Study Improves Understanding of Mitochondrial Transcription, Mechanics


A new study by Children’s Hospital of Philadelphia researchers answers a long-standing question about how mitochondrial DNA figures in the production of cellular energy. The study, which was led by Neal Sondheimer, M.D., Ph.D., director of the Sondheimer laboratory at Children’s Hospital, improves our understanding of how mitochondria work, and could eventually lead to new ways of treating mitochondrial diseases.

The mitochondrion is a key supplier of the energy needed for the multiple functions of our cells. These organelles, which are found each cell, play a pivotal role in human health, because when the mitochondrial power plants of our cells become damaged, the energy output for the body’s cells and tissues progressively declines.

Mitochondria contain their own DNA, called mitochondrial DNA (mtDNA). While the DNA in a cell’s nucleus encodes the structure of both the cell and the mitochondria, mtDNA encodes key portions of the wiring diagram for the cellular power plants. The purpose of Dr. Sondheimer’s team’s study was to determine how mtDNA is used to create proteins used in the generation of cellular energy.

In order to make new proteins, mtDNA must be converted, or transcribed, into mitochondrial RNA (mRNA). But exactly how mtDNA does this has been a source of some controversy. While some investigators suggested the existence of a second heavy strand promoter – a specialized segment of DNA required for RNA synthesis, located on the “heavy” strand of mitochondrial DNA – some researchers doubted the second promoter’s existence because they couldn’t get it to work in the lab.

In addition to determining how to make the promoter, known as HSP2, work, Dr. Sondheimer and his team identified several of its key features. The most important and “unexpected” feature of HSP2 is that a protein that normally activates mitochondrial promoters, transcription factor A (TFAM), acts to block transcription at HSP2. The study team’s finding “suggests that the cell may manipulate TFAM levels to change the genes that are expressed by the mitochondrion,” Dr. Sondheimer said.

Because determining the inner workings of the mitochondria could provide a major new approach to understanding and developing therapies for myriad rare and common diseases, the study’s findings could have significant repercussions.

“Although this finding has no immediate impact upon the care of our patients, it may have relevance in the future for patients who are unable to generate sufficient amounts of proteins encoded by the mitochondrial DNA to keep cellular function normal,” Dr. Sondheimer noted.

“If we are able to manipulate the pathways that control gene expression, it could form the basis of a new way of treating mitochondrial disease,” Dr. Sondheimer added.

The study was published March 26 in the Proceedings of the National Academy of Sciences. In addition to Dr. Sondheimer, the study’s co-authors were Ornella Zollo, Ph.D., in the Division of Child Rehabilitation at Children’s Hospital, and Valeria Tiranti, Ph.D., of the IRCCS Foundation Neurological Institute in Milan, Italy.

Douglas C. Wallace, Ph.D., director of the Center for Mitochondrial and Epigenomic Medicine at Children’s Hospital, acted as the article’s editor. Support for the study was provided by an NIH grant as well as the Children’s Hospital of Philadelphia Pediatric Development Fund.