title: Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling.
abstract: 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.
authors.affiliation: Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cipolat
authors.forename: Tomasz
authors.initials: T
authors.lastname: Rudka
authors.forename: Dieter
authors.initials: D
authors.lastname: Hartmann
authors.forename: Veronica
authors.initials: V
authors.lastname: Costa
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Serneels
authors.forename: Katleen
authors.initials: K
authors.lastname: Craessaerts
authors.forename: Kristine
authors.initials: K
authors.lastname: Metzger
authors.forename: Christian
authors.initials: C
authors.lastname: Frezza
authors.forename: Wim
authors.initials: W
authors.lastname: Annaert
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
authors.forename: Carmen
authors.initials: C
authors.lastname: Derks
authors.forename: Tim
authors.initials: T
authors.lastname: Dejaegere
authors.forename: Luca
authors.initials: L
authors.lastname: Pellegrini
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.forename: Luca
authors.initials: L
authors.lastname: Scorrano
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002100:Cachexia / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D005804:Genes, Lethal; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D045304:Cytochromes c; D045726:Metalloproteases; C485223:PARL protein, human; C512710:PARL protein, mouse; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse