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Caspase-2 resides in the mitochondria and mediates apoptosis directly from the mitochondrial compartment

M Lopez-Cruzan1, R Sharma1, M Tiwari1

  • 1Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MED 238D.2, San Antonio, TX 78229-3900, USA.

Cell Death Discovery
|March 29, 2016
PubMed

Insights

Mitochondrial caspase-2 is essential for apoptosis triggered by oxidative stress. This study confirms caspase-2

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Apoptosis Research

Background:

  • Caspase-2's role in apoptosis is established, but its mitochondrial localization and function remain unclear.
  • The mechanism by which caspase-2 contributes to oxidative stress-induced apoptosis is not fully understood.

Purpose of the Study:

  • To investigate the subcellular localization of caspase-2, specifically its presence and function within mitochondria.
  • To determine if caspase-2 is essential for apoptosis induced by mitochondrial oxidative stress.

Main Methods:

  • Immunoblotting and confocal microscopy to detect caspase-2 in purified mitochondrial fractions.
  • Fluorescence resonance energy transfer (FRET) analysis to assess mitochondrial caspase-2 activity.
  • Cell-free apoptotic assays using liver fractions from wild-type and Caspase-2 knockout (Casp2-/-) mice.
  • Assessment of cytochrome c release and cell viability in response to oxidative stress in Casp2-/- cells.

Main Results:

  • Caspase-2 was detected in purified mitochondrial fractions from cultured cells and liver hepatocytes.
  • Mitochondrial caspase-2 was shown to be functionally active.
  • Cell-free assays confirmed a direct role for mitochondrial caspase-2 in apoptosis.
  • Caspase-2 knockout cells exhibited reduced cytochrome c release and protection against mitochondrial oxidative stress.

Conclusions:

  • Caspase-2 is constitutively present and functionally active within mitochondria.
  • Mitochondrial caspase-2 is a critical mediator of apoptosis induced by oxidative stress targeting the mitochondrial electron transport chain.

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