α-Synuclein Interactions in Mitochondria-ER Contacts: A Possible Role in Parkinson's Disease

Abstract

Endoplasmic reticulum-mitochondria contact sites regulate various biological processes, such as mitochondrial dynamics, calcium homeostasis, autophagy and lipid metabolism. Notably, dysfunctions in these contact sites are closely related to neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. However, details about the role of endoplasmic reticulum-mitochondria contact sites in neurodegenerative diseases remain unknown. In Parkinson's disease, interactions between α-synuclein in the contact sites and components of tether complexes that connect organelles can lead to various dysfunctions, especially with regards to calcium homeostasis. This review will summarize the main tether complexes present in endoplasmic reticulum-mitochondria contact sites, and their roles in calcium homeostasis and trafficking. We will discuss the impact of α-synuclein accumulation, its interaction with tethering complex components and the implications in Parkinson’s disease pathology.

A Mitochondrial Inside-Out Iron-Calcium Signal Reveals Drug Targets for Parkinson’s Disease

“…Alpha-synuclein aggregation is a pathological hallmark of PD. Emerging evidence has shown that alphasynuclein has profound functions at the mitochondria or to impact mitochondria, including mitochondrial oxidative phosphorylation, dynamics, mitophagy, Ca 2+ , and iron homeostasis 7,33,[55][56][57][58][59][60] .…”

Multiple tethers of organelle contact sites are involved in α-synuclein toxicity in yeast

“…Indeed, α-syn was reported to bind and affect the function of ER-mitochondria contact sites. This binding might trigger mitochondrial and ER dysfunction as well as enhanced altered general and selective autophagy and thus impact the progression of the disease (Guardia-Laguarta et al, 2014;Paillusson et al, 2016;Gomez-Suaga et al, 2017;Liu et al, 2018;Erustes et al, 2022).…”

“…Wild-type (WT) α-syn, a primarily cytoplasmic protein, was shown to associate with contact sites between the ER and mitochondria in cell lines and brain tissue obtained from mice and humans. Aggregation-prone clinical α-syn mutants displayed an altered interaction with these contacts, leading to a decrease in MCS function, increased mitochondrial fragmentation, and disturbed mitochondrial calcium signaling (Cali et al, 2012;Guardia-Laguarta et al, 2014;Paillusson et al, 2017;Erustes et al, 2022). These results suggest that the multiorganelle cytotoxic mechanism of α-syn might involve affecting organelle communication via MCSs.…”

“…Moreover, α-syn appears to affect the coordination among organelles directly. Recently, α-syn was shown to associate with membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and the mitochondria (Cali et al, 2012;Guardia-Laguarta et al, 2014Paillusson et al 2017;Erustes et al 2022). MCSs are regions where tethering proteins establish an apposition between the membranes of different organelles (Elbaz-Alon et al, 2014;Scorrano et al, 2019).…”

The Role of Cardiolipin in Mitochondrial Function and Neurodegenerative Diseases

“…The formation of α-syn fibrils increased in the presence of CL leading to the unfolded protein response (UPR) in the ER and mitochondria [87]. Interestingly, the localization of αsyn at ER-mitochondrial contact sites was also reported in different models [108,109]. These studies have shown that the overexpression of α-syn disrupted the physical contacts and Ca 2+ transfer between the two organelles, leading to alterations in mitochondrial metabolism.…”