Quintana-Cabrera 2016 Abstract Mito Xmas Meeting Innsbruck

Cyclophilin D stabilizes FOF1-ATPase dimers and cristae shape to modulate permeability transition pore.

Link:

Quintana-Cabrera R, Corrado M, Scorrano L (2016)

Event: Mito Xmas Meeting 2016 Innsbruck AT

The permeability transition pore (PTP) represents a major trigger of mitochondrial-mediated cell death, accounting for necrosis and tissue damage subsequent to a wide spectrum of insults, such as cardiac or brain ischemia. Although FOF1-ATPase dimers have been recently proposed as a core constituent of PTP, its complete molecular identity and interactors are still under debate. However, there is wide consensus on the role of cyclophilin D (CyPD) as a positive PT modulator, yet the mechanism by which it regulates PTP remains obscure.

Here we provide evidence that the matrix protein CyPD stabilizes ATPase dimers in mitochondria. Upon genetic or pharmacological interference with CyPD, FOF1-ATPase dimers are loss, preventing PT opening. As a result of reduced ATPase dimerization cristae collapse and mitochondrial bioenergetics is compromised, as revealed by a higher susceptibility to membrane potential loss and matrix acidification upon complex III blockage.

In sum, CyPD stabilization of FOF1-ATPase dimers determines mitochondrial cristae structure and bioenergetics, favoring PTP opening in stress conditions. Importantly, our findings unveil a structural role for CyPD in the formation of PTP, challenging novel approaches in the prevention of PTP-mediated cell death.

Labels:

Stress:Ischemia-reperfusion, Permeability transition 

Enzyme: Complex III 

Event: A2, Oral 

Affiliations

Quintana-Cabrera R(1,2), Corrado M(3) and ScorranoL(1,2)

1. Dulbecco-Telethon Inst, Venetian Inst Molecular Medicine, Padova, Italy
2. Dept Biology, Univ Padova, Italy
3. Max Planck Inst Immunology Epigenetics, Freiburg, Germany