Exosome Release Is Modulated by the Mitochondrial-Lysosomal Crosstalk in Parkinson’s Disease Stress Conditions

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta region of the brain. The main pathological hallmark involves cytoplasmic inclusions of αsynuclein and mitochondrial dysfunction, which is observed in other part of the central nervous system other than SN suggesting the spread of pathogenesis to bystander neurons. The inter-neuronal communication through exosomes may play an important role in the spread of the disease; however, the mechanisms are not well elucidated.Mitochondria and its role in inter-organellar crosstalk with multivesicular body (MVB) and lysosome and its role in modulation of exosome release in PD is not well understood. In the current study, we investigated the mitochondria-lysosome crosstalk modulating the exosome release in neuronal and glial cells. We observed that PD stress showed enhanced release of exosomes in dopaminergic neurons and glial cells. The PD stress condition in these cells showed fragmented network and mitochondrial dysfunction which further leads to functional deficit of lysosomes and hence inhibition of autophagy flux. Neuronal and glial cells treated with rapamycin showed enhanced autophagy and inhibited the exosomal release. The results here suggest that maintenance of mitochondrial function is important for the lysosomal function and hence exosomal release which is important for the pathogenesis of PD.

Association Between Mitochondrial Function and Rehabilitation of Parkinson's Disease: Revealed by Exosomal mRNA and lncRNA Expression Profiles

“…The qRT-PCR validation for the DEmRNA of interest and related DElncRNAs revealed upregulated expression level of NDUFB7 in pre-rehab PWPs compared to post-rehab PWPs. The release of damage-related molecules of mitochondria is a potential mechanism connecting mitochondrial dysfunction with systemic inflammation in the setting of various diseases, such as PD (Currim et al, 2021 ). A previous study indicated that mildly damaged mitochondria were primed by serine/threonine-protein kinase PINK1 and Parkin and generated mitochondrial-derived vesicles (MDVs; Mclelland et al, 2014 ).…”

Exosome Biogenesis and Lysosome Function Determine Podocyte Exosome Release and Glomerular Inflammatory Response during Hyperhomocysteinemia

“…As an inhibitor of mammalian target of rapamycin, rapamycin has been reported to inhibit exosome release from neuronal cells and glial cells. 65 Moreover, mammalian target of rapamycin reportedly regulates the lysosomeeMVB interaction and exosome release in smooth muscle cells. 23 The results with rapamycin confirmed the vital role of lysosomes in the regulation of exosome release in podocytes.…”

Role of Ceramides and Lysosomes in Extracellular Vesicle Biogenesis, Cargo Sorting and Release

“…Several diseases can arise due to lysosomal dysfunction, as exemplified by the neurodegenerative disorder [ 180 ]. In other diseases, such as AD and Parkinson’s, toxic proteins are aggregated inside EVs that once released, contribute to inflammation and disease progression [ 181 , 182 , 183 ]. Presence of key proteins, such as DJ-1, Parkin or PINK1 are all involved in lysosomal dysfunction, mitophagy, and neurodegenerative diseases [ 184 , 185 ].…”