Scientists at the University of Illinois Chicago have identified a process by which enzymes can help prevent heart damage in chemotherapy patients. The enzymes are normally found in a cell’s mitochondria, but when heart cells are put under stress from certain types of chemotherapy drugs, the enzymes move into the cell’s nucleus, where they are able to keep the cells alive. The paper “Nuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism” appears in Nature Communications.

“Chemotherapy-induced cardiac damage remains a leading cause of death amongst cancer survivors. Anthracycline-induced cardiotoxicity is mediated by severe mitochondrial injury, but little is known about the mechanisms by which cardiomyocytes adaptively respond to the injury. We observed the translocation of selected mitochondrial tricarboxylic acid (TCA) cycle dehydrogenases to the nucleus as an adaptive stress response to anthracycline-cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes and in vivo,” write the investigators.

“The expression of nuclear-targeted mitochondrial dehydrogenases shifts the nuclear metabolic milieu to maintain their function both in vitro and in vivo. This protective effect is mediated by two parallel pathways: metabolite-induced chromatin accessibility and AMP-kinase (AMPK) signaling. The extent of chemotherapy-induced cardiac damage thus reflects a balance between mitochondrial injury and the protective response initiated by the nuclear pool of mitochondrial dehydrogenases. “Our study identifies nuclear translocation of mitochondrial dehydrogenases as an endogenous adaptive mechanism that can be leveraged to attenuate cardiomyocyte injury.”

“As chemotherapy has become more and more effective, we have more  cancer survivors. But the tragic part is that a lot of these survivors now have problems with heart failure,” explained co-senior author, Sang Ging Ong, PhD, assistant professor of pharmacology and medicine.

Rise of cardio-oncology

This has led to the rise of the cardio-oncology field. Most previous research in the field focused on the mechanisms by which chemotherapy drugs damaged the mitochondria of heart cells. This research team was interested in investigating a different angle: Why do some patients’ hearts escape damage? Is there something particular about their cells that is protecting them?

First the team discovered that when the heart cells were stressed by chemotherapy, the mitochondrial enzymes moved into the cell’s nucleus—an unusual phenomenon. But they didn’t know if that movement was the cause of the cell’s damage or the means of its protection, explained, Jalees Rehman, PhD, co-senior author, Benjamin Goldberg Professor and head of the UIC department of biochemistry and molecular genetics.

“We really didn’t know which way it would go,” he said.

heart cells
Human induced pluripotent stem cell-derived heart cells (cardiomyocytes) show the cardiac proteins Actinin (red) and Troponin T (green) as well as the nucleus (blue). Image adapted from the research paper. [Creative Commons license]
To find out, the researchers generated versions of the enzymes that would specifically move into the nucleus and bypass the mitochondria. They discovered that this relocation fortified the cells, keeping them alive. They demonstrated that this process worked in both heart cells generated from human stem cells and in mice exposed to chemotherapy.

“This seems to be a new mechanism by which heart cells can defend themselves against chemotherapy damage,” noted Rehman, who is also a member of the University of Illinois Cancer Center.

The discovery suggests new clinical possibilities. Doctors could test individual patients to see if heart cells generated from personalized stem cells would adequately protect themselves from chemotherapy by moving their enzymes from their mitochondria into the cell’s nucleus. Doctors could draw blood from the patient, make stem cells from the blood cells and then use those personalized stem cells to generate heart cells with the same genetic makeup as the patient’s heart cells.

“Assessing the injury caused by chemotherapy and the enzyme movement from the mitochondria into the nucleus of those heart cells in a lab would help determine what the patient’s likely response would be to chemotherapy,” according to Rehman.

In patients with inadequate protection, one could then enhance the protection by increasing the enzyme movement and protection of the heart cells.

The plan to do more studies looking at whether this method could help prevent heart damage from other conditions, such as high blood pressure and heart attacks, and whether it would work in other cells, such as those in blood vessels.

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