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Environmental Factor, October 2013

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Penn State professor explores consequences of non-regulated mitochondrial transcription

By Deepa Singh

Craig Cameron, Ph.D.

Cameron has received several awards from the Penn State Eberly College of Science, including his appointment earlier this year as the Eberly Chair in Biochemistry and Molecular Biology. He has also received the American Heart Association Established Investigator Award. (Photo courtesy of Steve McCaw)

Matthew Young, Ph.D.

Matthew Young, Ph.D., visiting fellow in the Mitochondrial DNA Replication Group, was host of the talk and shared Cameron’s interest in the field of mechanisms of mitochondrial dysfunction that could lead to various diseases. (Photo courtesy of Steve McCaw)

William Copeland, Ph.D.

William Copeland, Ph.D., front, chief of the Laboratory of Molecular Genetics and head of the Mitochondrial DNA Replication group, led the discussion following Cameron’s talk. (Photo courtesy of Steve McCaw)

Pennsylvania State University Professor Craig Cameron, Ph.D., spoke Sept. 23 at NIEHS on “Human Mitochondrial Transcription.” Hosted by Matthew Young, Ph.D., the talk was the final seminar in the 2013 Laboratory of Molecular Genetics Fellows Invited Guest Lecture Series.

The talk focused on the importance and function of the highly variable noncoding sequences of mitochondrial DNA in transcription regulation. “There might be a link between the changes in the noncoding sequences variability, which is seen in human populations, and diseases caused due to mitochondrial dysfunction,” said Cameron, who holds a number of patents, and has served as a consultant for several pharmaceutical companies in the development of vaccines for viral diseases.

Mitochondria, also known as the powerhouse of the cell, are important for a wide range of cellular processes. Therefore, mitochondrial dysfunction can cause various metabolic, degenerative, and age-related diseases. According to Cameron, better understanding mitochondrial transcription and how to influence it might lead to the discovery of more effective drugs for treating these diseases.

Inhibiting mitochondrial RNA polymerase

The research in Cameron’s lab focuses on the development of strategies to treat and prevent infections by RNA viruses. Currently, viral infections are treated with the use of antiviral ribonucleosides, with a synthetic base replacing the normal base. The idea behind this strategy is that the viral RNA polymerase promiscuously incorporates these synthetic compounds into nascent RNA, terminating viral RNA synthesis. 

Cameron’s lab contributed to this idea by showing that these antiviral ribonucleosides are RNA virus mutagens and were, in fact, increasing the number of mutations per genome, thus causing a genetic meltdown of the virus population. However, because of their adverse toxic effects on patients, none of these compounds survived all three phases of clinical trials.

Cameron’s group later discovered that the human mitochondrial RNA polymerase (POLRMT) was an off-target for these antiviral ribonucleosides, and they were unknowingly inhibiting mitochondrial transcription as well. “These studies are beneficial for the antiviral drug discovery industry, since it demands ribonucleoside analogs that are substrates for the viral RNA polymerase and not for the POLRMT, as the safest and most efficient way of treating RNA virus infections,” he said.

Misregulation implicated in a range of human diseases, including cancer

Cameron also discussed his lab’s contribution to the existing knowledge of the mitochondrial transcription machinery. It is known that the human mitochondrial genome encodes 13 proteins involved in the electron transport chain, on two different intensity strands — the heavy strand and the light strand. It was previously believed that transcription starts from two sites, known as the light strand promoter (LSP) and heavy strand promoter (HSP).

However, Cameron presented compelling evidence to show that transcription can be initiated from three sites in human mitochondrial DNA, consistent with the presence of three promoters (LSP, HSP1 and HSP2). Initiation from each promoter exhibits unique factor requirements implying the existence of regulated transcription in the cell. He explained, “The majority of the noncoding region between the light and the heavy strand promoter contributes to the transcription regulation, perhaps providing a link between misregulated transcription and disease.”

Despite insights from new investigations by his group, Cameron recognizes how much remains to be understood about mitochondrial transcription. “These are really the early days of this [research]. … There really is a lot of regulation yet to be discovered.” Cameron closed his talk with an appeal to the NIH intramural community to expand its research efforts in this area.

(Deepa Singh, Ph.D., is a visiting fellow in the NIEHS Mechanisms of Mutation Group.)

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