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Caspases indirectly regulate cleavage of the mitochondrial fusion GTPase OPA1 in neurons undergoing apoptosis

F Alexandra Loucks1, Emily K Schroeder, Amelia E Zommer

  • 1Research Service, Veterans Affairs Medical Center, Denver, Colorado, USA.

Brain Research
|December 3, 2008
PubMed

Insights

Mitochondrial dynamics protein OPA1 is cleaved during neuronal apoptosis, a process linked to neurodegeneration. Caspases indirectly regulate this OPA1 cleavage, impacting mitochondrial fragmentation.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Mitochondrial Dynamics

Background:

  • Mitochondrial fission and fusion, regulated by dynamin GTPases, are crucial for neuronal health.
  • Imbalances in these processes, such as increased fission (Drp1) or decreased fusion (OPA1), lead to neuronal apoptosis and neurodegeneration.
  • Post-translational processing of OPA1 affects its function, with aberrant processing observed during apoptosis in non-neuronal cells.

Purpose of the Study:

  • To investigate the post-translational processing of OPA1 during neuronal apoptosis.
  • To identify the mechanisms and caspases involved in OPA1 cleavage in neurons.

Main Methods:

  • Exposure of cerebellar granule neurons (CGNs) and neuroblastoma cells to pro-apoptotic stressors.
  • Treatment with pan-caspase or caspase-8 inhibitors.
  • Analysis of OPA1 cleavage, mitochondrial fragmentation, and cytochrome c release.
  • In vitro cleavage assays with recombinant caspase-8 and digitonin-permeabilized mitochondria.

Main Results:

  • A novel N-terminal cleavage of OPA1 was observed in CGNs and neuroblastoma cells under apoptotic stress.
  • OPA1 cleavage occurred concurrently with mitochondrial fragmentation and cytochrome c release.
  • Caspase-8 inhibition blocked OPA1 cleavage and mitochondrial fragmentation, but recombinant caspase-8 did not directly cleave OPA1 in vitro.
  • Active caspases (caspase-8 or -3) stimulated OPA1 cleavage in permeabilized mitochondria, suggesting involvement of an intermembrane space protease.
  • The N-terminal truncation removed a critical residue (K301) in the OPA1 GTPase domain.

Conclusions:

  • This study demonstrates OPA1 cleavage during neuronal apoptosis for the first time.
  • Caspases act as indirect regulators of OPA1 processing in degenerating neurons.
  • OPA1 N-terminal cleavage contributes to mitochondrial fragmentation and neuronal cell death.

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