Mitochondiral Derived Vesicles (MDVs) in Cardiomyopathy and Neurodegenrative Diseases

Mitochondrial Derived Vesicle (MDV) are membranous structure derived from the budding of mitochondria, their size ranges from 70-150 nm. They mediate the trafficking of oxidised protein and lipids towards lysosome for degradation. They are functionally important in maintaining mitochondria homeostasis. MDV transports mitochondria autoantigen to the cell surface to trigger the immune response.

Cardiomyocyte has a large number of mitochondria. MDVs are normally produced by heart mitochondria and upregulated in a stressed condition. In hypoxic myocardial infarction, MDVs are timely released and act in a defence mechanism against mitochondrial stress. In cardiomyocytes under the heavy hypoxic condition, the number of MDVs released are more than normal. Initially, in the hypoxic condition, the number of MDVs released are greater within 1 hour, and as the time passes (i.e. in the span of 12 hours) their number declines. This causes a decrease in their effectiveness and leads to cell death. Rab9 plays an important role in guiding mitochondria for the release of MDV in myocardial ischemia. There are two pathways that regulate the cellular apoptosis: 1) External 2) Internal. External pathway is called the death receptor pathway initiated by binding death ligands to cell surface receptors. And the internal pathway is called the mitochondrial pathway. In the internal pathway, mitochondrial intermembrane proteins are released into the cytoplasm and activate caspases 9 and 3 that leads to intranuclear lamina degradation and reduces DNA integrity thereby gradually leading to cell death. MDVs reduce the caspase 9 activation, ROS production and upregulate ATP levels thereby suggesting that MDVs have a protective role in hypoxia cardiomyocyte apoptosis through mitochondrial pathway and maintains mitochondrial function. MDVs regulate mitochondria quality control by transporting proteins to lysosomes for degradation.

Mitochondrial quality control pathway is essential for cell health and survival. Changes in these pathways lead to neurodegenerative diseases and cardiomyopathy. Mitochondrial damage recruit’s serine/threonine kinase PINK1 which gets imported into the mitochondria from the cytosol. They get accumulated and recruit Parkin on mitochondrial outer membrane (MOM). Also, E3 ubiquitin ligase gets activated that ubiquitylation of several MOM proteins. They ensure proper encapsulation and trafficking of MOM proteins along the mitophagy pathway. Mitochondrial derived vesicle pathway delivers damaged or oxidised portions proteins or lipids of mitochondria into the lysosomes. MDV pathways depend on Parkin function (PINK1). Retromer (complex of proteins) pathway also carries some MDV specific cargo to the degradation unit. VPS35 is the subunit of retromer protein that if gets mutated causes onset of Parkinson disease and causes periodical cause of disease. WASH is a protein complex that regulates endosomal protein sorting its interaction with VPS35 gets disturbed with VPS35 mutation. Parkin is involved in the endosomal pathway that mediates mitochondrial sequestration and degradation by utilising Rab5 early endosomal pathway. Parkin dependent MDV are shuttled via the endosomal pathway to the lysosome independent of ATG5 or LC3. But MDVs require Syntaxin-17 to form a soluble NSF attachment receptor (SNARE). SNARE forms a complex with SNAP29 and VAMP7 to mediate the fusion with the lysosome.

MDV pathway is a collection of numerous pathways. Mutation in Tollip and Tom1 is involved in dysfunction in Alzheimer disease as they carry out endocytic trafficking. Tollip interacts with Tom1 (a protein that inhibits cell activation by microbial products/ protects the cell from inflammation) also clears polyQ aggregates in Huntington's disease. Tom1 also interacts with actin motor Myosin VI mediating autophagosome lysosome fusion. Both these proteins ensure turnover of MDVs through the endosomal system. Tollip interacts and recruits Parkin to the vesicular compartment and regulates MDV lysosomal docking. Tollip organises endosomal positioning and cargo trafficking of mitochondrial damaged constituents. It also routes the endosome to lysosome. MDVs released from heavy hypoxia treated cells contain more Bcl-2 and in the stressed condition, it gets transferred to less healthy mitochondria under hypoxia condition. Less healthy mitochondria lead to activation of Bax and Bak and gets accumulated on mitochondria outer membrane. They undergo oligomerization and mediate mPTP opening through it the proapoptotic factors are released. Bcl-2 may bind to BAX and suppress apoptosis. Parkin and Tollip are important in trafficking MDV to degradation. Upon mitochondrial damage. Parkin protein gets accumulated and recruits Tollip associated membrane compartment to traffic damaged mitochondrial constituents to the endosomal system.