Formation of mitochondrial‐derived vesicles is an active and physiologically relevant mitochondrial quality control process in the cardiac system

Abstract

Key points: Mitochondrial‐derived vesicle (MDV) formation occurs under baseline conditions and is rapidly upregulated in response to stress‐inducing conditions in H9c2 cardiac myoblasts. In mice formation of MDVs occurs readily in the heart under normal healthy conditions while mitophagy is comparatively less prevalent. In response to acute stress induced by doxorubicin, mitochondrial dysfunction develops in the heart, triggering MDV formation and mitophagy. MDV formation is thus active in the cardiac system, where it probably constitutes a baseline housekeeping mechanism and a first line of defence against stress. The formation of mitochondrial‐derived vesicles (MDVs), a process inherited from bacteria, has emerged as a potentially important mitochondrial quality control (QC) mechanism to selectively deliver damaged material to lysosomes for degradation. However, the existence of this mechanism in various cell types, and its physiological relevance, remains unknown. Our aim was to investigate the dynamics of MDV formation in the cardiac system in vitro and in vivo. Immunofluorescence in cell culture, quantitative transmission electron microscopy and electron tomography in vivo were used to study MDV production in the cardiac system. We show that in cardiac cells MDV production occurs at baseline, is commensurate with the dependence of cells on oxidative metabolism, is more frequent than mitophagy and is up‐regulated on the time scale of minutes to hours in response to prototypical mitochondrial stressors (antimycin‐A, xanthine/xanthine oxidase). We further show that MDV production is up‐regulated together with mitophagy in response to doxorubicin‐induced mitochondrial and cardiac dysfunction. Here we provide the first quantitative data demonstrating that MDV formation is a mitochondrial QC operating in the heart.