Mitochondrial‐Derived Vesicle Formation in Cardiac Mitochondrial Quality Control

Abstract

Mitochondrial quality control (QC) is critical for maintenance of efficient cardiac function. Recently, a novel mechanism of mitochondrial QC, acting upstream of autophagy, has been uncovered – mitochondrial derived vesicle (MDV) formation. Our aim was to demonstrate MDV formation in a cardiac model and determine its relevance in mitochondrial pathophysiology. In H9c2 cardioblasts, common mitochondrial stressors (antimycin‐A and H2O2) resulted in a significant increase in MDV formation after only 60 min of exposure. The chemotherapeutic doxorubicin (DOX) induced maximal MDV formation after 30 min of treatment, with the levels of MDVs returning to baseline at 24h. In vivo MDV formation and response to stress was analyzed in mice subjected to Sham injection or acute DOX treatment. Despite the absence of echocardiographic differences between groups, mitochondrial functional analysis revealed decreased mitochondrial respiratory capacity, increased ROS production, and susceptibility to PTP opening in the DOX‐treated group. Morphological analysis by TEM revealed a substantial increase in the number of MDVs in the heart of DOX‐treated animals. Our results thus demonstrate that in a cardiac cell model MDV formation is a fast‐response mechanism of mitochondrial QC stimulated by mitochondrial and cellular stressors. Moreover, in addition to the previous reports of in vitro MDV formation, this study demonstrates the existence and responsiveness of MDV formation in cardiac mitochondrial QC.