Cyclophilin D knockout mice do not accumulate succinate during cardiac ischemia

Dear Editor, A key driver of cardiac ischemia/reperfusion injury (IRI) and target for cardioprotection is the mitochondrial permeability transition pore (PTP). Persistent opening of the PTP leads to depolarization and increased permeability of the mitochondrial inner membrane followed by swelling and rupture, culminating in cell death [1]. The molecular characterization of the PTP remains contentious, however, cyclophilin D (CyD; a mitochondrial matrix peptidyl prolyl isomerase encoded by Ppif) is an important PTP modulator. Much of the evidence for the pathological role of the PTP in IRI comes from Ppif−/− mice which lack CyD [2]. Isolated mitochondria from these mice are highly resistant to PTP-induction and their hearts are profoundly protected against IRI in vivo. Based in part on observations from Ppif−/− mice, CyD has become a major target for the treatment of IRI, most notably through its potent inhibition by cyclosporin A (CsA). Blocking the PTP with CsA showed promise both in vitro and in pre-clinical animal models, although translation to patients was disappointing [3].