FOXO3a-dependent PARKIN negatively regulates cardiac hypertrophy by restoring mitophagy

Abstract

Background Sustained cardiac hypertrophy often develops maladaptive myocardial remodeling, and eventually progresses to heart failure and sudden death. Therefore, maladaptive hypertrophy is considered as a critical therapeutic target for many heart diseases. Mitophagy, a crucial mechanism in mitochondria quality control and cellular homeostasis, has been implicated in diverse cardiac disorders such as myocardial infarction, diabetic cardiomyopathy, cardiac hypertrophy and heart failure. However, what role mitophagy plays in heart diseases remains an enigma. PARKIN functions as an E3 ubiquitin protein ligase and mediates mitophagy cascades. It is still unclear whether PARKIN participates in the regulation of cardiac hypertrophy. Results PARKIN was downregulated in cardiomyocytes and hearts under hypertrophic stress. Enforced expression of PARKIN inhibited Ang II-induced cardiomyocyte hypertrophy. Compared to wide-type mice with Ang II-induced cardiac hypertrophy, Parkin transgenic mice subjected to Ang II administration showed attenuated cardiac hypertrophy and improved cardiac function. In addition, mitophagy machinery was impaired in response to Ang II, which was rescued by overexpression of PARKIN. PARKIN exerted the anti-hypertrophy effect through restoring mitophagy. In further exploring the underlying mechanisms, we found that PARKIN was transcriptionally activated by FOXO3a. FOXO3a promoted mitophagy and suppressed cardiac hypertrophy by targeting Parkin. Conclusions The present study reveals a novel cardiac hypertrophy regulating model composed of FOXO3a, PARKIN and mitophagy program. Modulation of their levels may provide a new approach for preventing cardiac hypertrophy and heart failure. Graphical Abstract

Prmt6-Foxo3a Attenuates Apoptosis by Upregulating Parkin Expression in Intestinal Ischemia-Reperfusion Injury

“…Foxo3a is a transcription factor that essential for cell survival and stress response, which involved in various cellular processes, including apoptosis and mitochondrial dynamics (28). Emerging evidence have demonstrated that Parkin interact with Foxo3a to coordinate mitochondrial dynamics, enhance mitochondrial quality control, and suppress cell apoptosis (42,43). In this study, we found Foxo3a blinds to Parkin and regulates the expression of Parkin protein.…”

“…This hyperactivation of FoxO3a could potentially play a role in the transcriptional regulation of the Parkin pathway as FoxO3a has been identified as a transcriptional regulator of Parkin, influencing cell proliferation, migration, and apoptosis in gastric cancer (21). In addition, Sun et al (43) have reported that FoxO3a regulates Parkin transcription by binding to the consensus sequence within the Parkin gene’s promoter region, thereby playing a critical role in mitophagy and autophagy processes in cardiac hypertrophy . These findings are consistent with ours.…”

Mitochondrial quality control in health and cardiovascular diseases

“…In addition, the same study showed that Prdx3 interacts with PINK1 and blocks its proteolytic cleavage during mitophagy, playing a protective role during hypertrophy-induced mitochondrial dysfunction (Sonn et al, 2022). Of note, Parkin levels decline in hypertrophic cardiomyocytes, as well as mouse hearts, and overexpression of Parkin in mice blocked Ang-IIinduced hypertrophy and improved heart function via boosting mitophagy, highlighting the importance of clearance of damaged mitochondria during cardiac hypertrophy (Sun et al, 2022).…”

Synaptotagmin-1 attenuated myocardial programmed necrosis and ischemia/reperfusion injury through the mitochondrial pathway

“…Echocardiography was carried out as we described previously [32]. In brief, 1-2 weeks after I/R injury, transthoracic echocardiography was performed under 2% iso urane anaesthesia to analyze cardiac structure and function using Prospect High Resolution Imaging System equipped with a 40 MHz probe.…”