New functions of mitochondria associated membranes in cellular signaling

Abstract

In all eukaryotic cells, the endoplasmic reticulum (ER) and the mitochondria establish a tight interplay, which is structurally and functionally modulated through a proteinaceous tether formed at specific subdomains of the ER membrane, designated mitochondria-associated membranes or MAMs. The tethering function of the MAMs allows the regulation of lipid synthesis and rapid transmission of calcium (Ca(2+)) signals between the ER and mitochondria, which is crucial to shape intracellular Ca(2+) signaling and regulate mitochondrial bioenergetics. Research on the molecular characterization and function of MAMs has boomed in the last few years and the list of signaling and structural proteins dynamically associated with the ER-mitochondria contact sites in physiological and pathological conditions, is rapidly increasing along with the realization of an unprecedented complexity underlying the functional role of MAMs. Besides their established role as a signaling hub for Ca(2+) and lipid transfer between ER and mitochondria, MAMs have been recently shown to regulate mitochondrial shape and motility, energy metabolism and redox status and to be central to the modulation of various key processes like ER stress, autophagy and inflammasome signaling. In this review we will discuss some emerging cell-autonomous and cell non-autonomous roles of the MAMs in mammalian cells and their relevance for important human diseases. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.

Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance

“…The molecular and functional characterisation of MAMs in physiological and pathological conditions has improved in the last few years, highlighting unexpected roles for MAMs in cellular signalling [7]. Particularly, we recently demonstrated that cyclophilin D (CYPD), a mitochondrial protein known to modulate the opening of the PTP [8], also interacts with the VDAC-GRP75-IP3R complex at the MAM interface in both heart [9] and liver [10].…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…Thus, to define a specific MAM proteome, sophisticated isolation strategies combined with quantitative mass spectrometry approaches are required in the future. Nevertheless, to date a considerable number of proteins is generally accepted to be significantly enriched in the MAM and can be used as marker proteins for this subcompartment (Vance, 2014;van Vliet et al, 2014). Since the MAM is continuous with the remaining ER it is also pertinent to discuss the mechanisms which lead to enrichment of specific proteins in this membrane subcompartment.…”

“…Further signaling networks, in which mitochondria and the ER were reported to cooperate at the MAM are involved in the activation of the antiviral innate immune response (Marchi et al, 2014;van Vliet et al, 2014). Cytosolic pathogen recognition receptors RIG-I are able to detect cytosolic foreign RNA and subsequently induce the production of type I interferons and proinflammatory cytokines (Sumpter et al, 2005).…”

“…In 1990, however, J. Vance discovered that the microsomes co-sedimenting with mitochondria represent a specialized cellular subcompartment and proposed the name "mitochondria associated membrane of the endoplasmic reticulum" (MAM) (Vance, 1990) (Figure 1). In the decades after this ground-breaking discovery our understanding of the functional significance of the MAM has greatly advanced revealing that this special ER compartment communicates with mitochondria in order to fulfill a plethora of functions associated with, among others, lipid metabolism and Ca 2+ signaling but also the regulation of mitochondrial maintenance and programmed cell death/cell survival reflecting different levels of complexity (Raturi and Simmen, 2013;Vance, 2014;van Vliet et al, 2014). As these diverse functions imply, it is still not clear if there is one single MAM compartment or if there are several MAMs equipped with a specialized sub-proteome in order to fulfill different functions.…”

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

“…MAMs are responsible for regulating mitochondrial shape and motility, as well as bioenergetics and redox status. Besides that, MAMs have a central role in the modulation of several key processes for cell survival, such as ER stress, autophagy, inflammasome signaling and apoptosis [32]. MAMs composition and abundance are highly dynamic being modulated by metabolic demands and cellular insults in order to adapt to different conditions.…”