Research in my laboratory centers around investigations
into the molecular mechanisms of aging. One of the major ideas about the cause
of aging postulates that mitochondria slowly lose their capacity to generate
energy as individuals age. It is known that the frequency of mitochondrial
DNA mutations rises exponentially with aging. It has also been shown that
in many tissues mitochondrial respiratory capacity declines with age. The
decrease in ATP synthesis compromises cellular physiological function leaving
the cell vulnerable to stress and less able to repair damage -culminating
in senescence. One major source of that stress derives from the mitochondria
itself ' namely reactive oxygen species that are natural byproducts of respiration.
It is thought that the age-related increase in mtDNA mutations results in
higher levels of oxidative stress which, in turn, not only causes damage to
proteins and other cellular macromolecules, but also, in a Catch 22, leads
to further elevations in the levels of mtDNA mutations. This viscous circle
ultimately culminates in either cell death or the vulnerability to late-onset
diseases like Alzheimer's, Parkinson's, and Type II Diabetes.
(Fig. 1) The top mouse is a 6 week old transgenic in congestive heart
failure. The bottom mouse is his normal brother. (Fig. 2) Three transgenic
mice with dilated cardiomyopathy. Note that the hearts look like blown up
balloons.
The Jewel of the Nile. The right heart was removed from a 6 month old
transgenic mouse; the one on the left is from a same aged control littermate.
Note the enlarged atria -- the rabbit ears. The ventricles are also enlarged.
We are testing the above scenario by studies of transgenic mouse models for
mitochondrial based disease. We have created a transgenic mouse, which rapidly
accumulates mutations only in the mitochondrial DNA of the heart. Figure 1
shows one of these mice next to a control littermate at about 6 weeks of age.
These mice develop cardiac disease early in life, which often is manifested
as congestive heart failure. At the time this mouse developed severe heart
failure, its cardiac mitochondria had a frequency of mitochondrial DNA mutations
that would normally be found in an 80-year-old person. Thus, these mice have
old mitochondria in a young body. As mutation frequencies rise, their hearts
dilate in order to maintain cardiac performance Figure 2. An enlarged heart
(Figure 3) is also characteristic in many cases of human heart disease. We
are characterizing these transgenic mice at the molecular level to discover
how the rising frequency of mitochondrial DNA mutations leads to heart disease.
Surprisingly, our studies so far suggest that whatever the molecular mechanism
is, it does not appear to involve a decline in the ability of the mitochondria
to generate ATP. Neither, does it appear to result from an increase in oxidative
stress. Our current hypothesis is that the mutations lead to a dysregulation
of the mitochondrial permeability transition pore which is intimately linked
to the regulation of apoptosis and, thus, cell survival. Perturbations in
the function of that pore are hypothesized to communicate to the nucleus via
signal transduction pathways involving nuclear receptor – possibly the
peroxisome-proliferator activated receptors.