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.

Keywords: UPR; endoplasmic reticulum; mitochondria; protein folding; proteostasis.

Figure 1

ER and Mitochondrial Proteostasis- (A) Proteostasis encompasses processes such as protein synthesis, degradation, and folding. A balance amongst such processes supports optimal proteome integrity. (B) Dysregulated proteostasis occurs when environmental conditions, including cardiac pathology, cause an imbalance in these processes, which activates adaptive compensatory responses, such as the unfolded protein responses (UPRs) in various organelles. (C) The UPR in the endoplasmic reticulum (ER) is called the UPR^ER. Increased levels of misfolded proteins in the ER activate three ER transmembrane proteins, ATF6, IRE1, and PERK, which cause increases in the transcription factors ATF6, XBP1, and ATF4, which together regulate genes designed to rebalance ER proteostasis. PERK also phosphorylates eIF2a, which arrests translation of most mRNAs, thus relieving the protein-folding burden on the ER and allowing for cell survival (D). (E) Continued dysregulation of proteostasis leads to chronic activation of the UPR^ER proximal sensors and cell death. (F) The UPR in mitochondria (mt) is called the UPR^mt. The levels of the mitochondrial proteases, LonP1 and CLpP decrease upon dysregulation of mitochondrial proteostasis. Decreased LonP1 and CLpP contribute to increasing the level of the transcription factor, ATF5, which regulates genes designed to rebalance mitochondrial proteostasis. (G) A potential integration point between the UPR^ER and the UPR^mt is the ability of the UPR^ER-activated transcription factor, ATF4 to increase expression of the UPR^mt protease, LonP1. (H) Another potential integration point between the UPR^ER and the UPR^mt is the ability of PERK to tether the ER to mitochondria at contact sites called mitochondrial associated membranes (MAMS).

Figure 2

Roles for the UPR^ER and UPR^mt in Cardiac Pathology- (A) In mouse models of cardiac ischemia/reperfusion and pathological cardiac hypertrophy there is evidence for activation of all three arms of the UPR^ER. (Center) Upon activation each arm of the UPR induces canonical ER stress response genes which support protection for ATF6 and IRE1/XBP1s and damage for PERK/ATF5. However, the ATF6 and IRE1/XBP1s arms of the UPR^ER also induce non-canonical gene programs that foster protection in the heart (left and right). (B) In mouse models of cardiac pathology the LonP1 and ATF5 aspects of the UPR^mt are activated and both are protective in these disease settings.