Mitochondrial Rhomboid PARL Regulates Cytochrome c Release during Apoptosis via OPA1-Dependent Cristae Remodeling

Sara Cipolat, Tomasz Rudka, Dieter Hartmann, Veronica Costa, Lutgarde Serneels, Katleen Craessaerts, Kristine Metzger, Christian Frezza, Wim Annaert, Luciano D'Adamio, Carmen Derks, Tim Dejaegere, Luca Pellegrini, Rudi D'Hooge, Luca Scorrano, Bart De Strooper

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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.

Original languageEnglish (US)
Pages (from-to)163-175
Number of pages13
JournalCell
Volume126
Issue number1
DOIs
StatePublished - Jul 14 2006

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Cipolat, S., Rudka, T., Hartmann, D., Costa, V., Serneels, L., Craessaerts, K., Metzger, K., Frezza, C., Annaert, W., D'Adamio, L., Derks, C., Dejaegere, T., Pellegrini, L., D'Hooge, R., Scorrano, L., & De Strooper, B. (2006). Mitochondrial Rhomboid PARL Regulates Cytochrome c Release during Apoptosis via OPA1-Dependent Cristae Remodeling. Cell, 126(1), 163-175. https://doi.org/10.1016/j.cell.2006.06.021