The DJ-1-derived peptide, ND-13, confers cardioprotection by inhibiting mitochondrial fission and preserving mitochondrial bioenergetics via the RhoA-ROCK1-Drp1 pathway
Authors: Prakash Aishwarya , Crespo-Avilan Gustavo E , Loo Sze Jie , Yap En Ping , Chua Jasper , Jianhong Ching , Yitong Zeng , Lin Ying-Hsi , Contreras Whendy , Yu Fan , Cong Shuo , Dam Linh Chi , Ramachandra Chrishan J , Kalkhoran Siavash Beikoghli , Lu Shengjie , Offen Daniel , Hernandez-Resendiz Sauri , Hausenloy Derek J 
Published: June 2024

AbstractBackgroundAcute myocardial infarction (AMI) and post-infarct heart failure (HF) are among the leading causes of death and disability worldwide. As such, new treatments are urgently needed to protect the heart against the detrimental effects of acute ischemia/reperfusion injury (IRI), in order to prevent the onset of HF and improve clinical outcomes following AMI. Given that mitochondrial dysfunction is a key determinant of IRI-induced cardiomyocyte death in AMI, we investigated ND-13, a 13-amino acid peptide derived from the pro-survival protein DJ-1, as a novel mitoprotective strategy for limiting myocardial infarct size (IS) following AMI.Methods and ResultsIn isolated adult Dendra-2 mice cardiomyocytes subjected to simulated IRI, treatment with ND-13 peptide reduced cell death by 42%, decreased phosphorylation of Drp1 at Ser616 and inhibited mitochondrial fission, improved mitochondrial respiratory function, decreased oxidative stress, and preserved ATP levels. Treatment of cardiomyocytes with ND-13 decreased levels of RhoA and reduced activity of downstream ROCK1, the latter of which is known to phosphorylate Drp1 at Ser616. Inex vivoLangendorff-perfused hearts subjected to IRI, treatment with ND-13 at reperfusion reduced IS by 43%, attenuated oxidative stress and preserved post-infarct cardiac contractile function. Finally,in vivoadministration of ND-13 peptide at reperfusion in mice subjected to acute myocardial IRI reduced IS by 35% at 72-hours of reperfusion, and restored mitochondrial bioenergetics in cardiomyocytes isolated from the area-at-risk following 2-hours reperfusion as evidenced by preservation of key metabolites involved in glucose oxidation and fatty acid oxidation. The cardioprotective phenotype translated to improved cardiac function and less adverse left ventricular remodelling at 28 days post-infarction.ConclusionsWe show for the first time the mitoprotective effects of the DJ-1-derived peptide, ND-13, administered at the onset of reperfusion following AMI. We found that ND-13 protects mitochondria by inhibiting IRI-induced mitochondrial fission and preserved mitochondrial function following IRI via the RhoA-ROCK-Drp1 pathway. These findings highlight ND-13 as a novel mitoprotective agent which has the therapeutic potential for limiting IS and preventing HF in patients with AMI.Clinical PerspectiveWhat Is New?Administration of the DJ-1-derived peptide, ND-13, at the onset of reperfusion reduced myocardial infarct size and preserved cardiac contractile function following acute myocardial ischemia/reperfusion injury (IRI).The cardioprotective effect of ND-13 treatment was mediated by inhibition of IRI-induced mitochondrial fission and improvement in mitochondrial bioenergetics via the RhoA-ROCK-Drp1 pathway.What are the Clinical Implications?Treatment with ND-13 peptide at the onset of reperfusion has the therapeutic potential to reduce myocardial infarct size and prevent the onset of heart failure in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention.