Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling.

By S. Cipolat, T. Rudka, D. Hartmann, Veronica Costa, L. Serneels, K. Craessaerts, K. Metzger, C. Frezza, W. Annaert, L. D’Adamio and 6 more. Cell, 2006

759 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7cbd3002761064d1deb59a48e2097c219d97d1f1

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In Molecular Biology

1. D. C. Chan
2. R. Youle
3. Douglas R. Green
4. Guido Kroemer
5. B. Westermann
6. L. Galluzzi
7. L. Scorrano
8. J. Nunnari

Citations in the corpus

• Unraveling the Complex Interplay Between T Cell Metabolism and Function (2018, background): “(40) and the proteolytic cleavage of mediators of mitochondrial cristae structure (41).”
• Mitochondria and cell death: outer membrane permeabilization and beyond (2010, background): “Two IMS proteins, optic atrophy protein 1 ( OPA1 ; a dynamin-like GTPase) and presenilins-associated rhomboid-like protein ( PARL ; a rhomboid protease) have been found to regulate cristae remodelling during apoptosi”
• Mitochondria in Apoptosis: Bcl-2 family Members and Mitochondrial Dynamics (2011, background): “These data favor a model in which mitochondrial fission inhibition could retard cytochrome c release by preventing the remodeling of mitochondria cristae, a process that is thought to be required for efficient cytochrome c mobilization (Cipolat et al., 2006; Yamaguchi et al., 2008).”
• Mitochondrial membrane permeabilization in cell death. (2007, background): “The proteolytic activation of Opa1 is mediated by PARL (presenilin-associated rhomboid-like), a serine protease localized in the IM and whose yeast ortholog is implicated in mitochondrial fusion (136).”
• Targeting mitochondria for cancer therapy (2010, background): “Presenilin-associated rhomboid-like ( PARL ) is an integral protease of the inner membrane that modulates cytochrome c release by cleaving the dynamin-related protein optic atrophy 1 ( OPA1 ), thereby controlling the remodelling of cristae independently of mitochondrial fusion”
• Mitochondria: In Sickness and in Health (2012, background): “This protection is in part due to the role of OPA1 in the integrity of crista junctions and its ability to limit the release of proapoptotic IMS components (Cipolat et al., 2006; Frezza et al., 2006).”
• Mechanisms of mitochondrial fission and fusion. (2013, background): “It was initially reported that mammalian Opa1 is also cleaved by a rhomboid protease (Cipolat et al. 2006), but subsequent experiments with knockout cells for this rhomboid did not show an effect on Opa1 (Griparic et al. 2007).”
• OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. (2006, positive): “Parl is also a prerequisite for the antiapoptotic function of OPA1 (Cipolat et al., 2006).”
• Mitochondrial dynamics in mammalian health and disease. (2009, methodology): “To date, the main identified role for PARL is the generation of a soluble Opa1 isoform detected in the intermembrane space (IMS), which represents 4% of total IMS Opa1 in mitochondria (60, 101).”
• Mitochondrial dynamics and mitochondrial quality control (2014, background): “Second, damaged outer mitochondrial membrane proteins can be degraded by the proteasome [3].”
• PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin (2010, neutral): “Cell Culture HeLa YFP-Parkin, E18 Rat cortical neurons, PINK1 SV40transformed MEF cells, PINK1 SV40-transformed MEF, M17 neuroblastoma control shRNA, M17 neuroblastoma PINK1, Mfn1/2 MEF, and Parl MEF cell lines have been described previously [21,25,29,33,57,58].”
• The BCL-2 Family Reunion (2010, background): “The tight junctions in the IMM that compartmentalize cristae are secured by two splicing variants of OPA1 that are speculated to oligomerize, and this function is independent of OPA-1’s regulation of mitochondrial morphology (Cipolat et al., 2006; Frezza et al., 2006).”
• Mitochondrial fusion and fission in cell life and death (2010, background): “Several proteases have been implicated in alternative processing of mammalian OPA1, including the rhomboid-related protease presenilins-associated rhomboid-like (PARL”
• Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. (2008, neutral): “presenilin-associated rhomboid-like protease (PARL), m-AAA Paraplegin, and AFG3L2 proteases inmammals [69,72,73].”