Modulation of mitochondrial permeability transition pores in reperfusion injury: Mechanisms and therapeutic approaches

Ischemia/reperfusion injury is attracting continuous interest in science for two reasons: because it affects several clinical conditions and because it has been identified, albeit in broad terms, the molecular entity becoming activated by the reperfusion damage paradoxes. Indeed, calcium, oxygen-dependent oxidative stress and pH would activate conformational changes in the mitochondrial cristae embedded F1/FO ATP synthase, allowing the formation of pores in the inner mitochondrial membrane thus increasing its permeability. This is a key determinant for mitochondrial stress, cell death and tissue dysfunction. Targeting each of these factors has never contributed to improved clinical outcome of the patients affected by reperfusion damage; now, the focus on the PTP opening could represent the closest target to solve this pathway made by extensive cell death when the tissues become revascularized. In this review, we summarized last knowledge about the structure, the modulation and the therapeutic targeting of the PTP, focusing on ATP synthase and cardiac ischemia/reperfusion.From research conducted over the last 10 years, it emerges that c subunit of ATP synthase, and in general this multiprotein complex, has a key role in the PTP activity in the ischemic cardiac disease. Its expression and conformational changes inside mitochondria are the culprits of an exacerbated reperfusion injury both at in vitro level and in human studies. The possibility to target c subunit and PTP opening for future therapeutic approaches as adjuvants to conventional therapies is also discussed.image