Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death

Abstract

Mitochondria play a critical role in mediating both apoptotic and necrotic cell death. The mitochondrial permeability transition (mPT) leads to mitochondrial swelling, outer membrane rupture and the release of apoptotic mediators. The mPT pore is thought to consist of the adenine nucleotide translocator, a voltage-dependent anion channel, and cyclophilin D (the Ppif gene product), a prolyl isomerase located within the mitochondrial matrix. Here we generated mice lacking Ppif and mice overexpressing cyclophilin D in the heart. Ppif null mice are protected from ischaemia/reperfusion-induced cell death in vivo, whereas cyclophilin D-overexpressing mice show mitochondrial swelling and spontaneous cell death. Mitochondria isolated from the livers, hearts and brains of Ppif null mice are resistant to mitochondrial swelling and permeability transition in vitro. Moreover, primary hepatocytes and fibroblasts isolated from Ppif null mice are largely protected from Ca2+-overload and oxidative stress-induced cell death. However, Bcl-2 family member-induced cell death does not depend on cyclophilin D, and Ppif null fibroblasts are not protected from staurosporine or tumour-necrosis factor-alpha-induced death. Thus, cyclophilin D and the mitochondrial permeability transition are required for mediating Ca2+- and oxidative damage-induced cell death, but not Bcl-2 family member-regulated death.

Mitochondria as therapeutic targets for cancer chemotherapy

“…Hepatocyte mitochondria from control and Ppif À/À mice exhibited identical cyt c release patterns when treated with recombinant Bax or t-Bid (truncated Bid) proteins, whereas Ppif À/À mitochondria were protected from Ca 2 þ -induced cyt c release (Baines et al, 2005;Nakagawa et al, 2005). This indicates that the MOMP induced by proapoptotic Bcl-2 family members can occur independently from CypDregulated events.…”

Multiple Pathways to the Same End: Mechanisms of Myonuclear Apoptosis in Sarcopenia of Aging

“…Indeed, it was demonstrated that mPTP formation and apoptotic cell death could still occur in the absence of either ANT [57] or VDAC [58]. In contrast, overexpression of CyPD induced mitochondrial swelling and spontaneous cardiac apoptosis, whereas mice lacking cardiac CyPD were protected from ischemia/reperfusion-induced cell death [59]. Once MOMP has occurred, the release of apoptogenic factors stored in the mitochondrial intermembrane space ensues, initiating the series of events that culminate in cell death [31].…”

Mitochondria and aging: A role for the mitochondrial transition pore?

“…Currently, a common agreement considers that cyclophilin D (CypD), a soluble protein located within the mitochondrial matrix, is the main partner of the mPTP (Gutiérrez‐Aguilar & Baines, 2015) and that mPTP formation is greatly sensitized by CypD which lowers the calcium threshold required to trigger mPTP opening. The crucial role of CypD has been shown by deletion of the gene in mice, allowing mitochondria to sustain high calcium concentrations and thus conferring major desensitization of mPTP (Baines et al., 2005). Two opening states of the pore have been distinguished, a permanent or long‐lasting state which is associated with cell death, and a transient opening state having a physiological role by providing a pathway to release ROS and calcium from mitochondria which is also regulated by CypD (Elrod et al., 2010; Hausenloy, Wynne, Duchen, & Yellon, 2004; Petronilli et al., 1999).…”