Overexpression of alpha-synuclein inhibits mitochondrial Ca2+ trafficking between the endoplasmic reticulum and mitochondria through MAMs by altering the GRP75-IP3R interaction

Author(s)

Erustes, Adolfo Garcia ^[1] ; D'Eletto, Manuela ^[2] ; Guarache, Gabriel Cicolin ^[1] ; Ureshino, Rodrigo Portes ^{[3, 4]} ; Bincoletto, Claudia ^[1] ; da Silva Pereira, Gustavo Jose ^[1] ; Piacentini, Mauro ^[2] ; Smaili, Soraya Soubhi ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, Dept Pharmacol, Escola Paulista Med, Rua Tres de Maio 100, BR-04044020 Sao Paulo, SP - Brazil

^[2] Univ Roma Tor Vergata, Dept Biol, Rome - Italy

^[3] Univ Fed Sao Paulo, Inst Ciencias Ambientais Quim & Farmaceut, Dept Biol Sci, Diadema - Brazil

^[4] Univ Fed Sao Paulo, Lab Mol & Translat Endocrinol, Escola Paulista Med, Sao Paulo - Brazil

• Document type: Journal article
• Source: Journal of Neuroscience Research; SEP 2021.
• Web of Science Citations: 0

Abstract

Mitochondria-associated ER membranes (MAMs) are formed by close and specific components in the contact sites between the endoplasmic reticulum (ER) and mitochondria, which participate in several cell functions, including lipid metabolism, autophagy, and Ca2+ signaling. Particularly, the presence of alpha-synuclein (alpha-syn) in MAMs was previously demonstrated, indicating a physical interaction among some proteins in this region and a potential involvement in cell dysfunctions. MAMs alterations are associated with neurodegenerative diseases such as Parkinson's disease (PD) and contribute to the pathogenesis features. Here, we investigated the effects of alpha-syn on MAMs and Ca2+ transfer from the ER to mitochondria in WT- and A30P alpha-syn-overexpressing SH-SY5Y or HEK293 cells. We observed that alpha-syn potentiates the mitochondrial membrane potential (Delta psi(m)) loss induced by rotenone, increases mitophagy and mitochondrial Ca2+ overload. Additionally, in alpha-syn-overexpressing cells, we found a reduction in ER-mitochondria contact sites through the impairment of the GRP75-IP3R interaction, however, with no alteration in VDAC1-GRP75 interaction. Consequently, after Ca2+ release from the ER, alpha-syn-overexpressing cells demonstrated a reduction in Ca2+ buffering by mitochondria, suggesting a deregulation in MAM activity. Taken together, our data highlight the importance of the alpha-syn/MAMs/Ca2+ axis that potentially affects cell functions in PD. (AU)

• FAPESP's process: 16/05580-3 - Study of alpha-synuclein in MAMs: the role of mortalin and transglutaminase 2 in the stressful condition induced by mutated alpha-synuclein.
• Grantee: Adolfo Garcia Erustes
• Support type: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 19/14722-4 - Two-Pore Channels receptors and TFEB-3 autophagy modulation in human hepatocellular carcinoma
• Grantee: Gustavo José da Silva Pereira
• Support type: Regular Research Grants
• FAPESP's process: 19/02821-8 - Autophagy modulation by cannabinoids: neuroprotection in Parkinson's Disease
• Grantee: Soraya Soubhi Smaili
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 17/10863-7 - Study of lipophagy mediated by two-pore channels receptors
• Grantee: Gustavo José da Silva Pereira
• Support type: Regular Research Grants
• FAPESP's process: 16/20796-2 - Study of estrogen receptors mediated autophagy against tau toxicity in cell and zebrafish models
• Grantee: Rodrigo Portes Ureshino
• Support type: Research Grants - Young Investigators Grants
• FAPESP's process: 13/20073-2 - Autophagy as a protective mechanism in senescent rats
• Grantee: Soraya Soubhi Smaili
• Support type: Regular Research Grants