PROJECT SUMMARY/ABSTRACT Cancer-related fatigue (CRF) occurs in 82%-96% of cancer patients receiving chemotherapy (CT) and it is one of the most prevalent side effects of CT in patients with breast cancer. CT-induced CRF is a distressing, persistent sense of exhaustion related to the disease or its treatment, and negatively impacts health outcomes (e.g., depression, sleep disturbance, poor quality of life). Despite various attempts to investigate the etiology of CRF, the biochemical mechanisms remain elusive. The proposed study aims to investigate the molecular- genetic pathway of mitochondrial bioenergetics and their association with CT-induced CRF symptoms experienced by patients with breast cancer receiving CT-containing anthracyclines, compared to those with non-anthracycline-based CT. Anthracycline-based CT has been associated with mitochondrial dysfunction through increased mitochondrial reactive oxygen species (ROS) and an induced decrease in muscle strength. Deficiency of adenosine triphosphate (ATP) has been proposed as the basis of fatigue. Peripheral blood mononuclear cells (PBMCs) of fatigued patients with prostate cancer has exhibited reduced ATP coupling efficiency compared to those without fatigue. In patients with prostate cancer undergoing radiotherapy, we found that CRF severity was significantly correlated with altered mitochondrial genes and impaired mitochondrial oxidative phosphorylation (OXPHOS). In patients with breast cancer suffering from CT-induced CRF, we intend to determine whether there is a similar altered expression of mitochondrial-related genes with defective bioenergetics in PBMCs and platelets. We propose that the chemotherapeutic agent (anthracycline- based regimen) targets cell cycle progression, which triggers genetic and cellular instability, altering expression of mitochondrial genes and proteins, inducing reduced electron transport chain (ETC) enzymatic activity and impaired OXPHOS, resulting in ATP depletion and excessive ROS generation, leading to the development and intensification of CRF. This R21 proposal will reveal the linkage between changes in the molecular- genetic pathway of mitochondrial bioenergetics and CT-induced CRF when controlling for relevant covariates. Specific aims are to: (1) Characterize the profile of mitochondria-related genes associated with CRF symptoms in patients with breast cancer receiving anthracycline-based CT, compared to patients with non-anthracycline-based CT at baseline, midpoint, and endpoint of CT. (2) Identify the profile of mitochondrial bioenergetics associated with CRF symptoms in patients with breast cancer receiving anthracycline-based CT, compared to patients with non-anthracycline-based CT, at each time point. Understanding the molecular- genetic bioenergetics underpinning CRF will provide novel insights needed for targeted approaches to mitigate CT-induced CRF. The results will also advance symptom science, enable us to discover biomarkers, identify thera...