Author + information
- San Diego State University Heart Institute and the Department of Biology, San Diego State University, San Diego, California
- ↵∗Address for correspondence:
Dr. Christopher C. Glembotski, SDSU Heart Institute and Department of Biology, San Diego State University, 5500 Campanile Drive, San Diego, California 92182.
As the powerhouse of cardiac myocytes mitochondria are responsible for generating most of the chemical energy in the form of ATP that is required for cardiac contractility and robust heart function (1). Mitochondrial dysfunction and consequent decreases in ATP contribute to pathology in heart disease (1). Although numerous studies have shown that heart disease is associated with, if not caused by, the misfolding of proteins outside mitochondria in cardiac myocytes (2), little is known about the effects of protein misfolding in mitochondria, which could have dire effects on myocardial energy generation and cardiac function. In this issue of the Journal, Smyrnias et al. (3) examined the effects of left ventricular pressure overload on the misfolding of mitochondrial proteins. They showed that pressure overload in mice activates an intracellular signaling program called the mitochondrial unfolded protein response (UPRmt), and that pharmacological boosting of the UPRmt reduces cardiac pathology in this model. They also showed that hearts from patients with aortic stenosis, which is often associated with left ventricular pressure overload (4), exhibited increased expression of genes associated with the UPRmt. This study suggests that cardiac pathology causes the misfolding of mitochondrial proteins, which activates adaptive aspects of the UPRmt, and that by minimizing the misfolding of mitochondrial proteins, enhancing the UPRmt might serve as a potential therapeutic strategy for treating heart disease.
Studies of the UPRmt and other unfolded protein responses in C. elegans, yeast, and mammalian cells form most of the basis of our understanding of the pathological consequences in the heart of toxic misfolded proteins (5,6). Quality control pathways, such as the unfolded protein responses, are designed to guard against the accumulation of toxic misfolded proteins by detecting them and then reconfiguring the cellular machinery in ways that augment protein-folding capacity, while also increasing the degradation of misfolded proteins (7). Distinct unfolded protein responses are activated by misfolded proteins in different organelles. For example, the UPRmt, which is activated by misfolded proteins in mitochondria, reconfigures the cellular machinery to remedy this impairment, which ensures the maintenance of optimal mitochondrial performance and, in the heart, robust cardiac myocyte contractility (8) (Figure 1, steps 1 and 2). The UPRmt is involved in a major aspect of mitochondrial quality control: the removal of dysfunctional mitochondria by mitophagy. Mitophagy is impaired in the diseased heart in ways that challenge the maintenance of optimally functioning mitochondria, leading to increases in dysfunctional mitochondria, which, due to reduced ATP generation, places cardiac myocyte contractility at risk. The misfolding of mitochondrial proteins that are critical for mitochondrial function activates both mitophagy and the UPRmt (9). This coactivation of the UPRmt and mitophagy implicates the importance of the UPRmt as a regulator of mitochondrial quality control in the heart. Further underscoring the crucial nature of the UPRmt in the heart are studies in other cells and organs showing that the UPRmt is activated by imbalances in the levels of the proteins that comprise the electron transport chain, by decreased levels of mitochondrial chaperones, and by reactive oxygen species (5).
Much of what is known about the UPRmt has come from studies in C. elegans (5,6); these studies lead to inferences about how the UPRmt might function in cardiac myocytes. A key regulator of the UPRmt is cyclic AMP-dependent transcription factor ATF-5 (Atf5) (10), a transcription factor that localizes to mitochondria when mitochondrial protein folding is optimal. Under these conditions, mitochondrial proteases, such Lon protease homolog, mitochondrial (LonP1) and ATP-dependent Clp protease proteolytic subunit (ClpP), degrade Atf5 so it does not function as a transcription factor (Figure 1, step 3). However, when misfolded proteins accumulate in mitochondria, which decreases ATP and impairs cardiac contractility (Figure 1, steps 4 and 5), LonP1 and ClpP are diverted to degrading those misfolded proteins to minimize their toxic effects on mitochondrial function (Figure 1, step 6). This diversion of mitochondrial proteases away from Atf5 allows the level of Atf5 to increase, which leads to its export from mitochondria into the cytosol and eventually to the nucleus (Figure 1, step 7). In the nucleus Atf5 binds to and increases the transcription of genes encoding proteins that improve mitochondrial protein folding, including mitochondrial chaperones; increases in Atf5 also induce the mitochondrial proteases LonP1 and ClpP8 (Figure 1, step 8); thus, increased levels of Atf5 and the genes it transcriptionally induces are indicators of UPRmt activation. Indeed, Smyrnias et al. (3) showed that Atf5 and its target genes were induced in mouse hearts subjected to chronic pressure overload, as well as in the hearts of patients with aortic stenosis. They went on to demonstrate that treating mice with nicotinamide riboside, which is known to induce the UPRmt, decreased pathology and improved cardiac performance during pressure overload (3).
Interestingly, UPRmt activation induces the C/EBP transcription factor CCAT-enhancer-binding protein homologous protein (CHOP), which under these conditions induces many genes that encode adaptive proteins of the UPRmt (11). Consistent with this was the finding by Smyrnias et al. (3) that CHOP was also increased by pressure overload and aortic stenosis (3). This finding raises the question of overlap between unfolded protein responses, because CHOP is also induced by the endoplasmic reticulum unfolded protein response (UPRER). The UPRER is analogous to the UPRmt, in that misfolded proteins lead to its activation, but differs from the UPRmt in that it is misfolded proteins in the endoplasmic reticulum (ER) that activate the UPRER. Further distinguishing the UPRmt and the UPRER are that the initiators of the 2 responses differ, consistent with their different subcellular locations (5). However, even though they are initiated by protein misfolding in 2 different subcellular locations and by different sensors of misfolded proteins, and even though the UPRmt and the UPRER induce mostly different gene programs, they do induce several common regulatory proteins, one of which is CHOP. However, in contrast to the UPRmt, where CHOP is adaptive (10), when CHOP is induced by the UPRER it is maladaptive, leading to the death in cells where the adaptive aspects of the UPRER are insufficient for restoring protein folding in the ER (12). Findings such as this highlight the fact that there is overlap between cellular unfolded proteins responses, such as the UPRmt and the UPRER, and that in the case of one of the common genes, CHOP, there must be some yet-to-be-discovered, stress-specific mechanisms that dictate the dramatically different functions of such overlapping regulatory proteins (5).
While much remains to be learned about the diverse cellular unfolded protein responses, the study here by Smyrnias et al. (3) provides important new information about one of these responses, the UPRmt, demonstrating that key features of this important unfolded protein response are activated in pressure overload and that, in this setting, the UPRmt appears to serve an adaptive, protective role in the heart.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2019 American College of Cardiology Foundation
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