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Mitochondria, Apoptosis and Aging

 

Two major mechanisms are involved in the aging process: telomere shortening and free radical attacks.  Mitochondria are the primary source of free radicals due to inevitable leakage of electrons from the electron transport chain.  Since free radicals are highly reactive, they may interact with DNA and proteins to alter cellular functions.  A very destructive target is the voltage-dependent anion channel (VDAC) which plays the central role in mitochondria-mediated apoptosis.

As mentioned in the p53 page, the release of cytochrome c from mitochondria into the cytoplasm, in concert with Apaf1, can activate caspase 9, which then activate caspase 3 to execute the death program.  Cytochrome c and other small molecules may pass through the mitochondrial permeability transition pore which comprises VDAC in the outer membrane, the adenine nucleotide translocator (ANT) in the inner membrane, and several auxiliary proteins that include the Bcl-2 family involved in apoptosis.

The Bcl-2 family of proteins may be divided into three groups: 

  1. Anti-apoptotic. They share sequence homology at BH1, BH2, BH3, and BH4 domains (BH = Bcl-2 homology).  Examples: Bcl-2 itself and Bcl-xL.
  2. Pro-apoptotic. They share sequence homology at BH1, BH2 and BH3 domains.  Examples: Bax and Bak
  3. BH3-only proteins. They are pro-apoptotic, but share homology only at the BH3 domain.  Examples: Bid, Bik, and Bim. 

It has been shown that the BH4 domain is required for anti-apoptotic activity and that the BH3 domain is essential and sufficient for pro-apoptotic activity (reference).  Both Bcl-2/Bcl-xL and Bax/Bak interact with VDAC (not ANT) to change the membrane permeability (reference). The anti-apoptotic Bcl-2 and Bcl-xL close the VDAC channel. The pro-apoptotic Bax and Bak can open the VDAC channel to release cytochrome c.  The action of the BH3-only proteins is not clear.

Free radicals such as superoxide (O2·-) can also open the VDAC channel, resulting in the release of cytochrome c and cell death (reference).  This could be a major mechanism for the aging process.  Several studies have documented a significant loss of cardiac and skeletal myocytes during normal aging (reference).

Free radicals and telomer shortening may both contribute to the aging process in the following way.  The free radicals cause cell death.  Although new cells may be generated by cell division, the telomer will become shorter in the daughter cells (unless there is sufficient telomerase to extend the telomer).  As the telomer length decreases substantially, it will activate p53 to stop the cell division.  Thus, aged cells will no longer produce new cells.

The longevity gene Sir2

Sir2 is known to increase the life-span of various species. Recently, it has been shown that Sir2 can increase FOXO's ability to resist oxidative stress (reference).

 

Review Articles:

p16 and ARF: activation of teenage proteins in old age - J. Clin. Invest., 2004.

The expanding role of mitochondria in apoptosis - Genes and Development, 2001.

BCL-2 family members and the mitochondria in apoptosis - Genes and Development, 1999.

Viral homologs of BCL-2: role of apoptosis in the regulation of virus infection - Genes and Development, 2002.

Receptor- and mitochondrial-mediated apoptosis in acute leukemia: a translational view - Blood, 2001.