PT  - JOURNAL ARTICLE
AU  - Ahmed A. Mohsin
AU  - Qun Chen
AU  - Nanhu Quan
AU  - Thomas Rousselle
AU  - Michael W. Maceyka
AU  - Arun Samidurai
AU  - Jeremy Thompson
AU  - Ying Hu
AU  - Ji Li
AU  - Edward J. Lesnefsky
TI  - Mitochondrial Complex I Inhibition by Metformin Limits Reperfusion Injury
AID  - 10.1124/jpet.118.254300
DP  - 2019 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 282--290
VI  - 369
IP  - 2
4099  - http://jpet.aspetjournals.org/content/369/2/282.short
4100  - http://jpet.aspetjournals.org/content/369/2/282.full
SO  - J Pharmacol Exp Ther2019 May 01; 369
AB  - Transient, reversible blockade of complex I during early reperfusion after ischemia limits cardiac injury. We studied the cardioprotection of high dose of metformin in cultured cells and mouse hearts via the novel mechanism of acute downregulation of complex I. The effect of high dose of metformin on complex I activity was studied in isolated heart mitochondria and cultured H9c2 cells. Protection with metformin was evaluated in H9c2 cells at reoxygenation and at early reperfusion in isolated perfused mouse hearts and in vivo regional ischemia reperfusion. Acute, high-dose metformin treatment inhibited complex I in ischemia-damaged mitochondria and in H9c2 cells following hypoxia. Accompanying the complex I modulation, high-dose metformin at reoxygenation decreased death in H9c2 cells. Acute treatment with high-dose metformin at the end of ischemia reduced infarct size following ischemia reperfusion in vitro and in vivo, including in the AMP kinase-dead mouse. Metformin treatment during early reperfusion improved mitochondrial calcium retention capacity, indicating decreased permeability transition pore (MPTP) opening. Acute, high-dose metformin therapy decreased cardiac injury through inhibition of complex I accompanied by attenuation of MPTP opening. Moreover, in contrast to chronic metformin treatment, protection by acute, high-dose metformin is independent of AMP-activated protein kinase activation. Thus, a single, high-dose metformin treatment at reperfusion reduces cardiac injury via modulation of complex I.