Where the endoplasmic reticulum and the mitochondrion tie the knot: The mitochondria-associated membrane (MAM)

Abstract

More than a billion years ago, bacterial precursors of mitochondria became endosymbionts in what we call eukaryotic cells today. The true significance of the word "endosymbiont" has only become clear to cell biologists with the discovery that the endoplasmic reticulum (ER) superorganelle dedicates a special domain for the metabolic interaction with mitochondria. This domain, identified in all eukaryotic cell systems from yeast to man and called the mitochondria-associated membrane (MAM), has a distinct proteome, specific tethers on the cytosolic face and regulatory proteins in the ER lumen of the ER. The MAM has distinct biochemical properties and appears as ER tubules closely apposed to mitochondria on electron micrographs. The functions of the MAM range from lipid metabolism and calcium signaling to inflammasome formation. Consistent with these functions, the MAM is enriched in lipid metabolism enzymes and calcium handling proteins. During cellular stress situations, like an altered cellular redox state, the MAM alters its set of regulatory proteins and thus alters MAM functions. Notably, this set prominently comprises ER chaperones and oxidoreductases that connect protein synthesis and folding inside the ER to mitochondrial metabolism. Moreover, ER membranes associated with mitochondria also accommodate parts of the machinery that determines mitochondrial membrane dynamics and connect mitochondria to the cytoskeleton. Together, these exciting findings demonstrate that the physiological interactions between the ER and mitochondria are so bilateral that we are tempted to compare their relationship to the one of a married couple: distinct, but inseparable and certainly dependent on each other. In this paradigm, the MAM stands for the intracellular location where the two organelles tie the knot. Resembling "real life", the happy marriage between the two organelles prevents the onset of diseases that are characterized by disrupted metabolism and decreased lifespan, including neurodegeneration and cancer. This article is part of a Special Issue entitled: Mitochondrial dynamics and physiology.

Mitofusin 2 ablation increases endoplasmic reticulum–mitochondria coupling

“…Despite recent EM evidence (19) demonstrating that Mfn2 ablation results in an increase of the tight contacts between ER and mitochondria, the idea that Mfn2 is the key molecular component tethering the two organelles continues to be widely accepted (16,17,35,36). This classical model is based not only on morphological data obtained by confocal microscopy but also on functional evidence, in particular the reduced Ca 2+ transfer from the ER to mitochondria in Mfn2 −/− cells (18).…”

“…We further biochemically evaluated the association of the two organelles by quantifying, after partial mitochondria purification by differential centrifugation, the MAMs that remain associated with them (17). The amount of ER proteins contaminating crude mitochondria fractions is an indirect value of the ER-mitochondria physical association.…”

“…Several proteins have been suggested to be involved in maintaining a given distance between ER and mitochondria (16), allowing their correct organization, mutual interactions, and Ca 2+ cross talk (17). In mammalian cells, mitofusin 2 (Mfn2), located on both the outer mitochondrial membrane (OMM) and the ER surface, has been proposed to take part at the level of MAMs in homotypic interactions, and heterocomplexes engaging the Mfn2 homolog Mfn1 on mitochondria, that may contribute to ERmitochondria tethering (18).…”

Molecular mechanisms regulating NLRP3 inflammasome activation

“…107 These recent findings suggest that the mitochondria-associated membrane (MAM) structure -the physiological interaction between the endoplasmic reticulum and mitochondria -is critical for various biological functions including inflammasome activation. 108 Recently, resveratrol, a natural polyphenol, was shown to suppress the assembly of ASC and NLRP3 by inhibition of the acetylated a-tubulin-mediated spatial arrangement of mitochondria and endoplasmic reticulum, resulting in decreased NLRP3 inflammasome activation. 109 Moreover, when at least two NLRs are activated (e.g., by Salmonella enterica serovar Typhimurium), NLRC4 and NLRP3 are simultaneously present in a single inflammasome complex in macrophages to drive IL-1b processing.…”

Caught in the act – protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease

“…A black background to the amino acid residue indicates identical residues, a red background to the amino acid residue indicates similar residues, and a yellow background divergent residues. metabolism and autophagy (Raturi and Simmen, 2013;Sood et al, 2014;Theurey et al, 2016). Mammalian MAMs are formed by protein tethers, similar to the tetrameric tethering complexes in fungi known as ER-mitochondria encounter structures (ERMES) (Kornmann et al, 2009).…”