Mitochondria-associated membranes in aging and senescence: structure, function, and dynamics

Abstract

Sites of close contact between mitochondria and the endoplasmic reticulum (ER) are known as mitochondria-associated membranes (MAM) or mitochondria-ER contacts (MERCs), and play an important role in both cell physiology and pathology. A growing body of evidence indicates that changes observed in the molecular composition of MAM and in the number of MERCs predisposes MAM to be considered a dynamic structure. Its involvement in processes such as lipid biosynthesis and trafficking, calcium homeostasis, reactive oxygen species production, and autophagy has been experimentally confirmed. Recently, MAM have also been studied in the context of different pathologies, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, type 2 diabetes mellitus and GM1-gangliosidosis. An underappreciated amount of data links MAM with aging or senescence processes. In the present review, we summarize the current knowledge of basic MAM biology, composition and action, and discuss the potential connections supporting the idea that MAM are significant players in longevity.

Fig. 1

The historical timeline of the most important experimental observations and key discoveries in the course of studies devoted to interactions between mitochondria and the ER

Fig. 2. ROS-producing proteins localized in mitochondria, the ER, and MAM

Schematic representation of ER, mitochondria, and MAMs with major mechanism of ROS production and Ca²⁺ cross-talk. 2OGDH Oxoglutarate dehydrogenase, CYB5R3 NADH:cytochrome b5 reductase, cyt. c cytochrome c, DHODH dihydroorotate dehydrogenase, Ero1 endoplasmic reticulum oxireductin, ETF electron transfer flavoprotein-ubiquinone oxidoreductase, Ero1α endoplasmic reticulum oxidoreductin, GPDH glycerol-3-phosphate dehydrogenase, GRP75 75 kDa glucose-regulated protein, NADH:ubiquinone oxidoreductase (I), CoQH2-cytochrome c reductase (III), IMM inner mitochondrial membrane, IP3R inositol triphosphate receptor, KGDHC α-ketoglutarate dehydrogenase complex, MAO monoamine oxidases A/B, Nox4 NADPH oxidase 4, OMM outer mitochondrial membrane, p66Shc p66Shc protein, PDI protein disulfide isomerase, PDH pyruvate dehydrogenase, VDAC voltage-dependent anion channel

Fig. 3. Mitochondrial calcium uptake as a function of passage number

Mitochondrial Ca²⁺ responses ([Ca²⁺]_mit) in MEFs during ATP challenge as a function of a passage number. The pseudocolor scale (on the right) indicates the approximate changes of mitochondrial calcium level, where light pink represents low Ca²⁺ and red high (physiological) Ca²⁺ levels. Blue dots—represent senescence marker, β-galactosidase activity

Fig. 4. Lipid network at the MAMs

The ER-mitochondria contact sites integrate assembly of autophagosomes, synthesis, and trafficking of phospholipids, cholesterol (Chol) and ceramides (Cer) by a network of MAM- residing enzymes. AP autophagosome, LC3B microtubule-associated protein 1 light chain 3, CL cardiolipin, PA phosphatidic acid, PS phosphatidylserine, PE phosphatidylethanolamine, PC phosphatidylcholine, Preg pregnolone