2018 / 25 January

Apoptosis


Apoptosis is a specialized form of programmed cell death, characterized by lack of inflammatory response. It is an active process regulated by proteins that often affects only single cells or small groups of cells.

So, what is the biochemical pathway leading to apoptosis? Activation of caspases cascade.

Caspase activation is the crucial step because caspases activate proteases and also endonucleases, which break down cytoskeleton and nucleus respectively. Caspase activation occurs by two pathways, intrinsic and extrinsic.

Intrinsic mitochondrial pathway

  • Interaction between anti-apoptotic protein such as BCL-2 and BCA-x and pro-apoptotic protein such as BAX and BAK. Due to membrane damage (cellular injury), DNA damage, or decreased hormonal stimulation of cell (ex – endometrial cells in lack of estrogen), Bcl2 can be inactivated. Leakage of cytochrome C will then activate caspase.

Extrinsic pathway

  • FAS ligand binds to FAS death receptor (CD95) on target cell and target cell dies via activation of caspases.
  • Cytotoxic CD8+ T-cell pathway: When CD8+ cells recognize foreign antigen on Major Histocompatibility Complex (MHC-I) receptors, they release perforins that make holes on a target cell. Then, they release granzymes that enters target cell and activates caspases.
  • Tumor necrosis factor-alpha (TNF-alpha) is a trigger the extrinsic or intrinsic apoptotic pathway.

Watch this video that explains the functioning of the extrinsic and intrinsic apoptotic pathways

Alterations of apoptosis pathways can result in human diseases. Either reduce and increase apoptosis may lead to pathology. Diseases in which alterations of apoptosis are involved are:

  • Cancer: mutations in BCL-2 Family and p53 proteins are frequently associated with human cancers. B-cell lymphomas carry a typical translocation t(14;18) that results in Bcl-2 gene over-expression.
  • Neurodegenerative diseases: Alzheimer’s disease is a common progressive neurodegenerative disorder in which neuronal apoptosis plays an important role. Accumulation of amyloid-β peptides in extracellular senile plaques results in caspase 3 activation and apoptosis. Loss of neurons leads to progressive dementia.
  • Stroke: in ischemic brain damage inflammation has a crucial function. Also during brain ischemia, TNF, Fas, and FasL levels seem to be increased.
  • Heart diseases: Apoptosis is increased in both acute and chronic heart pathologies. Ischemia-reperfusion injury leads to increased apoptosis by inducing damage in mitochondrial components. In the other hand, in heart failure cardiomyocytes show a modest increase in apoptosis.
  • Bacterial and viral infections: Bacteria structural components as lipopolysaccharide in Gram-negatives, lipoteichoic acid the major constituent of the cell wall of Gram-positives and lipoarabinomannan in Mycobacteria are considered apoptogenic molecules. Thus bacterias can trigger both intrinsic and extrinsic apoptotic pathways.During viral infections host cells can limit o viral infection by cell-mediated immune response, inflammation and programmed cell death. Also, viruses have developed several strategies to inhibit or delay cell death. For example, Hepatitis B virus induces apoptosis by activating the endoplasmic reticulum (ER) stress pathway.
  • Autoimmune diseases: Science evidence supports the idea that inappropriate regulation of apoptosis in leukocytes may lead to autoimmune disease. Extrinsic apoptotic pathway plays a key role in the control of autoreactive T and B cells, and can strongly contribute to autoimmune diseases pathogenesis.

References:

  • Elmore S. Apoptosis: A Review of Programmed Cell Death. Toxicologic pathology. 2007;35(4):495-516. doi:10.1080/01926230701320337.
  • Schultz DR, Harrington WJ Jr. Apoptosis: programmed cell death at a molecular level. Semin Arthritis Rheum. 2003 Jun;32(6):345-69.
  • Favaloro B, Allocati N, Graziano V, Di Ilio C, De Laurenzi V. Role of Apoptosis in disease. Aging (Albany NY). 2012;4(5):330-349.

Further reading:

  • Apoptosis and Caspases in Neurodegenerative Diseases (link)

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