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.

Causal roles of mitochondrial dynamics in longevity and healthy aging

“…Furthermore, processes requiring ER involvement which directly or indirectly affect mitochondrial shape such as Ca 2+ buffering, mitophagy, and ER‐UPR are all dysregulated with age indicating that ER dysfunction can itself contribute to mitochondrial dynamic dysregulation. Consistent with the importance of ER‐mitochondria encounter structures, ERMES (mitochondria‐ER contact sites, MAM equivalents) are also decreased in senescent yeast cells suggesting that maintenance of ER‐mitochondria proximity might be effective in conservation of organelle function . Whether shared mitochondrial and ER functions and dynamics co‐evolved and whether their interactions can be altered to decrease age‐related organellar dysregulation await further scientific attention.…”

“…Conversely, ER might function to increase DRP1‐independent constriction of the mitochondria if fission rates are low. Indeed, reduced mitochondria‐ER contacts have been reported in aged cells, suggesting that with age ER regulation of mitochondrial dynamics might decline and contribute to age‐associated imbalance in mitochondrial dynamics . Furthermore, in addition to fission proteins, MFN2 but not MFN1 was shown to localize to ER .…”

BCL-w: apoptotic and non-apoptotic role in health and disease

“…Cellular senescence is a form of cell cycle arrest that can develop in response to DNA damage, nutrient deficiency, telomere shortening, oxidative stress, and oncogene activation. Senescence induction is often executed as a barrier against tumorigenesis, but senescent cells can produce growth factors and cytokines, collectively named as the senescent-associated secretory phenotype (SASP), which can promote tumor development 150 . It was demonstrated that co-inhibition of BCL-w and BCL-X L by specific siR-NAs or by a BH3 mimetic (ABT-737) induced apoptosis in senescent human fibroblasts in vitro 151 .…”

Targeting mitochondria‐associated membranes as a potential therapy against endothelial injury induced by hypoxia

“…Therefore, MAMs are involved in steroid synthesis, phospholipid metabolism, autophagy, inflammation and mitochondrial bioenergetics. Recent studies have described the important role of MAMs in the pathogenesis of several diseases such as senescence, Alzheimer's disease, obesity and myocardial ischemia‐reperfusion . However, the role of MAMs in hypoxia‐induced mitochondrial impairment and injury in ECs remains unclear.…”

“…Recent studies have described the important role of MAMs in the pathogenesis of several diseases such as senescence, Alzheimer's disease, obesity and myocardial ischemia-reperfusion. [20][21][22][23] However, the role of MAMs in hypoxia-induced mitochondrial impairment and injury in ECs remains unclear.…”