Endoplasmic reticulum-mitochondria tethering in neurodegenerative diseases

Abstract

Endoplasmic reticulum (ER) and mitochondria are tubular organelles with a characteristic "network structure" that facilitates the formation of inter-organellar connections. As a result, mitochondria-associated ER membranes (MAMs), a subdomain of the ER that is tightly linked to and communicates with mitochondria, serve multiple physiological functions including lipid synthesis and exchange, calcium signaling, bioenergetics, and apoptosis. Importantly, emerging evidence suggests that the abnormality and dysfunction of MAMs have been involved in various neurodegenerative disorders including Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. This review will focus on the architecture and function of MAMs and its involvement in the neurodegenerative diseases.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Mitochondria-ER tethering; Mitochondria-associated ER membrane; Parkinson’s disease.

Fig. 1

Global view of the architecture/choreography of ER–mitochondria contacts. As depicted, a part of ER tubule and mitochondria form quasi-synaptic structure. Several pairs of integral membrane proteins located on mitochondria and ER important for MERC formation and physical tethering of the organelles were identified, including Mfn1/2 tether, Fis1-Bap31 tether, VAPB-PTPIP51 tether and IP3R-grp75-VDAC1 tripartite complex. The latter is essential for the efficient Ca²⁺ transfer from the ER to mitochondria. MAM: mitochondria associated ER membrane, OMM = outer mitochondrial membrane, IMM: inner mitochondrial membrane, Mx = matrix, ETC: electron transport chain, TAC: tricarboxylic acid cycle