2006 Award WinnerDr. Luca Scorrano
Venetian Institute of Molecular Medicine, Padova, Italy
Luca Scorrano, born 1971Current appointments
Group Leader, Venetian Institute of Molecular Medicine
Assistant Telethon Scientist, Dulbecco-Telethon Institute
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Mitochondria are essential organelles for life and death of the cell. They produce most ATP and integrate apoptotic signals by releasing cytochrome c in the cytosol, where it activates the effector caspases. The release of cytochrome c is accompanied by fragmentation of the mitochondrial network and by profound changes of the inner membrane of the organelle. This latter “cristae remodelling pathway” is required to release the vast majority of cytochrome c.
OPA1, a dynamin related protein of the inner mitochondrial membrane mutated in dominant optic atrophy, seemed a natural candidate to control cristae remodelling. OPA1 drives fusion by cooperating with Mitofusin 1. Separately from this pro-fusion function, OPA1 protects from apoptosis by impinging on the cristae remodelling pathway. Oligomers that contain integral membrane and soluble OPA1, generated by posttranslational modification by PARL, an inner mitochondrial membrane rhomboid protease, are disrupted early during remodelling of the cristae.
The essential role of PARL in this process was confirmed by the analysis of mice lacking PARL, which display multi-organ failure due to excess apoptosis. This is sustained by increased cytochrome c release, which can be normalized by the targeted reintroduction of OPA1 in the intermembrane space of PARL-/- mitochondria.
Thus, the cristae remodelling pathway, controlled by OPA1, is a novel step of the mitochondrial involvement in apoptosis, that can be pharmacologically targeted.Laudatio for Dr. Scorrano held by Professor Kai Simons