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

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 α‐synuclein (α‐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 α‐syn on MAMs and Ca2+ transfer from the ER to mitochondria in WT‐ and A30P α‐syn‐overexpressing SH‐SY5Y or HEK293 cells. We observed that α‐syn potentiates the mitochondrial membrane potential (Δψm) loss induced by rotenone, increases mitophagy and mitochondrial Ca2+ overload. Additionally, in α‐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, α‐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 α‐syn/MAMs/Ca2+ axis that potentially affects cell functions in PD.

Mitochondrial Dysfunction in Parkinson’s Disease: From Mechanistic Insights to Therapy

“…The pathogenicity of α-syn is associated with its aggregation. Accumulation of α-syn is directly related to increased Ca 2+ levels in mitochondria ( Erustes et al, 2021 ), which increases oxidative stress and cytochrome C release. Reduced levels of voltage dependent anion channel protein 1 (VDAC1) in the SNpc neurons of sporadic PD patients was associated with aggregations of α-syn ( Chu et al, 2014 ), which may have been mediated by the activation of the mitochondrial permeability transition pore (mPTP).…”

Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites

“…SNCA localizes to MAMs, while mutant forms are less abundant and seem to prefer mitochondrial localization (Guardia-Laguarta et al, 2014 ). When overexpressed, wild-type and mutant SNCA bind and disrupt tethers: SNCA specifically hampers the IP 3 R/GRP75 interaction in the IP 3 R/GRP75/VDAC1 complex (Erustes et al, 2021 ), and binds VAPB in the PTPIP51/VAPB tether (Paillusson et al, 2017 ). Moreover, in SNCA A53T transgenic mice, Mfn1 and Mfn2 levels decrease in an age-dependent manner, possibly contributing to the reduced MAM tethering (Xie and Chung, 2012 ) and speculatively also leading to less mito-LE/Lys contacts, as this is observed upon Mfn2 knockdown in erythroid progenitors (Khalil et al, 2017 ).…”

“…Moreover, in SNCA A53T transgenic mice, Mfn1 and Mfn2 levels decrease in an age-dependent manner, possibly contributing to the reduced MAM tethering (Xie and Chung, 2012 ) and speculatively also leading to less mito-LE/Lys contacts, as this is observed upon Mfn2 knockdown in erythroid progenitors (Khalil et al, 2017 ). The SNCA-dependent MAM disruption impairs the Ca 2+ transfer from ER to mitochondria, and leads to a decreased ATP production and mitochondrial fragmentation (Paillusson et al, 2017 ; Erustes et al, 2021 ). Importantly, the expression level of SNCA appears to be a key factor in the modulation of MAMs.…”

α-Synuclein pathology and reduced neurogenesis in the olfactory system affect olfaction in a mouse model of Parkinson’s disease

“…To establish a mechanism that explained the temporal susceptibility of olfactory neurons to the hA30P mutant α-syn, we investigated the anomalies in synaptic architecture and intracellular signaling pathways in 12-14 months mice. Synaptic transmission is regulated by α-syn through interactions with synaptic vesicle membranes and impacting on the presynaptic architecture (106)(107)(108). To explore this in the α-syn-Tg mice, we performed an ultrastructural analysis and quantified excitatory and inhibitory synapses and mitochondria in the projection neurons synaptic regions of the OB and APC, the glomeruli and layer 1, respectively.…”