Related Experiment Video

Updated: Jun 24, 2026

Examining BCL-2 Family Function with Large Unilamellar Vesicles
08:35

Examining BCL-2 Family Function with Large Unilamellar Vesicles

Published on: October 5, 2012

Mitochondrial apoptosis induced by BH3-only molecules in the exclusive presence of endoplasmic reticular Bak

Martina Klee1, Kathrin Pallauf, Sonia Alcalá

  • 1Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.

The EMBO Journal
|April 3, 2009
PubMed

Insights

BH3-only proteins can trigger apoptosis via Bak in the endoplasmic reticulum (ER), initiating an ER-to-mitochondria pathway. This discovery reveals a novel route for programmed cell death independent of the mitochondria.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Apoptosis Research

Background:

  • Bak and Bax are key proteins in apoptosis, found in mitochondria and the endoplasmic reticulum (ER).
  • Mitochondrial Bak/Bax are known to mediate apoptosis initiated by BH3-only proteins.
  • The apoptotic potential of ER-localized Bak/Bax remains largely unexplored.

Purpose of the Study:

  • To investigate if ER-localized Bak can mediate apoptosis.
  • To explore the signaling pathway from the ER to mitochondria involving Bak.
  • To understand the role of calcium and ER-stress machinery in this process.

Main Methods:

  • Utilized cell models expressing Bak exclusively in ER membranes.
  • Administered BH3-only proteins (BimEL, Puma) targeted to the ER.
  • Monitored cytochrome c release and apoptosis.
  • Investigated the role of calcium and IRE1alpha/TRAF2 signaling.

Main Results:

  • Cells with ER-localized Bak underwent cytochrome c release and apoptosis upon stimulation with ER-targeted BimEL and Puma.
  • Calcium was essential but not sufficient for this apoptotic pathway.
  • The IRE1alpha/TRAF2 ER-stress pathway was found to cooperate with calcium in transmitting signals to mitochondria.

Conclusions:

  • BH3-only proteins can utilize ER-localized Bak to activate an ER-to-mitochondria apoptotic signaling route.
  • This pathway induces cytochrome c release and apoptosis independently of the canonical mitochondrial Bak/Bax.
  • The findings reveal a new layer of complexity in apoptotic regulation, highlighting an alternative route for programmed cell death.

More Related Videos

Detection of Mitochondria Membrane Potential to Study CLIC4 Knockdown-induced HN4 Cell Apoptosis In Vitro13:20

Detection of Mitochondria Membrane Potential to Study CLIC4 Knockdown-induced HN4 Cell Apoptosis In Vitro

Published on: July 17, 2018

Isolation and Functional Analysis of Mitochondria from Cultured Cells and Mouse Tissue09:27

Isolation and Functional Analysis of Mitochondria from Cultured Cells and Mouse Tissue

Published on: March 23, 2015

Related Concept Videos

The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Apoptosis01:30

Apoptosis

Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size reduction of the tissue.
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
Cellular Injury V: Apoptosis and Autophagy01:22

Cellular Injury V: Apoptosis and Autophagy

Cells respond to damage and stress through highly coordinated processes that decide whether they survive or undergo controlled self-destruction. Two major pathways involved in this regulation are apoptosis, a type of programmed cell death, and autophagy, a survival mechanism that helps cells adapt to adverse conditions.ApoptosisApoptosis removes aged or injured cells to maintain tissue balance. During this process, the cell shrinks, chromatin condenses and fragments, and membrane-bound...
Autophagic Cell Death01:18

Autophagic Cell Death

Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and pro-apoptotic...
Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...