By the time PD symptoms manifest, as much as 60-70% of dopaminergic cells are already lost. Degeneration of the neuronal network leads to miscommunication between dopaminergic cells located in various brain regions involved in motor coordination. Neural energy restriction triggers axonal damage and represents one of the main mechanisms underlying network degeneration.
The transport of mitochondria from one cell to another is part of a regular dialogue between cells during development and is critical for maintaining cell function and survival. Mitochondrial capacity to change both shape and length permits them to be transported between cells by mechanisms such as direct transfer via tunneling nanotubes (TNTs)1 and indirect transfer via released microvesicles. Translocation of healthy mitochondria to damaged/injured axonal sites, is crucial in maintaining neuronal activity. Mitochondrial transfer from mesenchymal stem cells to damaged cells has been proven to mediate regenerative processes2–4. Horizontal transfer or delivery of mitochondria from one cell to another involves the rescue of damaged cells5, and represents a potential approach to revert neurodegeneration.
In the current proposal, we will study the role of extracellular mitochondria in PD and AD pathology, with a focus on protective effects mediated by indirect transfer (release of mitochondrial vesicles or transplantation of exogenous mitochondria) to support damaged PD or AD cells. Extracellular mitochondria were discovered as components of apoptotic bodies, extracellular microvesicles or mitochondrial-derived vesicles (mitoEVs)6,7, but also as free circulating mitochondrial DNA (mtDNA)8,9. Mitovesicles differ from intracellular mitochondria. They are 10-fold smaller, lack cristae and mitochondrial ribosomes. EVs can be generally divided into two categories: a) exosomes, formed via the fusion of a multivesicular body (MVB) with the plasma membrane, and b) larger microvesicles, which are considered to form from the direct budding of vesicles from the plasma membrane, process thought to be occurring during mitoEVs formation10. mitoEVs are heterogenous in size and cargo and we aim to decipher their cargo and function on recipient cells in PD conditions.
This project will provide a comprehensive overview of extracellular mitochondrial function and mitoEVs as key components of PD/AD pathology, allowing identification of mitochondria-associated biomarker(s). We will focus on PD/AD pathology with the key objective to provide a molecular fingerprint of mitoEVs in PD/AD and information on how mitoEVs and mitochondrial transfer affect human neurons.
The characterization of Extracellular vesicles during aging and neurodegenerative diseases
Year of approval
2023
Institute
RuG - Faculty of Science and Engineering
Primary applicant
Dolga, A.