ER-MITOCHONDRIA DISTANCE CONTROLS PROTEIN AND LIPID HOMEOSTASIS, MITOCHONDRIAL CALCIUM UPTAKE AND BIOENERGETICS: IMPLICATIONS FOR ALZHEIMER’S AND PARKINSON’S DISEASE

Mitochondria-ER contact sites (MERCS) play crucial role in the regulation of many cellular processes, yet they are altered in numerous pathologies, including neurodegenerative diseases. Here, we show that physical parameters of MERCS, such as the transversal distance between ER and mitochondria, determine MERCS functional features. First, using previously published linkers, we demonstrate that stabilization of MERCS at 5 and 10 nm in HeLa cells differentially affects global protein synthesis; also, lipidomic analysis reveals alteration in lipid composition. Interestingly, the effect on cellular homeostasis differs dependently on the introduced EML distance. Next, by extending the palette of ER-mitochondrial linkers to 15, 20 and 30 nm, we investigated MERCS distance-dependence of mitochondrial Ca2+ uptake. We found a bell-shaped ER-mitochondria distance dependence of Ca2+ flux, with 20 nm representing the optimal distance for both Ca2+ transport and OxPhos. Exploiting this result, we demonstrate that stabilizing MERCS at 20 nm rescues impaired mitochondrial Ca2+ uptake in human iPSC-derived astrocytes from Parkinson’s disease patients, as well as in astrocytes from 3xTg-AD Alzheimer’s disease mouse model. Altogether, our results suggest that the prospect of manipulating the ER-mitochondrial distance may be a key to understanding the molecular mechanisms leading to the development of many diseases and provide proof of principle that stabilizing MERCS at defined distance may represent a promising strategy for the development of novel therapeutic approaches.