Targeting ER-mitochondria communication through sigma-1 receptor ligands in physiopathology and neurodegenerative disorders

Endoplasmic reticulum (ER)-associated mitochondrial membranes (MAMs) are highly functionalized domains of interaction between ER and mitochondria in the cells, stabilized by proteic bridges and sequestering numerous proteic assemblies. Through MAMs, ER and mitochondria exchange Ca 2+ , proteins, lipids or small signaling molecules. Ca 2+ exchanges are driven by IP 3 receptors (IP 3 Rs) on ER and VDAC1/MCU complexes, mNCS, UCPs, and Letm1 on mitochondrial membranes. MAM dysfunctions are responsible of several mitochondrial diseases or genetic syndroms, and directly contribute to the neurodegenerative processes in Alzheimer, Parkinson, Huntington diseases and amyotrophic lateral sclerosis. Targeting MAMs fonctionality by drug candidates is a novel pharmacological area of research and it may offer effective and potentially wide spectrum therapeutic strategies. We are interested since several years in developing drug candidates targeting the sigma-1 chaperone protein (S1R). Highly expressed in MAMs, S1R interacts with IP 3 Rs, ER stress sensor proteins (BIP, IRE1), or steroids (pregnenolone) to potentiate focused Ca 2+ exchanges between the organelles, stabilize mitochondrial physiology (particularly by interacting with complex I) and maintain MAM integrity. We will here detail the physiopathological importance of targeting MAMs and describe new drug development programs with new S1R agonists or positive modulators that already showed very promising efficacy in several neurodegenerative pathologies.