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The mitochondrial fission protein hFis1 requires the endoplasmic reticulum gateway to induce apoptosis

Emilie Alirol1, Dominic James, Denise Huber

  • 1Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, I-35129 Padova, Italy.

Molecular Biology of the Cell
|August 18, 2006
PubMed

Insights

Mitochondrial fission protein hFis1 causes mitochondrial fragmentation independently of apoptosis. Cell death induced by hFis1 relies on endoplasmic reticulum (ER) function, not direct BAX/BAK activation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mitochondrial fission is crucial for cell division and apoptosis.
  • The hFis1 protein initiates caspase-dependent cell death via cytochrome c release.
  • The precise mechanisms linking hFis1, mitochondrial dynamics, and apoptosis remain unclear.

Purpose of the Study:

  • To investigate the relationship between hFis1-induced mitochondrial fission and apoptosis.
  • To determine the specific pathways through which hFis1 triggers cell death.
  • To elucidate the role of the endoplasmic reticulum (ER) in hFis1-mediated apoptosis.

Main Methods:

  • Utilized Bax/Bak double knockout (DKO) cells to separate fission from apoptosis.
  • Employed an hFis1 mutant affecting its intermembrane region.
  • Assessed mitochondrial fragmentation, organelle dysfunction, and cell death.
  • Investigated the role of ER function by selective correction in DKO cells.
  • Analyzed calcium (Ca2+) dependence and BAX/BAK activation.

Main Results:

  • hFis1 induced mitochondrial fragmentation in DKO cells, but not apoptosis, indicating genetic distinctness.
  • An hFis1 mutant also caused fission without cell death, further dissociating the processes.
  • Restoration of ER function in DKO cells reinstated hFis1-induced cell death.
  • hFis1 did not directly activate BAX and BAK but induced Ca2+-dependent mitochondrial dysfunction.
  • hFis1 acts as a bifunctional protein regulating mitochondrial fragmentation and ER-mediated apoptosis separately.

Conclusions:

  • Mitochondrial fragmentation and apoptosis induced by hFis1 are genetically separable processes.
  • hFis1-mediated cell death is dependent on endoplasmic reticulum (ER) integrity and function.
  • hFis1 regulates mitochondrial fragmentation and ER-mediated apoptosis through independent mechanisms.

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