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Review
. 2022 Aug 19:10:946678.
doi: 10.3389/fcell.2022.946678. eCollection 2022.

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

Pablo Morgado-Cáceres  1   2   3 , Gianella Liabeuf  1   4   5 , Ximena Calle  1   2 , Lautaro Briones  1   4   6 , Jaime A Riquelme  1   2 , Roberto Bravo-Sagua  1   4   7 , Valentina Parra  1   2   8
Affiliations
Review

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

Pablo Morgado-Cáceres et al. Front Cell Dev Biol. .

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.

Keywords: aging; cellular diffentiation; chronic diseases; endoplasmic reticulum; mitochondria.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
MERCs participate throughout the cell life cycle. (A) MERCs are sites of close apposition between ER and mitochondria, maintained by proteins such as Vesicle-associated membrane protein-associated protein B (VAPB) and Protein tyrosine phosphatase-interacting protein 51 (PTPIP51), which form a bridge between the surfaces of both organelles. GRP75, on the other hand, tethers the IP3R and VDAC Ca2+ channels to allow for an efficient Ca2+ transfer. Mitofusins (MFNs) are present at the surface of both ER and mitochondria, purportedly forming a tether between both; however, this is a matter of controversy, as they have been proposed to also antagonize ER-mitochondria interaction. PACS-2, instead, is an ER-resident sorting protein enriched in MERCs, which governs MERCs composition. (B) MERCs have different functions according to the cell’s requirements. They participate in cell division, differentiation, death, survival and senescence via regulation of mitochondrial dynamics, Ca2+ homeostasis or ROS production.
FIGURE 2
FIGURE 2
MERCs fulfill various roles, according to the cell type. MERCs differentiate both in structure and function, according to the cell’s differentiation state, participating in crucial processes such as motor, nervous, metabolic and immunological responses. Age-related changes in MERCs are heavily implicated in the development of multiple pathologies. T-tubules: transverse tubules.
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