Integrating ER and Mitochondrial Proteostasis in the Healthy and Diseased Heart

Abstract

The integrity of the proteome in cardiac myocytes is critical for robust heart function. Proteome integrity in all cells is managed by protein homeostasis or proteostasis, which encompasses processes that maintain the balance of protein synthesis, folding, and degradation in ways that allow cells to adapt to conditions that present a potential challenge to viability (1). While there are processes in various cellular locations in cardiac myocytes that contribute to proteostasis, those in the cytosol, mitochondria and endoplasmic reticulum (ER) have dominant roles in maintaining cardiac contractile function. Cytosolic proteostasis has been reviewed elsewhere (2, 3); accordingly, this review focuses on proteostasis in the ER and mitochondria, and how they might influence each other and, thus, impact heart function in the settings of cardiac physiology and disease.

Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact

“…Cardiovascular disease is also linked to mitochondrial dysfunction through proteostasis failure related to lipid accumulation and ROS activity (Alam et al, 2020;Arrieta et al, 2020). Alterations in ribosome assembly, mitochondria, and cytosol translation pathway in the cell models, internal organs, and muscles (Figures 2 and 3) suggest the presence of proteostasis failure (Lu and Guo, 2020).…”

Mitochondrial Quality Control Governed by Ubiquitin

“…In fact, the physical interaction between these tubular organelles supports the transfer of lipids, calcium ions and other metabolites, localizes to DNA nucleoids and regulates mitochondrial dynamics (Helle et al, 2013;Raturi and Simmen, 2013;van Vliet et al, 2014;Phillips and Voeltz, 2016;Moltedo et al, 2019). Recent studies suggest an intricate cooperation between ER and mitochondria in proteostasis (Dederer et al, 2019;Matsumoto et al, 2019), which constitute a newly developing research field promising for the development of therapeutic interventions as proposed for cardiac pathologies (Arrieta et al, 2020).…”

Mitochondrial Membrane Intracellular Communication in Healthy and Diseased Myocardium

“…Moreover, PERK was cardioprotective in conditions of pressure overload-induced congestive HF (Liu et al, 2014 ). These studies indicate the complexity of the UPR ER and showcases that there are instances where it is adaptive, and other cases where it is maladaptive (Arrieta et al, 2020 ). Hence, mild and short-lived cardiac ER stress may be beneficial to clear unfolded, misfolded, or aged proteins to maintain proper cardiac function.…”

“…A healthy heart depends on balanced maintenance of contractile function and constant energy production. Regulation of cellular protein integrity in the heart is termed proteostasis, which involves heat shock response chaperones, autophagy, the ubiquitin–proteasome system, and the unfolded protein response (UPR) ( Figure 2 ) (Arrieta et al, 2020 ). These processes all act when the mitochondria are under cellular stress.…”