PARIS (Parkin Interacting Substrate) is a newly identified KRAB and zinc finger protein, acting as a transcriptional inhibitor for PGC-1 . Previous studies showed that Parkin, the E3 ubiquitin ligase, ubiquitinates PARIS and thus marks it for degradation via the protease system. It has been shown that PARIS plays a role for neurodegeneration in Parkinson's disease. However, the role of PARIS in the heart has not been previously studied. The objective of this study is to elucidate the role of PARIS in the context of mitochondrial biogenesis after myocardial ischemia. This report shows that the level of the protein PARIS decreases in both HL-1 cells (cardiac muscle cell line) during simulated ischemia and in the ischemic mouse heart, correlating with decreased mitochondrial content in these cells. Furthermore, most of the mitochondrial biogenesis factors increase expression during the ischemic stress. However, PARIS expression returns to baseline after 24h of reperfusion at a time when markers of mitochondrial biogenesis are high. Knockdown of PARIS via transcriptional targeting of siRNA did not alter markers of mitochondrial biogenesis under regular growth conditions but increased the rate of mitochondrial biogenesis during 24h reperfusion after ischemia. Taken together, these results indicate that degradation of PARIS during ischemic stress permits mitochondrial biogenesis during reperfusion. If PARIS expression is silenced during reperfusion, then the rate of mitochondrial biogenesis is increased in the HL-1 cells. Therefore, degradation of PARIS is a response to ischemic stress that facilitates mitochondrial biogenesis during the recovery phase.