Data from Casin et al "Loss of cyclophilin D prolyl isomerase activity desensitizes mitochondrial permeability transition pore opening in isolated cardiac mitochondria, but does not protect in myocardial ischemia-reperfusion injury"

To define the role of CyPD prolyl isomerase activity in regulating PTP and necrotic cell death, we used CRISPR/Cas 9 to generate novel homozygous germline knock-in mice with a prolyl isomerase-dead CyPD R96G mutation in all cells (CyPD^R96G). Our data suggest prolyl isomerase activity is required for Ca²⁺-activated PTP in isolated mitochondria. Loss of isomerase activity does not protect against I/R injury whereas CyPD deletion protects, implying that isomerase dead CyPD can activate I/R-mediated death. However, altered metabolism in CyPD knockout mice could play a role [7]. These data would be consistent with the hypothesis suggesting two PTPs. We propose that PTP1 activation by CyPD requires isomerase activity and is the main PTP activity measured in isolated mitochondria with Ca²⁺ overload, whereas PTP2, which we hypothesize is primarily responsible for cell death in I/R, is potentiated by mutant CyPD lacking isomerase activity. If correct, this hypothesis would suggest that studies of PTP in isolated mitochondria may not translate to protection in I/R.