Apoptosis and mitochondria dysfunction are key contributors to myocardial ischemia-reperfusion (MI-R) injury. SIRT4, a mitochondrial-localized sirtuin, controls cellular energy metabolism and stress response, and is abundantly present in the heart, however, its role in MI-R injury is not clear. In the current study, we demonstrate that SIRT4 is downregulated in cardiomyocytes both in vitro and in vivo models after MI-R. Functionally, SIRT4 overexpression decreases myocardial infarct size and serum creatine phosphokinase (CPK) level, and vice versa, SIRT4 depletion by siRNA increases myocardial infarct size and serum CPK level. Furthermore, we show that these protective roles of SIRT4 against MI-R injury are associated with preserved mitochondria! function and reduced myocardial apoptosis. Taken together, our findings indicate that SIRT4 ameliorates MI-R injury through regulating mitochondria] function and apoptosis, and suggest that manipulating SIRT4 may be of clinical benefit in MI-R injury. (C) 2018 Elsevier Inc. All rights reserved.