The Mitochondria-Endoplasmic Reticulum Contacts and Their Critical Role in Aging and Age-Associated Diseases

Abstract

The recent discovery of interconnections between the endoplasmic reticulum (ER) membrane and those of almost all the cell compartments is providing novel perspectives for the understanding of the molecular events underlying cellular mechanisms in both physiological and pathological conditions. In particular, growing evidence strongly supports the idea that the molecular interactions occurring between ER and mitochondrial membranes, referred as the mitochondria (MT)-ER contacts (MERCs), may play a crucial role in aging and in the development of age-associated diseases. As emerged in the last decade, MERCs behave as signaling hubs composed by structural components that act as critical players in different age-associated disorders, such as neurodegenerative diseases and motor disorders, cancer, metabolic syndrome, as well as cardiovascular diseases. Age-associated disorders often derive from mitochondrial or ER dysfunction as consequences of oxidative stress, mitochondrial DNA mutations, accumulation of misfolded proteins, and defective organelle turnover. In this review, we discuss the recent advances associating MERCs to aging in the context of ER-MT crosstalk regulating redox signaling, ER-to MT lipid transfer, mitochondrial dynamics, and autophagy.

Keywords: age-associated diseases; aging; endoplasmic reticulum; mitochondria; oxidative stress; senescence.

FIGURE 1

Overview of the key functions of the MERCs resident proteins. (a) The main ER–MT tethering factors are described from left to right. Although it is mainly localized at MT, a small amount of Mfn2 is found at ER, where it participates to the tethering of ER to MT through the formation of ER–Mfn2/MT–Mfn2 homodimers or ER–Mfn2/MT–Mfn1 heterodimers (de Brito and Scorrano, 2008; Cosson et al., 2012; Filadi et al., 2015; Naon et al., 2016). VAPB is an integral ER protein and binds the mitochondrial PTPIP51 protein. The reduced or increased expression of IP3R decreases or increases, respectively, the number of ER–MT contacts (Stoica et al., 2014; Gomez-Suaga et al., 2017). The ER-localized IP3R Ca²⁺ channel forms a tether with the mitochondrial Ca²⁺ channel VDAC. Their interaction is mediated by the mitochondrial chaperone 75 kDa Grp75 and modulates Ca²⁺ fluxes from the ER to the mitochondrial intermembrane space (Mendes et al., 2005; Szabadkai et al., 2006). The ER protein BAP31 interacts with the mitochondrial fission protein Fis1. The BAP31–Fis1 complex bridges the ER–MT interface and regulates the mitochondrial induction of apoptosis. The exact function of PACS2 at MERCS is still unknown but its depletion uncouples the ER from MT by inducing the cleavage of BAP31 and MT fragmentation (Simmen et al., 2005; Iwasawa et al., 2011). (b–e) Key cellular functions handled at MERCs (see the text for details). (b) MERCs are involved in lipid metabolism through the ER–MT exchange of PS, PE, PC, Cers, and Chol (Vance, 2014). (c) MERCs appear as sites promoting mitochondrial fission and fusion. During mitochondrial fission, INF2 recruits DRP1 at MERCs mediating the formation of the constriction ring around the mitochondrial outer membrane (Friedman et al., 2011; Chakrabarti et al., 2018). MFN2, the core component of mitochondrial fusion machinery, was found to localize at MERCs, were, together with OPA1, promotes the fusion of mitochondrial membranes. (d) ER–MT redox crosstalk occurs at MERCs where different mechanisms are responsible for ROS production: Ca²⁺ flux from the ER to MT through the IP3R/VADC Ca²⁺ channels, the oxidative folding activity of the ER chaperone Ero-1α, and the electron transport promoted by p66Shc at mitochondrial ETC. The high amount of ROS produced at MERCs generates redox nanodomains at ER–MT interface that modulates ER–MT apposition (Debattisti et al., 2017). (e) MERCs are emerged as important regulators of mitophagy/autophagy. During mitophagy, the MERCs localized Mfn2 is phosphorylated by PINK1. Phosphorylated Mfn2 recruits parkin that, in turn, mediates MFN2 ubiquitination leading to mitophagy initiation (Bockler and Westermann, 2014). Concomitantly, MERCs have been proposed as sites of autophagy initiation (Hamasaki et al., 2013; Bockler and Westermann, 2014). Upon starvation, the ER-resident protein STX17 recruits ATG14 to the MERCs. ATG14, along with other subunits of the Beclin 1/VPS34 complex, became enriched in the MAM and generates concentrated pools of PI3P necessary for IMs formation and expansion. The omegasome marker DFCP1 was also observed to translocate onto these PI3P-enriched regions with further associated markers like ATG5 (Axe et al., 2008; Hamasaki et al., 2013) contributing to the first steps of autophagosomes assembly.