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

Sara Cipolat1, Tomasz Rudka, Dieter Hartmann

  • 1Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy.

Cell
|July 15, 2006
PubMed

Insights

Presenilin-associated rhomboid-like (PARL) protein is essential for processing OPA1, a mitochondrial protein crucial for preventing apoptosis. PARL deficiency leads to multisystem atrophy and death in mice due to increased programmed cell death.

Area of Science:

  • Mitochondrial biology
  • Cellular apoptosis
  • Protease function

Background:

  • Rhomboids are integral membrane proteases involved in signaling.
  • Presenilin-associated rhomboid-like (PARL) is a mitochondrial rhomboid with an unknown function.
  • PARL's yeast ortholog is implicated in mitochondrial fusion.

Purpose of the Study:

  • To investigate the function of Presenilin-associated rhomboid-like (PARL) in mammals.
  • To determine PARL's role in mitochondrial function and apoptosis.
  • To elucidate the mechanism by which PARL influences cell death.

Main Methods:

  • Generation and analysis of Parl-/- mice.
  • Assessment of apoptosis in Parl-/- cells and tissues.
  • Mitochondrial morphology and function assays.
  • Analysis of OPA1 processing and localization.
  • Complementation studies using OPA1 targeted to the intermembrane space.

Main Results:

  • Parl-/- mice exhibit progressive multisystem atrophy and cachectic death post-development.
  • Increased apoptosis is observed in Parl-/- cells and tissues, both in vitro and ex vivo.
  • Parl-/- cells are unprotected against intrinsic apoptotic stimuli due to impaired OPA1 function.
  • Reduced levels of soluble OPA1 in the intermembrane space of Parl-/- mitochondria.
  • PARL is crucial for OPA1 processing and intermembrane space targeting.
  • Parl-/- mitochondria show accelerated cristae remodeling and cytochrome c release during apoptosis.

Conclusions:

  • PARL plays a critical role in regulating apoptosis by controlling OPA1 processing.
  • Regulated intramembrane proteolysis, mediated by PARL, is a key factor in controlling apoptosis.
  • PARL deficiency leads to mitochondrial dysfunction and increased susceptibility to apoptotic cell death.

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