biomolecules Review Mitochondria-Endoplasmic Reticulum Crosstalk in Parkinson’s Disease: The Role of Brain Renin Angiotensin System Components Tuladhar Sunanda 1,2 , Bipul Ray 1,2 , Arehally M. Mahalakshmi 1 , Abid Bhat 1,2 , Luay Rashan 3 , Wiramon Rungratanawanich 4 , Byoung-Joon Song 4 , Musthafa Mohamed Essa 5,6 , Meena Kishore Sakharkar 7, * and Saravana Babu Chidambaram 1,2, *   Citation: Sunanda, T.; Ray, B.; Mahalakshmi, A.M.; Bhat, A.; Rashan, L.; Rungratanawanich, W.; Song, B.-J.; Essa, M.M.; Sakharkar, M.K.; Chidambaram, S.B. Mitochondria-Endoplasmic Reticulum Crosstalk in Parkinson’s Disease: The Role of Brain Renin Angiotensin System Components. Biomolecules 2021, 11, 1669. https:// doi.org/10.3390/biom11111669 Academic Editor: Damiana Leo Received: 6 September 2021 Accepted: 4 November 2021 Published: 10 November 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; tuladharsunanda4@gmail.com (T.S.); bray365@gmail.com (B.R.); ammahalakshmi@jssuni.edu.in (A.M.M.); abidpharma8088@gmail.com (A.B.) 2 Centre for Experimental Pharmacology and Toxicology, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India 3 Biodiversity Research Centre, Dohfar University, Salalah 2059, Oman; lrashan@du.edu.om 4 Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892, USA; wiramon.rungratanawanich@nih.gov (W.R.); bj.song@nih.gov (B.-J.S.) 5 Department of Food Science and Nutrition, CAMS, Sultan Qaboos University, Muscat 123, Oman; Drmdessa@squ.edu.om 6 Ageing and Dementia Research Group, Sultan Qaboos University, Muscat 123, Oman 7 College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5A2, Canada * Correspondence: meena.sakharkar@usask.ca (M.K.S.); saravanababu.c@jssuni.edu.in (S.B.C.) Abstract: The past few decades have seen an increased emphasis on the involvement of the mitochondrial-associated membrane (MAM) in various neurodegenerative diseases, particularly in Parkinson’s disease (PD) and Alzheimer’s disease (AD). In PD, alterations in mitochondria, endo- plasmic reticulum (ER), and MAM functions affect the secretion and metabolism of proteins, causing an imbalance in calcium homeostasis and oxidative stress. These changes lead to alterations in the translocation of the MAM components, such as IP3R, VDAC, and MFN1 and 2, and consequently disrupt calcium homeostasis and cause misfolded proteins with impaired autophagy, distorted mitochondrial dynamics, and cell death. Various reports indicate the detrimental involvement of the brain renin–angiotensin system (RAS) in oxidative stress, neuroinflammation, and apoptosis in various neurodegenerative diseases. In this review, we attempted to update the reports (using various search engines, such as PubMed, SCOPUS, Elsevier, and Springer Nature) demonstrating the pathogenic interactions between the various proteins present in mitochondria, ER, and MAM with respect to Parkinson’s disease. We also made an attempt to speculate the possible involvement of RAS and its components, i.e., AT1 and AT2 receptors, angiotensinogen, in this crosstalk and PD pathology. The review also collates and provides updated information on the role of MAM in calcium signaling, oxidative stress, neuroinflammation, and apoptosis in PD. Keywords: ER stress; mitochondrial dysfunction; mitochondrial-associated membrane (MAM); ER–mitochondria crosstalk; brain renin angiotensin system 1. Parkinson’s Disease Parkinson’s disease (PD) was first described in 1817 by Dr. James Parkinson, a British physician, as “shaking palsy”. Global epidemiological data reveal that 1–2% of the population belonging to the age group of 65 years and 4–5% at the age of 85 and above are affected by PD, which indicates that ageing is one of the risk factors. Men are 1.5 times more prone to PD than women [1]. Biomolecules 2021, 11, 1669. https://doi.org/10.3390/biom11111669 https://www.mdpi.com/journal/biomolecules