Relations Between the Endoplasmic Reticulum and Mitochondria in Aging

This open access paper serves as a reminder that there is an enormous amount of complexity yet to be mapped and understood in cellular biochemistry, let alone in the way that this biochemistry changes over the course of aging. For example, there is still lot of room for discovery in, separately, the operation of mitochondria and the operation of the endoplasmic reticulum, both of which are of interest in the context of aging. Nothing in the cell is either static or stands alone, however, and so in addition to the internal operation of a specific type of cellular component, one has to also consider its relationships with other components, and how they interact in detail. It matters. This is one of the reasons why I am less optimistic about attempts to adjust the operation of metabolism in order to slow aging: the scope of work is enormous, given both the extent of the blank spaces still left on the map, and that filling in those blanks is necessary for meaningful progress along this road. One of the big advantages of the alternative course of action, of repairing the known root causes of aging, is that this attempts to revert metabolism back to the youthful configuration that we know works, even if we do not yet have a precise map to tell us exactly how and why it works.

Cellular organelles are no longer conceived as isolated entities with defined and unique functions, but as dynamic signaling nodes, where a single organelle may engage and influence the functioning of several cellular compartments and processes. Interorganelle interactions are facilitated by specialized structures that tie them together structurally and functionally. Mitochondria-associated membranes (MAMs) are subdomains that bring the endoplasmic reticulum (ER) and mitochondria into close proximity, enabling a complex cross talk. This physical association shapes mitochondrial morphology and dynamics, in addition to participate in the response to various stress stimuli, modulating metabolism, redox control, and apoptosis.

The ER is the primary site where transmembrane and secretory proteins are folded; in addition to operate as the main intracellular calcium reservoir and a site of lipid biosynthesis. Abnormal accumulation of misfolded proteins within the ER lumen may result in the loss of proteostasis, a condition referred to as ER stress. ER stress is triggered by physiological demands including high secretory activity, in addition to pathological conditions that may perturb protein folding and maturation, calcium homeostasis, redox balance, among other events. Under ER stress the unfolded protein response (UPR) is engaged, operating as a dynamic signaling network that enforces adaptive programs to restore proteostasis by reducing the load of unfolded proteins through the upregulation of genes involved in almost every aspect of the secretory pathway. However, if ER homeostasis cannot be restored, the UPR switches its signaling toward a proapoptotic mode to eliminate irreversibly damaged cells. Thus, the UPR is a central adjustor to control cell fate under ER stress, contributing to diverse pathological conditions including cancer, neurodegeneration, and diabetes, among others.

Interorganelle communication is emerging as a homeostatic network determining the switch from adaptive programs to cell death under stress conditions, where specialized sentinels are localized at organelle membranes to induce the core apoptosis pathway. Mitochondria represent an ancestral integrator of stress signals, modulating metabolic demands on a constantly fluctuating environment. Although the literature is still poor in relating the activity of the UPR to mitochondrial function, a new model is emerging where proteostasis and metabolic control are tightly interconnected at the structural and functional levels. This integration might be particularly relevant in pathological conditions such as diabetes and cancer, where the ER and mitochondria undergo high metabolic demands. The physical and functional relation between the ER and mitochondria has pleiotropic consequences to the cell by regulating autophagy, ROS production, metabolism, and protein synthesis.

At the intersection of all these processes, calcium mobilization is considered a key player in the dynamic cross talk between the ER and mitochondria. Importantly, different core members of the UPR are highly mutated in cancer, suggesting a direct contribution to disease initiation. Several pharmacological agents are available to target the UPR with interesting protective effects in cancer. It remains to be determined whether these therapeutic agents influence mitochondrial function through MAMs. Overall, the relevance of the intersection between ER and mitochondria is gaining increasing attention in recent years, and thus the specific activities of the UPR at MAMs needs to be systematically studied. Strategies to dissect and manipulate compartmentalized UPR responses may generate novel therapeutic insights, expanding the avenues in the area of drug discovery.

Link: https://doi.org/10.3389/fonc.2017.00055

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