by Buck Institute

Mitochondrial Ubiquinol Oxidation: Could this be the answer to stop tumor growth in its path?

By Joseph Morris and Haeli Lomheim, recent graduates from the Dominican University M.S. in Biological Sciences 

Cancer is the #2 cause of death in the US, and mainly affects older adults. While treatments and even cures have improved outcomes and saved countless lives, there are still far too many who succumb to this horrific disease. Scientists are always looking for a new “in”—something specific about cancer cells that they can target, while leaving healthy cells alone. Mitochondria, as the cells’ “powerhouse”, are an appealing target for energy-hungry cancer cells.

Cancer cells divide rapidly and need more energy than healthy cells. Because of this, researchers are investigating the cancer cell's energy source as a target for treatment. With this in mind, an emerging chemotherapeutic mechanism of action involves the inhibition of the mitochondrial electron transport chain (ETC), one of the ways that cells transform energy. The mitochondrial ETC is primarily made up of mitochondrial complexes I-V. The inhibition of these complexes by small molecules has produced higher mortality rates for cancer cells when compared to healthy cells. However, mitochondrial ETC activity is actually less active in most cancers. These cancers instead use alternative pathways to fuel themselves. The Chandel Lab, at Northwestern University, investigated this phenomenon to answer the question: If If cancer cells aren’t getting most of their energy through the mitochondria, how does inhibiting the mitochondrial electron transport chain disproportionately kill them?

To start, the Chandel Lab looked at bone cancer cells with a dysfunctional mitochondrial complex III and found that these cells could not sustain growth, so they examined how complex III impacts tumor growth. They found one process carried out by complex III is critical: oxidation of ubiquinol to ubiquinone. In this process, ubiquinol loses two electrons to become a form called ubiquinone; it is a vital part of maintaining mitochondrial function. When this oxidation process is interrupted, a cascade of other functions of the mitochondria become dysfunctional as a result, which ultimately ends up killing cancer cells. Because ubiquinol oxidation by complex III is required for tumor growth, they wanted to understand if other mitochondrial complexes were also necessary.

Next, The Chandel Lab investigated mitochondrial complex I to see if it’s required for tumor growth. They tested this by knocking out an essential subunit of complex I. Much like the cells with a dysfunctional complex III, they saw a dramatic reduction in cell growth. Because complex I was found to be vital as well, researchers investigated which functions of complex I contributed to reduced tumor growth. Two main functions were identified: proton-pumping and NAD+ regeneration, each of which contribute to important cellular processes. Through a series of experiments, the authors found that NAD+ regeneration but not proton-pumping was necessary for tumor growth.  

In their experiments, the Chandel Lab discovered distinct processes of mitochondrial complexes I and III that tumors rely on for growth, thus supporting the notion that these mitochondrial complexes could be potential targets for future cancer treatments. Building off the Chandel Lab’s research it would be interesting to see if their findings are as relevant for other cancer tissue types. This would help ensure the results in tumor reduction are universal and not specific to bone cancer. Additionally, understanding why inhibition of the mitochondrial electron transport chain affects cancer cells more than non-cancerous cells is critical in advancing inhibitors as a treatment option.


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