Objective: In this study, we aimed to investigate whether Parkinson’s disease (PD) associated calcium-independent phospholipase A2β (iPLA2β) regulates the integrity and functions of endoplasmic reticulum (ER)-mitochondria contacts

Background: Phospholipase A2 group VI (PLA2G6) is an autosomal recessive pathogenic gene of PD, which encodes the iPLA2β protein. The iPLA2β is widely distributed within cells, including the ER and mitochondria, and is able to regulate the functions of both organelles. However, whether the iPLA2β protein is involved in the regulation of ER-mitochondria contacts, also known as mitochondria-associated ER membrane (MAM), remains unknown.

Method: The effects of PLA2G6 mutation or deletion on the interaction between ER and mitochondria were detected using skin fibroblasts derived from patients with PD harboring PLA2G6 mutations, N2a Pla2g6 KO cells, and the Pla2g6 KO mice model. The Ca²⁺ transport from ER to mitochondria and mitochondrial ATP production were examined using real-time organelle Ca²⁺ fluorescence monitoring and oxygen consumption rate (OCR) assay. The MAM structure was isolated and purified from N2a cells, mice and human brains by differential centrifugation, and western blot (WB) was used to determine whether iPLA2β proteins were present in the MAM. The iPLA2β protein interactome in the MAM was searched and identified by mass spectrometry (MS), co-immunoprecipitation (co-IP), proximity ligation assay (PLA), blue native-polyacrylamide gel electrophoresis (BN-PAGE) experiments.

Results: We found that iPLA2β functions in controlling the ER-mitochondria contacts and Ca²⁺ transfer both in vitro and in vivo. Furthermore, the iPLA2β protein was found to be enriched in the MAM to physically interact with the inositol 1,4,5-trisphosphate receptor 1 (IP3R1)/glucose-regulated protein 75 (GRP75)/voltage-dependent anion channel 1 (VDAC1) complex and protect the integrity of this complex.

Conclusion: The iPLA2β protein was localized in the MAM to maintain the integrity and functions of MAM.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/ipla2%ce%b2-controls-er-mitochondria-tethering-and-ca2-transfer-in-parkinsons-disease/