Association between Mitochondrial Bioenergetics and Radiation-Related Fatigue: A Possible Mechanism and Novel Target

Fatigue is one of the cancer symptoms most often reported by patients receiving radiation therapy (XRT). Understanding the mechanism behind the development of cancer-related fatigue will enable the design of novel interventions for radiation-induced fatigue. This research proposal is designed to determine the association between mitochondrial bioenergetics and fatigue in prostate cancer patients receiving XRT.

We proposed a mechanism of mitochondrial bioenergetics for cancer-related fatigue based on a molecular-genetic approach, linking impaired ATP production as a consequence of XRT. This prospective, hypothesis-testing project uses a matched case-control, repeated-measures design. Peripheral blood will be collected from each subject at 3 timepoints (baseline, midpoint, and endpoint) to determine mitochondrial bioenergetics profile. Fatigue will be measured using validated questionnaires (The revised Piper Fatigue Scale and Patient Reported Outcomes Measurement Information System for Fatigue). Based on preliminary findings, we hypothesize that decreased BCS1L leads to a decrease of Rieske iron-sulfur protein incorporation into complex III. This incomplete complex III leads to a defect in complex III activity and causes impaired mitochondrial oxidative phosphorylation which results in decreased ATP production, contributing to fatigue. An increased fatigue score and decreased mitochondrial bioenergetics profile are anticipated to be observed during XRT. Furthermore, increased fatigue scores will be associated with decreased mitochondrial bioenergetics in fatigued prostate cancer patients undergoing XRT.

Our hypothesis provides a mechanism for impaired ATP production as a major consequence of XRT that leads to debilitating radiation-induced fatigue.

The results have the potential to identify targets for pharmacological and, in particular, nutraceutical interventions and initiate a new direction for design of interventions for cancer-related fatigue.