The Mitochondrial Unfolded Protein Response: A Novel Protective Pathway Targeting Cardiomyocytes

Abstract

Mitochondrial protein homeostasis in cardiomyocyte injury determines not only the normal operation of mitochondrial function but also the fate of mitochondria in cardiomyocytes. Studies of mitochondrial protein homeostasis have become an integral part of cardiovascular disease research. Modulation of the mitochondrial unfolded protein response (UPRmt), a protective factor for cardiomyocyte mitochondria, may in the future become an important treatment strategy for myocardial protection in cardiovascular disease. However, because of insufficient understanding of the UPRmt and inadequate elucidation of relevant mechanisms, few therapeutic drugs targeting the UPRmt have been developed. The UPRmt maintains a series of chaperone proteins and proteases and is activated when misfolded proteins accumulate in the mitochondria. Mitochondrial injury leads to metabolic dysfunction in cardiomyocytes. This paper reviews the relationship of the UPRmt and mitochondrial quality monitoring with cardiomyocyte protection. This review mainly introduces the regulatory mechanisms of the UPRmt elucidated in recent years and the relationship between the UPRmt and mitophagy, mitochondrial fusion/fission, mitochondrial biosynthesis, and mitochondrial energy metabolism homeostasis in order to generate new ideas for the study of the mitochondrial protein homeostasis mechanisms as well as to provide a reference for the targeted drug treatment of imbalances in mitochondrial protein homeostasis following cardiomyocyte injury.

Figure 1

Regulatory mechanism of mitochondrial unfolded protein response. Mitochondrial unfolded protein response plays an important regulatory role in cell physiological activities. Under stress stimulation conditions such as ischemia/hypoxia or inflammation, the homeostasis of intracellular environment and mitochondrial homeostasis will be further destroyed. Oxidative phosphorylation (OXPHOS) disturbance, excessive ROS, impaired complex assembly (mitotic nucleoprotein imbalance), and accumulation of misfolded proteins further activate HSP47/PDIA46/ERDJ4 under the induction of mitochondrial proteins. Meanwhile, BIP/HRD-1 and IRE1α will activate in the intima. Together with HSP47/PDIA46/ERDJ4, it regulates the homeostasis of mitochondrial matrix and mitochondrial proteins, which is an important mechanism affecting mitochondrial protein homeostasis.

Figure 2

UPRmt is involved in cardiomyocyte mitochondrial homeostasis dysregulation and cardiomyocyte apoptosis. Mitochondrial ROS-induced mitochondrial oxidative stress is activated during the initial stages of myocardial injury and cardiomyocyte apoptosis. The mitochondrial membrane permeability transition pore (mPTP) is further activated, which induces an imbalance between the inner and outer mitochondrial environment, which in turn leads to a massive loss of mitochondrial membrane potential (MMP) and dysfunction of mitochondrial energy metabolism. This process activates the mitochondrial pathway of apoptosis, which in turn leads to cell death or apoptosis/necroptosis. UPRmt can be further activated under mild stress stimulation. Repairing mildly compromised mitochondrial oxidative stress damage or dysfunction, UPRmt can clear misfolded proteins (chaperones) or cleavage proteases. Unrepairable mitochondria may further undergo mitophagy, and mitochondrial DNA renewal and regeneration occurs through mitochondrial dynamics and mitochondrial biosynthesis.

Figure 3

Bidirectional regulation of UPRmt in cardiomyocyte mitochondrial injury and mitochondrial biogenesis, a double-edged sword. With mitochondrial aging and stress-induced mitochondrial death, the function of the mitochondrial respiratory chain will be severely affected, which will lead to mitochondrial ATP synthesis dysfunction, excessive accumulation of mitochondrial ROS, and then mitochondrial respiratory complexes dysfunction. It will eventually lead to mitochondrial oxidative phosphorylation dysfunction and mitochondrial tricarboxylic acid cycle dysfunction, which may be an important cause of mitochondrial protein dysfunction and mitochondrial damage. In the state of mild mitochondrial damage, UPRmt is activated, which in turn affects mitochondrial biosynthesis and mitochondrial homeostasis, providing a guarantee for the balance of intracellular homeostasis. In states of mild mitochondrial damage or dysfunction, UPR is beneficial as it reduces reactive oxygen species (ROS) production and increases ATP activity to protect mitochondrial function.

Figure 4

Work together to coordinate cardiomyocytes mitochondrial homeostasis, interaction of UPR with autophagy and mitophagy. The unfolded protein response (UPR) interacts with mitophagy and autophagy. Autophagy can form autophagosomes through the separation membrane initiated by wrapping cytoplasmic components (proteins and organelles) in cardiomyocytes inside the cell. These damaged or redundant proteins and organelles eventually fuse with lysosomes, which in turn are degraded. This process induces the activation of eIF2a and ATF4.Moreover, the accumulation of useless or damaged mitochondria in organelles also removes redundant or dysfunctional mitochondria by activating nonreceptor-mediated (PINK/Parkin) or receptor-mediated (FUNDC1) mitophagy. UPR can also coordinate with FUNDC1-mediated mitophagy under the activated state to jointly protect the mitochondria of cardiomyocytes under inflammation and maintain mitochondrial homeostasis. Mechanistically, deletion of autophagy genes may also induce UPR, suggesting a negative feedback mechanism. When the synergistic effect of mitochondrial UPR and mitophagy is dysregulated, it leads to dysregulation of cardiomyocyte homeostasis, activates cardiomyocyte mitochondrial dysfunction and mediates mitochondrial pathway apoptosis.

Figure 5

Stress factor-induced UPRmt is blocked and mitochondrial dynamics and biosynthesis dysfunction. Under the influence of stress factors, mitochondrial quality control can synergize with UPRmt. Hypoxia/ischemia, inflammation and hyperglycemia/hyperlipidemia induce mitochondrial dysfunction, which in turn leads to the activation of mitochondrial fission kinesins MFF/Fis1/Drp1 and the inhibition of the expression of mitochondrial fusion proteins OPA1/Mfn1 and Mfn2. This in turn leads to aggravated mitochondrial fission and mitochondrial dysfunction. This further leads to PGC1a and NRF1/NRF2-mediated mitochondrial biosynthesis impairment, decreased Tfam and mitochondrial transcription levels, and disturbance of the tricarboxylic acid cycle and oxidative phosphorylation levels, which may be important pathways of mitochondrial damage. At this time, UPR is activated, which may indirectly compensate for mitochondrial biosynthesis dysfunction and maintain cardiomyocyte function and cardiac function.