SIRT5 is a sirtuin family member that participates in dynamic and reversible protein chemical modification after translation. It has pivotal roles in the regulation of numerous aspects of myocardial energy metabolism and cardiac functions. Recent studies suggest that down-regulation of this regulator significantly increased the extent of myocardial infarction during ischemia-reperfusion injury (IRI). Accordingly, SIRT5 is emerging as a major contributor to the pathogenesis of IRI and may possess therapeutic potential for reversing mitochondrial respiratory chain disturbances and cellular damage attributed to ischemia-reperfusion. To better understand this specific mechanism, we reviewed the structure of SIRT5, its gene distribution and the SIRT5 pathways that influence myocardial IRI associated with mitochondrial dynamics and oxidative phosphorylation.