Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Abstract

Cardiac disease is still the leading cause of morbidity and mortality worldwide, despite some exciting and innovative improvements in clinical management. In particular, atrial fibrillation (AF) and heart failure show a steep increase in incidence and healthcare costs due to the ageing population. Although research revealed novel insights in pathways driving cardiac disease, the exact underlying mechanisms have not been uncovered so far. Emerging evidence indicates that derailed proteostasis (i.e., the homeostasis of protein expression, function and clearance) is a central component driving cardiac disease. Within proteostasis derailment, key roles for endoplasmic reticulum (ER) and mitochondrial stress have been uncovered. Here, we describe the concept of ER and mitochondrial stress and the role of interactions between the ER and mitochondria, discuss how imbalance in the interactions fuels cardiac ageing and cardiac disease (including AF), and finally assess the potential of drugs directed at conserving the interaction as an innovative therapeutic target to improve cardiac function. of 15including the ubiquitin-proteasomal system (UPS) and autophagy [9]. In general, cellular stress, including stress caused by cardiac disease, activates multiple stress pathways, including the cytosolic heat shock response, the endoplasmic reticulum (ER) unfolded protein response (UPR ER ), and the mitochondrial UPR (UPR mt ) [10][11][12].Within the PQC, the ER and mitochondria play a critical role in the regulation of protein homeostasis and the maintenance of normal cellular function. The ER is an essential organelle involved in protein synthesis, folding, and trafficking. As protein folding is an error-prone process, the PQC system of the ER is specialized in optimizing this process, thereby preserving cardiac protein quality and homeostasis [13]. As approximately 30% of the cardiomyocyte volume is comprised of mitochondria, the maintenance of a healthy and functional mitochondrial PQC system, which includes molecular chaperones (e.g., HSP60 and HSP10) and proteases (e.g., ClpP), is critical to conserve the energy balance and cardiomyocyte function. The PQC system in mitochondria activates, upon stress, protein folding assistance mechanisms and promotes clearance of misfolded proteins to preserve mitochondrial function [14,15].Thus, a healthy proteostasis in cardiomyocytes safeguards the proper contractile function in the heart. The ER and mitochondria are essential organelles for regulating protein homeostasis, thereby guaranteeing cardiomyocyte function and survival. Therefore, a deeper understanding of ER and mitochondrial function during health and cardiac disease is required to ultimately develop novel therapeutic strategies. Role of the ER in Cardiac HealthThe ER is an essential organelle supporting multiple cellular processes such as protein synthesis, protein folding, regulation of Ca 2+ homeostasis, and contribution to the generation of autophagosomes and peroxisomes [16]. The ER lumen constitutes of a specialized fol...

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“…These processes all act when the mitochondria are under cellular stress. The mitochondrial protein folding environment is complex and the mitochondrial UPR (UPR mt ) is not as well-researched as its counterpart, the ER UPR (UPR ER ) (Li et al, 2019 ). UPR ER will be discussed in the next section.…”

“…Other proteins found in the SR involved in Ca 2+ signaling include Ca 2+ -ATPases (SERCAs), which work to import Ca 2+ into the ER and IP 3 Rs, which release Ca 2+ into the cytoplasm along with RyRs ( Figure 1 ) (Nixon et al, 1994 ). The SR is also the location that controls excitation–contraction coupling in cardiac myocytes (Li et al, 2019 ). When Ca 2+ homeostasis becomes dysfunctional, toxic misfolded proteins can accumulate and cause ER stress.…”