Mitigation of myocardial ischemia-reperfusion injury via HIF-1α-frataxin signaling.

MYOCARDIAL INFARCTION (MI) is a leading cause of death and disability globally that typically results from the abrupt occlusion of an epicardial coronary artery (9). As a result, cardiomyocytes distal to the occlusion are subject to oxygen and nutrient deprivation, which triggers mitochondrial electron transport chain (ETC) inhibition, reactive oxygen species (ROS) generation, and necrotic death of the ischemic core (6). While prompt reopening of the infarct-related artery is critical for salvaging viable myocardium, reperfusion itself is posited to inflict further damage via its ability to transiently hyperpolarize mitochondrial membranes, leading to massive bursts of ROS that open permeability transition pores to initiate apoptosis (4). Reperfusion injury can account for up to 50% of the final infarct size, but despite extensive research, no effective treatment has emerged. Greater understanding of the endogenous cardioprotective pathways recruited during ischemiareperfusion injury (IRI) might foster novel therapeutic strategies to improve outcomes after an MI. Hypoxia-inducible factor (HIF)-1 orchestrates the bodies adaptive response to oxygen deprivation and is the critical mediator of ischemic preand postconditioning (14, 15, 17, 18). It is a heterodimeric protein consisting of an oxygensensitive -subunit and a constitutive -subunit. Under normoxic conditions, HIF-1 undergoes rapid degradation, which is initiated by prolylhydroxylase domain proteins (PHDs) that are dependent on oxygen and iron-sulfur clusters (Fe-S) (5). At the onset of myocardial ischemia, cellular hypoxia directly inhibits PHDs to stabilize HIF-1 and, by inhibiting ETC activity, increases ROS release from complex I and III (7). In turn, ROS further augment HIF-1 levels partly by destabilizing Fe-S. HIF-1 mRNA levels are elevated in the hearts of patients with acute myocardial ischemia, and enhancement or inhibition of HIF-1 attenuates and worsens experimental IRI, respectively (8, 14). HIF-1 acts by binding onto hypoxiaresponsive elements in over 200 target genes and transcriptional coactivators (17). By augmenting angiogenic proteins, HIF-1 improves oxygen supply to ischemic territories. By suppressing mitochondrial function and switching metabolism from oxidative to glycolytic pathways, HIF-1 attenuates cardiac contractility to reduce oxygen demand. Inhibition of ETC activity during the ischemic phase is important as it reduces the magnitude of ROS production, permeability transition, and apoptosis at the onset of reperfusion. In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Nanayakkara et al. (13) provide evidence that the upregulation of frataxin is another mechanism via which HIF-1 mediates cardioprotection. Frataxin is an evolutionary-conserved mitochondrial matrix protein whose putative functions are thought to limit ROS production and oxidative stress (1). It is heavily implicated in the biogenesis of Fe-S, which are critical cofactors involved in ATP generation, intracellular oxygen, iron, and ROS sensing, and the replication and maintenance of the nuclear genome (10). During de novo Fe-S biogenesis, frataxin is hypothesized to chaperone iron onto multimeric protein complexes that assemble the clusters and transfers them onto apoproteins. Frataxin, which can sequester over 3,000 iron atoms, also donates iron to IX protoporphyrin during heme biosynthesis. Primary frataxin deficiency, as seen in the neurodegenerative disease Friedreich’s ataxia, is characterized by Fe-S depletion, mitochondrial iron accumulation, oxidative stress, and cardiomyopathy (1). This observation, coupled with other experimental data (16), inform the view that frataxin, irrespective of its role in Fe-S and heme biogenesis, functions also to maintain mitochondrial redox balance by sequestering free labile iron that can potentially generate dangerous hydroxyl radicals. Nanayakkara et al. (13) performed a series of studies to test the notion that a HIF-1 -frataxin-iron axis operates during myocardial IRI. After induction of IRI, the authors observed frataxin upgregulation in the hearts of wild-type mice but not in those of cardiomyocyte-specific HIF-1 knockout (KO) animals. Infarct size was significantly greater in HIF-1 KO mice, confirming the cardioprotective effect of HIF-1 . Knockdown of HIF-1 in H9C2 cardiomyocytes diminished frataxin levels, and a functional hypoxia-responsive element was found in the mouse frataxin promoter, implying a direct regulation of frataxin expression by HIF-1 . To explore downstream mechanisms, mitochondrial iron levels were quantified and found to be markedly elevated in the ischemic region of HIF-1 KO hearts compared with their nonischemic regions and wild-type animals. Mitochondrial iron levels were also increased in normoxic frataxin knockdown cells and become more so after the induction of hypoxia and/or HIF-1 inhibition. Furthermore, hypoxic H9C2 cells treated with a HIF-1 inhibitor exhibited the highest levels of ROS and mitochondrial membrane depolarization (a preapoptotic event), whereas cells overexpressing frataxin and those treated with an iron chelator and a HIF-1 inhibitor failed to show augmented ROS expression or mitochondrial membrane depolarization. Consequently, the authors concluded that HIF-1 partly cardioprotects by directly upregulating frataxin and that this upregulation restrains ROS production and mitochondrial membrane depolarization by preventing iron accumulation. While the study provides robust evidence that HIF-1 is cardioprotective partly via frataxin upregulation, the in vivo Address for reprint requests and other correspondence: D. Okonko, King’s College London, Cardiovascular Div., British Heart Foundation Ctr. of Excellence, James Black Ctr., 125 Coldharbour L., London, SE5 9NU, United Kingdom (e-mail: [email protected]). Am J Physiol Heart Circ Physiol 309: H728–H730, 2015; doi:10.1152/ajpheart.00553.2015. Editorial Focus