TY - JOUR
T1 - Mitochondrial Rhomboid PARL Regulates Cytochrome c Release during Apoptosis via OPA1-Dependent Cristae Remodeling
AU - Cipolat, Sara
AU - Rudka, Tomasz
AU - Hartmann, Dieter
AU - Costa, Veronica
AU - Serneels, Lutgarde
AU - Craessaerts, Katleen
AU - Metzger, Kristine
AU - Frezza, Christian
AU - Annaert, Wim
AU - D'Adamio, Luciano
AU - Derks, Carmen
AU - Dejaegere, Tim
AU - Pellegrini, Luca
AU - D'Hooge, Rudi
AU - Scorrano, Luca
AU - De Strooper, Bart
N1 - Funding Information:
Research in BDS laboratory is supported by a Freedom to Discover grant from Bristol-Myers-Squibb; a Pioneer award from the Alzheimer's Association; the Fund for Scientific Research, Flanders; K.U. Leuven (GOA); European Union (APOPIS: LSHM-CT-2003-503330); and Federal Office for Scientific Affairs, Belgium (IUAP P5/19). L.S. is an Assistant Telethon Scientist of the Dulbecco-Telethon Institute. This research was supported by Telethon Italy; AIRC Italy; Compagnia di San Paolo; Human Frontier Science Program Organization. We thank Dr. Katsuyoshi Mihara (Kyushu University, Fukuoka, Japan) for the kind gift of the p3xFLAG-CMV14-AIF-Opa1 (IMS-OPA1-FLAG) plasmid.
PY - 2006/7/14
Y1 - 2006/7/14
N2 - Rhomboids, evolutionarily conserved integral membrane proteases, participate in crucial signaling pathways. Presenilin-associated rhomboid-like (PARL) is an inner mitochondrial membrane rhomboid of unknown function, whose yeast ortholog is involved in mitochondrial fusion. Parl-/- mice display normal intrauterine development but from the fourth postnatal week undergo progressive multisystemic atrophy leading to cachectic death. Atrophy is sustained by increased apoptosis, both in and ex vivo. Parl-/- cells display normal mitochondrial morphology and function but are no longer protected against intrinsic apoptotic death stimuli by the dynamin-related mitochondrial protein OPA1. Parl-/- mitochondria display reduced levels of a soluble, intermembrane space (IMS) form of OPA1, and OPA1 specifically targeted to IMS complements Parl-/- cells, substantiating the importance of PARL in OPA1 processing. Parl-/- mitochondria undergo faster apoptotic cristae remodeling and cytochrome c release. These findings implicate regulated intramembrane proteolysis in controlling apoptosis.
AB - Rhomboids, evolutionarily conserved integral membrane proteases, participate in crucial signaling pathways. Presenilin-associated rhomboid-like (PARL) is an inner mitochondrial membrane rhomboid of unknown function, whose yeast ortholog is involved in mitochondrial fusion. Parl-/- mice display normal intrauterine development but from the fourth postnatal week undergo progressive multisystemic atrophy leading to cachectic death. Atrophy is sustained by increased apoptosis, both in and ex vivo. Parl-/- cells display normal mitochondrial morphology and function but are no longer protected against intrinsic apoptotic death stimuli by the dynamin-related mitochondrial protein OPA1. Parl-/- mitochondria display reduced levels of a soluble, intermembrane space (IMS) form of OPA1, and OPA1 specifically targeted to IMS complements Parl-/- cells, substantiating the importance of PARL in OPA1 processing. Parl-/- mitochondria undergo faster apoptotic cristae remodeling and cytochrome c release. These findings implicate regulated intramembrane proteolysis in controlling apoptosis.
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U2 - 10.1016/j.cell.2006.06.021
DO - 10.1016/j.cell.2006.06.021
M3 - Article
C2 - 16839884
AN - SCOPUS:33745685054
SN - 0092-8674
VL - 126
SP - 163
EP - 175
JO - Cell
JF - Cell
IS - 1
ER -