Protein Localization at Mitochondria-ER Contact Sites in Basal and Stress Conditions

Abstract

Mitochondria-endoplasmic reticulum (ER) contacts (MERCs) are sites at which the outer mitochondria membrane and the Endoplasmic Reticulum surface run in parallel at a constant distance. The juxtaposition between these organelles determines several intracellular processes such as to name a few, Ca²⁺ and lipid homeostasis or autophagy. These specific tasks can be exploited thanks to the enrichment (or re-localization) of dedicated proteins at these interfaces. Recent proteomic studies highlight the tissue specific composition of MERCs, but the overall mechanisms that control MERCs plasticity remains unclear. Understanding how proteins are targeted at these sites seems pivotal to clarify such contextual function of MERCs. This review aims to summarize the current knowledge on protein localization at MERCs and the possible contribution of the mislocalization of MERCs components to human disorders.

Keywords: ER stress; lipid rafts; mitochondria-ER contact sites; post-translational modifications; protein targeting.

Figure 1

Schematic of subcellular mechanisms for protein targeting at MERCs. Enrichment at mitochondria-ER interface can be achieved through classical targeting sequences (A); post-translational modifications such as phosphorylation, acetylation or sumoylation (B); conformational targeting (C), localization signal receptors (D), geometric protein localization (E) and localized synthesis (F).

Figure 2

Cartoon summarizing aspects pertaining to the organization of “nanodomains” on membranes, and their potential effects regarding recruitment of specific activities. “Lipid raft”-like domains may be stabilized by specialized membrane-binding proteins, such as caveolins (A), and/or through directional local synthesis and accumulation of specific lipid species (B). The subsequent definition of such membrane nanodomains may preclude lateral diffusion of specific transmembrane proteins (C), and or act as “molecular beacons” for the specific recruitment of proteins (D).