Modulating mitochondrial dynamics attenuates cardiac ischemia-reperfusion injury in prediabetic rats

Chayodom Maneechote1,2,3, Siripong Palee1,3, Sasiwan Kerdphoo1,3, Thidarat Jaiwongkam1,3, Siriporn C. Chattipakorn1,3, Nipon Chattipakorn1,2,3
1 Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
2 Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
3 Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand
Correspondence to: Nipon Chattipakorn:,
DOI: 10.1038/s41401-021-00626-3
Received: 8 October 2020
Accepted: 9 February 2021
Advance online: 12 March 2021


Mitochondria are extraordinarily dynamic organelles that have a variety of morphologies, the status of which are controlled by the opposing processes of fission and fusion. Our recent study shows that inhibition of excessive mitochondrial fission by Drp1 inhibitor (Mdivi-1) leads to a reduction in infarct size and left ventricular (LV) dysfunction following cardiac ischemia-reperfusion (I/R) injury in high fat-fed induced pre-diabetic rats. In the present study, we investigated the cardioprotective effects of a mitochondrial fusion promoter (M1) and a combined treatment (M1 and Mdivi-1) in pre-diabetic rats. Wistar rats were given a high-fat diet for 12 weeks to induce prediabetes. The rats then subjected to 30 min-coronary occlusions followed by reperfusion for 120 min. These rats were intravenously administered M1 (2 mg/kg) or M1 (2 mg/kg) combined with Mdivi-1 (1.2 mg/kg) prior to ischemia, during ischemia or at the onset of reperfusion. We showed that administration of M1 alone or in combination with Mdivi-1 prior to ischemia, during ischemia or at the onset of reperfusion all significantly attenuated cardiac mitochondrial ROS production, membrane depolarization, swelling and dynamic imbalance, leading to reduced arrhythmias and infarct size, resulting in improved LV function in pre-diabetic rats. In conclusion, the promotion of mitochondrial fusion at any time-points during cardiac I/R injury attenuated cardiac mitochondrial dysfunction and dynamic imbalance, leading to decreased infarct size and improved LV function in pre- diabetic rats.
Keywords: cardiac ischemia-reperfusion injury; obesity; prediabetes; mitochondrial dynamics; M1; Mdivi-1

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