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ERp57-associated mitochondrial μ-calpain truncates apoptosis-inducing factor

Taku Ozaki1, Tetsuro Yamashita, Sei-Ichi Ishiguro

  • 1Department of Biochemistry and Biotechnology, Division of Cell Technology, Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki 036-8561, Japan.

Biochimica Et Biophysica Acta
|June 19, 2008
PubMed

Insights

Mitochondrial micro-calpain activity is regulated by ERp57, a protein-disulfide isomerase. This interaction leads to the cleavage of apoptosis-inducing factor (AIF), impacting cellular processes.

Area of Science:

  • Mitochondrial biology
  • Protease regulation
  • Cellular signaling

Background:

  • Calpains are calcium-dependent proteases crucial for cellular functions.
  • Mitochondrial calpains lack the known inhibitor calpastatin, suggesting unique regulatory mechanisms.
  • Previous work characterized mitochondrial micro-calpain but its regulation remained unclear.

Purpose of the Study:

  • To identify endogenous regulatory molecules of mitochondrial micro-calpain.
  • To elucidate the role of ERp57 in mitochondrial calpain regulation.
  • To investigate the impact of ERp57-calpain interaction on apoptosis-inducing factor (AIF).

Main Methods:

  • Peptide mass fingerprinting using MALDI-TOFMS to identify proteins associated with mitochondrial micro-calpain.
  • Co-immunoprecipitation to confirm ERp57 and mitochondrial micro-calpain association.
  • Enzyme inhibition assays using PDI inhibitors (DTNB, PAO) and casein zymography.

Main Results:

  • ERp57, a protein-disulfide isomerase (PDI), was identified in association with mitochondrial micro-calpain.
  • PDI inhibitors and anti-ERp57 antibody disrupted mitochondrial micro-calpain activity.
  • ERp57-associated mitochondrial micro-calpain was shown to cleave AIF into a truncated form, inhibiting its release.

Conclusions:

  • ERp57 directly interacts with and regulates mitochondrial micro-calpain.
  • The ERp57-calpain complex plays a role in AIF processing within mitochondria.
  • This finding reveals a novel regulatory pathway for mitochondrial calpains and AIF.

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