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Researcher Underscores Importance of Intracellular Communication

By Brian Chorley
March 2010

Gerald Shadel, Ph.D.
Shadel said he was especially honored to be invited to speak by the LMG fellows and congratulated them and their colleagues on "the real gem of a lab here."
(Photo courtesy of Steve McCaw)

Jan Drake, Ph.D.
LMG Chief Jan Drake, Ph.D., was one of several LMG principal investigators in the audience. (Photo courtesy of Steve McCaw)

Paul Wade, Ph.D.
Scientists from other NIEHS labs, such as Laboratory of Molecular Carcinogenesis Principal Investigator Paul Wade, Ph.D., above, shared Shadel's research interests in interactions between nuclear-derived factors and the mitochondria. (Photo courtesy of
Steve McCaw)

Omari Bandele, Ph.D.
LMG Fellow Omari Bandele, Ph.D., above, stayed on the edge of his seat during most of the talk. Omari and Stumpf are members of the LMG Trainee Action Committee (http://www.niehs.nih.gov/research/atniehs/labs/lmg/resources.cfm) that sponsors the lecture series.
(Photo courtesy of Steve McCaw)

Yale University Professor of Pathology and Genetics Gerald Shadel, Ph.D. (http://www.med.yale.edu/genetics/fac/GeraldShadel.php)Exit NIEHS, spoke Feb. 2 on "Mitochondrial Signaling in Disease and Aging." Shadel's research is on the leading edge of efforts to unravel the pathology of dysfunctional mitochondria implicated in normal aging tissues, certain tumors, and late-onset diseases such a Alzheimer's, Parkinson's, and diabetes.

Nuclear-derived factors mediate mitochondrial disease

Commonly referred to as the "powerhouse of the cell," the mitochondria supply cells with chemical energy used by many cellular processes including motility, biosynthesis, and signaling. In his talk, Shadel explained that coordinated interaction exists between nuclear-derived factors and the mitochondria. Mutations in the nuclear and mitochondrial genomes can disrupt this molecular coordination, which can lead to mitochondrial-mediated disease.

As an example, Shadel described how inner ear hair cell loss can result from gene mutation of mitochondrial-derived ribosomal RNA (rRNA). The loss of these hair cells can lead to severe deafness in some individuals. The mutation alters methylation of the rRNA by the nuclear-derived enzyme methyltransferase, h-mtTFB1, which is important for mitochondrial protein translation and ribosome biogenesis.

Through a series of sophisticated experiments, Shadel's lab demonstrated that h-mtTFB1 overexpression resulted in altered global gene expression patterns similar to patterns found in cells that harbored a deafness-associated mtDNA mutation. Analysis of the gene expression pattern pinpointed disregulation of multiple downstream processes that could be involved in hair cell loss, including expression of genes that coordinate cell cycle and cell death.

Ataxia-telangiectasia, a mitochondrial disease?

Patients with the rare inherited disorder ataxia-telangiectasia (A-T) can exhibit an array of symptoms, including neurodegeneration, sensitivity to DNA damage, and immune system defects. These symptoms stem from specific mutations in the nuclear-derived gene Ataxia Telangiectasia Mutated (ATM). While the exact mechanisms that lead to clinical signs of the disease are not fully understood, Shadel presented compelling evidence that the mitochondria may be involved.

Shadel demonstrated that reduced amounts of functional ATM protein inhibited mitochondrial repair and maintenance. Importantly, mitochondrial disrepair was linked to memory T cell loss in preliminary studies. These findings may point to the mitochondrial-mediated suppression of immune response seen in A-T patients.

Efficient mitochondrial oxygen consumption may slow aging

In addition to its role in disease etiology, nuclear and mitochondrial communication appears to be important in aging. Reactive oxygen species (ROS), produced endogenously by the mitochondria as a byproduct of chemical energy synthesis, can have damaging effects on cellular macromolecules and DNA. Shadel said that many scientists believe that damage from more than average ROS exposure and resulting oxidative stress can shorten cellular lifespan.

This theory holds true in yeast, worms, and mouse cells, where reduced activity of the nuclear protein, mammalian target of raptor (mTOR), increases lifespan. Shadel explained that this effect is due to increased mitochondrial respiration and protein translation, which his lab demonstrated to be mediated by mTOR. As a result of reducing mTOR, the mitochondria consumed oxygen more efficiently, with less ROS production, while still creating chemical energy.

Shadel did warn that balance is key, however, and that ROS also benefits mitochondrial homeostasis. "ROS are not only damaging agents, but are also important signaling molecules that are sensed and controlled by conserved signal transduction pathways," he said. "Thus a new paradigm for mitochondrial pathogenesis is emerging in which signaling defects, as opposed to oxidative stress and disruption of energy metabolism, are the culprits."

Hosted by NIEHS Postdoctoral Fellow Jeffery Stumpf, Ph.D., of the Mitochondrial DNA Replication Group, Shadel's talk was the most recent presentation in the Laboratory of Molecular Genetics (LMG) Fellows Guest Lecturer series.

(Brian Chorley, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Environmental Genomics Group.)



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