Inter and intracellular mitochondrial transfer: Future of mitochondrial transplant therapy in Parkinson's disease

Parkinson's disease (PD) is marked by the gradual degeneration of dopaminergic neurons and the intracellular build-up of Lewy bodies rich in α-synuclein protein. This impairs various aspects of the mitochondria including the generation of ROS, biogenesis, dynamics, mitophagy etc. Mitochondrial dynamics are regulated through the inter and intracellular movement which impairs mitochondrial trafficking within and between cells. This inter and intracellular mitochondrial movement plays a significant role in maintaining neuronal dynamics in terms of energy and growth. Kinesin, dynein, myosin, Mitochondrial rho GTPase (Miro), and TRAK facilitate the retrograde and anterograde movement of mitochondria. Enzymes such as Kinases along with Calcium (Ca²⁺), Adenosine triphosphate (ATP) and the genes PINK1 and Parkin are also involved. Extracellular vesicles, gap junctions, and tunneling nanotubes control intercellular movement. The knowledge and understanding of these proteins, enzymes, molecules, and movements have led to the development of mitochondrial transplant as a therapeutic approach for various disorders involving mitochondrial dysfunction such as stroke, ischemia and PD. A better understanding of these pathways plays a crucial role in establishing extracellular mitochondrial transplant therapy for reverting the pathology of PD. Currently, techniques such as mitochondrial coculture, mitopunch and mitoception are being utilized in the pre-clinical stages and should be further explored for translational value. This review highlights how intercellular and intracellular mitochondrial dynamics are affected during mitochondrial dysfunction in PD. The field of mitochondrial transplant therapy in PD is underlined in particular due to recent developments and the potential that it holds in the near future.