ASSOCIATION OF MITOCHONDRIAL DYSFUNCTION WITH CANCER-RELATED FATIGUE
Background: Cancer-related fatigue (CRF) is a common and distressing symptom reported by cancer patients. CRF is poorly understood and is often thought to stem from central and peripheral mechanisms, involving neural and muscular mediators, respectively. Mitochondria’s role in neural and muscular dysfunctions may explain the biologic underpinnings of CRF. This novel, exploratory study is the first to investigate the association of mitochondrial dysfunction with CRF.
Methods: Participants were enrolled in an active, IRB-approved National Institutes of Health protocol (NCT# 00852111). Self-reported fatigue was assessed using the Functional Assessment of Cancer Therapy–Fatigue subscale (FACT-F). Subjects were grouped into high fatigue (HF) and low fatigue (LF), determined by a >3-point decrease in FACT-F score from baseline to end of EBRT, a change considered clinically-relevant. Central mediators of CRF were measured by Computerized Assessment of Mild Cognitive Impairment (CAMCI). Physical mediators of CRF measured maximum voluntary contraction (MVC) and decay using handgrip dynamometry. Peripheral blood was obtained to detect mitochondrial electron transport chain enzyme complexes (complexes I-IV; 1 kit for each complex) from cell lysates and mitochondrial antioxidant, manganese superoxide dismutase (SOD2) from sera using enzyme-linked immunosorbent assays (ELISA). All measures and peripheral blood were obtained at baseline and completion of EBRT. Nonparametric Wilcoxon rank-sum, Wilcoxon signed-rank tests, and paired t-tests were used to analyze the changes of study variables between baseline and completion of EBRT. Estimated correlations among mitochondrial biomarkers and fatigue were calculated using Spearman’s rank correlation coefficients.
Results: Fatigue scores of 12 men significantly decreased from baseline to completion of EBRT. Complex II and IV ELISA results were undetectable. There were no significant changes in the mean optical densities of complex I, III, and SOD2 enzymes or in central and peripheral mediators from baseline to end of EBRT. A trend in the change in complex I and III enzyme concentrations were different between the fatigue groups. Handgrip MVC trended towards significance at end of EBRT, where LF subjects had higher MVC than HF subjects. There were no significant correlations with mitochondrial enzymes and handgrip strength. For the group as a whole, correlations at treatment completion were observed for: mitochondrial complex III and attention (r=0.90, p=0.02), mitochondrial Complex III and memory (r=0.75, p=0.08), and mitochondrial Complex I and Total CAMCI Score (r=0.68, p=0.06).
Implications: The study findings suggest that mitochondrial dysfunction during EBRT may induce mental fatigue, not physical fatigue. Knowing relationships between mitochondria and fatigue have clinical implications: understanding specific mitochondrial functions that are associated with mental fatigue is informative in understanding the etiology of CRF; understanding specific molecules related to mitochondrial function enzymes that are correlated with mental fatigue can serve as interventional targets; and identifying potential interventional targets for CRF can assist in developing effective therapies and management for CRF.