The aging of ER-mitochondria communication: A journey from undifferentiated to aged cells

Abstract

The complex physiology of eukaryotic cells requires that a variety of subcellular organelles perform unique tasks, even though they form highly dynamic communication networks. In the case of the endoplasmic reticulum (ER) and mitochondria, their functional coupling relies on the physical interaction between their membranes, mediated by domains known as mitochondria-ER contacts (MERCs). MERCs act as shuttles for calcium and lipid transfer between organelles, and for the nucleation of other subcellular processes. Of note, mounting evidence shows that they are heterogeneous structures, which display divergent behaviors depending on the cell type. Furthermore, MERCs are plastic structures that remodel according to intra- and extracellular cues, thereby adjusting the function of both organelles to the cellular needs. In consonance with this notion, the malfunction of MERCs reportedly contributes to the development of several age-related disorders. Here, we integrate current literature to describe how MERCs change, starting from undifferentiated cells, and their transit through specialization, malignant transformation (i.e., dedifferentiation), and aging/senescence. Along this journey, we will review the function of MERCs and their relevance for pivotal cell types, such as stem and cancer cells, cardiac, skeletal, and smooth myocytes, neurons, leukocytes, and hepatocytes, which intervene in the progression of chronic diseases related to age.

Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice

“…Another important outcome of this study is the validation of the translational value of APP/PS1 mice that recapitulate changes in mitochondrial morphology and MERCS hypergeneration found in AD patients [ 28 , 92 ]. Many promising therapeutic strategies shown to be efficacious in mouse models of AD failed clinical trials, emphasizing the need for better preclinical models.…”

Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice

“…Other important outcome of this study includes the validation of translational value of APP/PS1 mice that recapitulate changes in mitochondrial morphology and MERCS hypergeneration found in AD patients [24,59]. Many promising therapeutic strategies shown efficacious in mouse models of AD failed clinical trials, emphasizing the need for better preclinical models.…”

Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease

“…Our results suggest that the protective effect of PDK4 deficiency on ED-induced mitochondria dysfunction, to a significant extent, is independent of the canonical function of PDK4. The direct involvement of MAM in regulating insulin signaling, mitochondrial dynamics, autophagy, inflammation, apoptosis and senescence pathways are well evident 15 , 53 , 54 . Interestingly, all these pathways were shown to play a role in the progression of ALD 37 , 55 , 56 .…”