Unfolding the roles of mitochondria as therapeutic targets for heart disease

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 function¹. Mitochondrial dysfunction and consequent reductions in ATP contribute to pathology in heart disease¹. While numerous studies have shown that heart disease is associated with, if not caused by the misfolding of proteins outside mitochondria in cardiac myocytes², 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 examined the effects of left ventricular pressure overload on the misfolding of mitochondrial proteins³. They showed that pressure overload in mice activates an intracellular signaling program called the mitochondrial unfolded protein response (UPR^mt), and that pharmacologic boosting of the UPR^mt reduces cardiac pathology in this model. They also showed that hearts from patients with aortic stenosis, which is often associated with left ventricular overload⁴, exhibited increased expression of genes associated with the UPR^mt. This study suggests that cardiac pathology causes the misfolding of mitochondrial proteins, which activates adaptive aspects of the UPR^mt, and that enhancing the UPR^mt might serve as a potential therapeutic strategy for treating heart disease.

Studies of the UPR^mt and other unfolded protein responses in C. elegans, yeast and mammalian cells provide important clues for 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 accumulation of toxic misfolded proteins by detecting them and then reconfiguring the cellular machinery in ways that augment cellular protein-folding capacity while also increasing the degradation of misfolded proteins⁷. There are distinct unfolded protein responses that are activated by misfolded proteins in different organelles. For example, the UPR^mt, 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 contractility⁸ (Figure 1, steps 1 and 2). The UPR^mt 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. Impaired folding of mitochondrial proteins that are critical for mitochondrial function is an activator of mitophagy and the UPR^{mt 9}. This co-activation of the UPR^mt and mitophagy implicates the importance of the UPR^mt as a regulator of mitochondrial quality control in the heart. Further underscoring the crucial nature of the UPR^mt in the heart are studies in other cells and organs showing that the UPR^mt 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 (ROS)⁵.

Figure 1 -.

Diagram of the roles for ATF5 in the mitochondrial unfolded protein response (UPR^mt) in the healthy and diseased heart. Steps 1–8 are described in the text of this article.

Much of what is known about the UPR^mt has come from studies in C. elegans^5,6 leading to many inferences about how the UPR^mt might function in cardiac myocytes. A key regulator of the UPR^mt is ATF5¹⁰, a transcription factor that localizes to mitochondria when mitochondrial protein folding are optimal. Under these conditions mitochondrial proteases, such LonP1 and 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 and the mitochondrial proteases, LonP1 and ClpP⁸ (Figure 1, step 8); thus, increased levels of ATF5 and the genes it transcriptionally induces are indicators of UPR^mt activation. Indeed, Smyrnias et al. 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 UPR^mt, decreased pathology and improved cardiac performance during pressure overload³.

Interestingly, UPR^mt activation induces the C/EBP transcription factor, CHOP, which under these conditions induces many genes that encode adaptive proteins of the UPR^{mt 11}. Consistent with this was the finding by Smyrnias et al that CHOP was also increased by pressure overload and aortic stenosis³. This finding raises the question of overlap between unfolded protein responses, since CHOP is also induced by the ER unfolded protein response, UPR^ER. The UPR^ER is analgous to the UPR^mt, in that misfolded proteins lead to its activation, but differs from the UPR^mt in that it is misfolded proteins in the ER that lead to activation of the UPR^ER. Further distinguishing the UPR^mt and the UPR^ER are that the initiators of the two responses differ, consistent with their different subcellular locations⁵. However, even though they are initiated by protein misfolding in two different subcellular locations, and by different sensors of misfolded proteins, the UPR^mt and the UPR^ER induce several common regulatory proteins, one of which is CHOP. However, in contrast to the UPR^mt, where CHOP is adaptive¹⁰, in the case of the UPR^ER, CHOP initiates apoptotic death in cells where the adaptive aspects of the UPR^ER are insufficient for restoring protein folding in the ER¹². Findings such as this highlight the fact that there is overlap between cellular unfolded proteins responses, such as the UPR^mt and the UPR^ER, but at least in the case of CHOP, there must be some yet-to-be-discovered, stress-specific mechanisms involved that dictate the dramatically different functions of such overlapping regulatory proteins⁵.

While much remains to be learned about the diverse cellular unfolded protein responses, the study here by Smyrnias et al provides important new information about one of these responses, the UPR^mt, demonstrating that key features of this important unfolded protein response are activated in pressure overload, and that in this setting, the UPR^mt appears to serve an adaptive, protective role in the heart.