The energy behind cancer
photo: Fred LeeBinghui Shen
The same is true for the cells in our bodies. They require reliable energy to grow and function properly, and if the balance shifts one way or the other, it could mean disease, including cancer.
Mitochondria are mini-organs within cells that act like power plants. They produce the energy that cells need to grow and function. For many years, researchers have thought that mitochondria 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.
A team led by Li Zheng, Ph.D., assistant research scientist, and under the direction of Binghui Shen, Ph.D., professor and director of the Division of Radiation Biology and associate chair of the Department of Cancer 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 mutations in mitochondrial DNA impact the development of cancer.
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 focuses 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, M.D., Ph.D., first suggested the role of mitochondria in cancer some 70 years ago. An expert in the ways cells generate energy, Warburg proposed 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.
“The fact that DNA2 is exclusively in mitochondria … 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.”