Hi, I'm Gerry Shadel from the Departments of Pathology and Genetics
at Yale University.
My colleagues and I have completed a study, described in our article in CELL,
that illuminates a new pathway through which mitochondrial stress leads to
hearing loss in mice.
Our results shed significant new light into maternally inherited deafness and
age-related hearing loss in humans as well as the complex tissue specificity of
mitochondrial disease pathology.
Mitochondria are essential organelles in your cells that are
required for energy production.
They also have DNA that you inherit from your mother.
There are many mutations in mitochondrial DNA that, if you inherit
from your mother, cause specific human diseases.
The specific mutation we studied in our investigations is one that causes
maternally inherited deafness.
And this mutation occurs in these large assemblies in mitochondria
called ribosomes.
And these ribosomes are important for expressing the genes that the
mitochondrial DNA encodes.
Specifically, the mutation is in the RNA subunit of the ribosome.
And what we found is that the mutation itself is not what's causing the disease,
but rather it's causing an increase in methylation in the RNA in a nearby site.
The breakthrough was really our understanding of the enzyme that
does that methylation.
When you overexpress that enzyme in cells it causes the cells to die by a
process called apoptosis.
What we found is that patient cell lines that have the deafness mutation are
also hyper-methylated and that they exhibit the same apoptotic
or cell death phenotype.
So that led us, really, to put two and two together where we thought if we
overexpressed this enzyme in mice, we would over hyper-methylate that
molecule and cause deafness modeling for human disease.
A major outstanding question in understanding mitochondrial pathology
is the often-extreme tissue specificity of the diseases that are associated
with mitochondrial dysfunction.
This is kind of curious, because mitochondria are generally thought of
as ubiquitous in all of your cells.
So it's not straightforward to understand why specific types of
dysfunction lead to tissue-specific effects.
The deafness mutation is a hallmark case in point.
It's a specific point mutation --- the only pathology you get is deafness.
What we found is that the diseased mitochondria from patient cell lines that
produce these reactive oxygen free radicals, activate a signaling pathway
that causes the cells to die.
In our mouse models, where we show that this pathway is active, if you
deactivate that pathway, we can actually spare them from going deaf.
There are several implications to our study.
First, we have elucidated an interesting pathway by which mitochondrial oxygen
radicals are actually acting in a signaling mode as opposed to a
damaging mode, which is what they're usually thought of in terms of
disease and aging.
Second, we have developed a really robust mouse model to study
mitochondrial diseases and the tissue specificity that they exhibit.
Thirdly, humans that have this mutation can go deaf when they're exposed to
certain environmental toxins --- for example, aminoglycoside antibiotics ---
so this mouse model will also be instrumental for trying to understand
the intersection between the environment and
genetics in this disease.
Lastly, the pathologies that we found in the mice, which is death of certain
critical cells in the inner ear, are the same types of pathology that we see in
humans when they lose their hearing normally as we age.
So if this pathway that we found is the same pathway, this is a new potential
way that we can therapeutically intercede and maybe perhaps prevent
age-related hearing loss.
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