Autophagy

When cells are faced with an inadequate supply of nutrients in their extracellular fluid (ECF), they may begin to cannibalize some of their internal macromolecules (e.g., proteins) and even organelles (e.g. mitochondria) for re-use of their components.

This phenomenon is called autophagy.

Three different mechanisms of autophagy have been discovered.

  • macroautophagy,
  • microautophagy, and
  • chaperone-mediated autophagy.

In macroautophagy,

  • a double membrane forms within the cell which
  • envelops the materials to be degraded into a vesicle called an autophagosome.
  • The autophagosome then fuses (using SNAREs) with a lysosome forming an autolysosome whose
  • hydrolytic enzymes degrade the materials.
  • When this is complete, fresh lysosomes are regenerated from the autolysosomes.

In microautophagy and chaperone-mediated autophagy, the material to be degraded is delivered directly to the lysosome.

Other Functions of Autophagy

  1. Shortly after fertilization, paternal mitochondria that entered the egg with the sperm [Link] are destroyed by macroautophagy.
  2. Early in embryonic development when the genes in the zygote nucleus begin to be expressed [Link], the messenger RNAs and proteins that the mother earlier had deposited in her egg are destroyed by autophagy.

  3. Autophagy occurs in many types of cells as their tissue is remodelled during development.

    Evidence:

    • As the Drosophila larva gets ready to pupate, the rising level of ecdysone triggers autophagy and programmed cell death in cells no longer needed in the adult (e.g., salivary gland cells).
    • Mice lacking certain of the genes needed for autophagy die early in embryonic development. They are unable to dispose of the corpses produced by programmed cell death (apoptosis).
  4. In mice, autophagy provides essential nutrients — especially amino acids — to the newborn pup during the critical hours after it has separated from its placenta but before nursing begins. Mice lacking certain autophagy genes die shortly after birth.

  5. Autophagy of improperly folded or aggregated proteins within the cell supplements the role of proteasomes in this function.
  6. Mitophagy is a special form of macroautophagy by which the cell gets rid of defective mitochondria and recycles their constituents. Damaged mitochondria expose a phospholipid, called cardiolipin, that normally is hidden in the inner mitochondrial membrane. Cardiolipin is an "eat me" signal for mitophagy.

    The effectiveness of mitophagy declines with age, which may account for the accumulation of cellular debris in the cells of aged animals [Link].

  7. Autophagy helps cells to destroy bacteria that invade them.

    • After Mycobacterium tuberculosis — the agent of "TB" — is engulfed into phagosomes, it survives by preventing their fusion with lysosomes [Link]. However, infected macrophages can get around this problem by destroying the phagosomes — and the bacteria within them — by autophagy instead.
    • Autophagy can also destroy bacteria (e.g., Listeria monocytogenes) that get into the cytosol.
  8. Autophagy also provides a mechanism for presenting intracellular antigens to CD4+ T cells. Normally intracellular antigens enter the class I pathway of antigen presentation to generate cytotoxic (CD8+) T cells while CD4+ T cells specialize in extracellular antigens (e.g., bacteria) that have been engulfed by endocytosis and enter the class II pathway. [Link to discussion of the pathways of antigen presentation.]

    The intracellular antigens diverted into the class II pathway by autophagy include
    • proteins synthesized by an infecting virus;
    • self-proteins.
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