Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling.
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.
Cipolat
Sara
S
Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy.
Rudka
Tomasz
T
Hartmann
Dieter
D
Costa
Veronica
V
Serneels
Lutgarde
L
Craessaerts
Katleen
K
Metzger
Kristine
K
Frezza
Christian
C
Annaert
Wim
W
D'Adamio
Luciano
L
Derks
Carmen
C
Dejaegere
Tim
T
Pellegrini
Luca
L
D'Hooge
Rudi
R
Scorrano
Luca
L
De Strooper
Bart
B
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
D024101:Mitochondrial Proteins; D045304:Cytochromes c; D045726:Metalloproteases; C485223:PARL protein, human; C512710:PARL protein, mouse; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse