the kinesin/dynein motor of the microtubules on which they move. The role of Miro1 in cardiomyocytes remains largely unknown.

Objective

In this study, we explored the role of Miro1 in the heart using cardiomyocyte-specific deletion of Miro1 in adult mice.

Method

We disrupted Miro1 in the adult heart using a heart-specific tamoxifen-inducible Cre recombinase. Two and five weeks after tamoxifen injection, mice were characterized via echocardiography, comprehensive morphological evaluation, metabolic analysis, and transcriptomic profiling.

Results

The disruption of Miro1 led to impaired left ventricular function with reduced contractility, subsequently progressing to dilated cardiomyopathy, as demonstrated by serial echocardiography, including tissue Doppler imaging. The cytoarchitecture of cardiomyocytes was altered and display altered mitochondrial architecture. Interestingly, these alterations were associated with an increased fibrosis (assessed by Sirius red staining). These functional and structural defects were preceded by early alterations in the cardiac gene expression program: major decreases in mRNA levels for cardiac α-actin, muscle creatine kinase, and calcium-handling genes and increases in mRNA levels for stress-induced genes such as beta-myosin heavy chain genes, atrial natriuretic factor and brain natriuretic peptide.

Conclusion

These results highlight the importance of Miro1 in the maintenance of heart homeostasis and function.