For many years, researchers have thought that mitochondria, the powerhouses of cells, may be important to the development of cancer. The theory has remained controversial and difficult to study, but City of Hope cancer biologists have made a discovery that could lead to new ways of testing it.
The study appears in the Nov. 7 issue of the journal Molecular Cell.
A team led by Li Zheng, Ph.D., assistant research scientist, and under the direction of Binghui Shen, Ph.D., professor and director in the Division of Radiation Biology, has found an enzyme that repairs human DNA exclusively in mitochondria. Since DNA repair is strongly tied to cancer, the team hopes to use the enzyme to create a model for studying how mitochondrial DNA mutations impact the development of cancer.
 Binghui Shen (Photo by Paula Myers) |
The research has led to a five-year, $2 million National Cancer Institute grant for Shen. The grant is actually Shen’s third consecutive cycle of funding related to this research project.
Mitochondria are mini-organs, or organelles, within cells. They act like generators that produce the energy that cells need to grow and function.
Mitochondria also are like cells within a cell. While most of a cell’s DNA is located in the nucleus, mitochondria have their own, exclusive DNA, which contains the genes that control their own operation. If that DNA gets damaged, it can upset normal energy production, leading to cell death or, worse, to diseased cells like those seen in cancer.
DNA can be damaged by a number of things, including toxins, radiation and certain byproducts of biochemical reactions — including the reactions mitochondria use to generate energy. Because these energy-producing reactions occur almost nonstop in mitochondria, the risk of DNA damage in mitochondria is high.
Fortunately, nature has devised several enzymes that can efficiently repair damaged DNA. Zheng has focused much of his research on an enzyme called DNA2.
In most organisms, from yeast to frogs, DNA2 repairs DNA in both the nucleus and mitochondria. But somewhere along the evolutionary tree, something changed, and DNA2 was evicted from the nucleus and moved exclusively to mitochondria.
“We were surprised by this,” said Zheng. “When we looked to see where human DNA2 appears in cells, we didn’t expect it to be only in mitochondria.”
That gave them an idea. Because human DNA2 only repairs mitochondrial DNA and not DNA in the nucleus, Zheng and Shen recognized they might be able to use it to control repair of DNA solely in the mitochondria. That would make it extremely valuable for experiments, since they could “dial-in” the amount of DNA damage in mitochondria and control how well the mitochondria generate energy, giving them a tool to study how the organelle influences cancer development.
Nobel laureate Otto Warburg first suggested the role of mitochondria in cancer some 70 years ago.
An expert in the ways cells generate energy, Warburg suggested that hurting a cell’s normal ability to generate energy could lead to cancer. Since then, further evidence has shown he was on to something, but a good model for confirming the theory remained out of reach.
In work recently published in Nature Medicine, the City of Hope group previously showed that a shortage of an enzyme called FEN1, which has similar properties to DNA2, leads to autoimmune disease, chronic inflammation and cancers.
“The fact that DNA2 is exclusively in mitochondria — in contrast to FEN1 — and that we now understand better how it works, may allow us to set up a model to study the impact of mitochondrial DNA mutations on cancer initiation and progression,” said Shen. “We still have a lot of work to do, though.”
Other members of the City of Hope team, who have contributed to this work, include Mian Zhou, M.D., Ph.D., Zhigang Guo, Ph.D., Huiming Lu, Limin Qian, Ph.D., Huifang Dai and Junzhuan Qiu, Ph.D.
