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

Abstract

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.

Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart

“…Theses vesicles are independent of Drp1 and have a diameter between 70 to 150nm [15, 16]. MDVs are produced in baseline conditions in cardiac H9C2 cells and in mouse heart tissue [17]. Stress increases the formation of these MDVs as observed after treatment with doxorubicin or antimycin A, in association with cardiac dysfunction [17, 18].…”

“…MDVs are produced in baseline conditions in cardiac H9C2 cells and in mouse heart tissue [17]. Stress increases the formation of these MDVs as observed after treatment with doxorubicin or antimycin A, in association with cardiac dysfunction [17, 18]. The formation of MDVs appears to be prior to mitophagy [15], suggesting a role for MDVs as a first defense before mitophagy, which is costlier for the cell.…”

Tying trafficking to fusion and fission at the mighty mitochondria

“…Subsequently, this frees up constriction sites for the recruitment and/or activation of Drp1 and promotes mitochondrial fission and fragmentation . MDVs are defined as structures with diameters of 70 to 150 nm, and are considered quality control mechanisms for mitochondria that deliver mitochondria‐related contents to the late endosome or multivesicular bodies . Although the exact mechanism of incorporation of the selected cargo is unclear, studies have shown that both the outer and inner membranes can be used to form MDVs, carrying membrane bound or mitochondrial matrix proteins .…”

Myocardial stress and autophagy: mechanisms and potential therapies

“…New tools for experimental manipulation of autophagy in cardiac disease states are under development, which can potentially allow tissue selective autophagy interventions targeted specifically to macro-autophagy processes. This is important in order to distinguish macro-autophagic processes from other related autophagic pathways also operational in most cell types, namely micro-autophagy (direct recruitment of cytosolic material to the lysosome 4 ), chaperone-mediated autophagy/endosomal micro-autophagy (single protein-recruitment to endosomes/lysosomes 5, 6 ) and mitochondria-derived vesicular autophagy (fusion of mitochondrial outer membranes with endosomes prior to lysosome degradation 7 ). This review focus is on macro-autophagy pathways and processes – and in particular highlights recent advances in defining the role of cargo-selective macro-autophagy subtypes in myocardial stress settings.…”