Peripheral blood mononuclear cells exhibit increased mitochondrial respiration after adjuvant chemo- and radiotherapy for early breast cancer

Abstract

Background: Adjuvant chemo- and radiotherapy cause cellular damage to tumorous and healthy dividing cells. Chemotherapy has been shown to cause mitochondrial respiratory dysfunction in non-tumorous tissues, but the effects on human peripheral blood mononuclear cells (PBMCs) remain unknown.

Aim: We aimed to investigate mitochondrial respiration of PBMCs before and after adjuvant chemo- and radiotherapy in postmenopausal patients with early breast cancer (EBC) and relate these to metabolic parameters of the patients.

Methods: Twenty-three postmenopausal women diagnosed with EBC were examined before and shortly after chemotherapy with (n = 18) or without (n = 5) radiotherapy. Respiration (O₂ flux per million PBMCs) was assessed by high-resolution respirometry of intact and permeabilized PBMCs. Clinical metabolic characteristics and mitochondrial DNA (mtDNA) content of PBMCs (mtDN relative to nuclear DNA) were furthermore assessed.

Results: Respiration of intact and permeabilized PBMCs from EBC patients significantly increased with adjuvant chemo- and radiotherapy (p = 6 × 10^-5 and p = 1 × 10^-7 , respectively). The oxygen flux attributed to specific mitochondrial complexes and respiratory states increased by 17-43% compared to before therapy initiation. Similarly, PBMC mtDNA content increased by 40% (p = 0.002). Leukocytes (p = 0.0001), hemoglobin (p = 0.0003), and HDL cholesterol (p = 0.003) concentrations decreased whereas triglyceride (p = 0.01) and LDL (p = 0.02) concentrations increased after treatment suggesting a worsened metabolic state. None of the metabolic parameters or the mtDNA content of PBMCs correlated significantly with PBMC respiration.

Conclusion: This study shows that mitochondrial respiration and mtDNA content in circulating PBMCs increase after adjuvant chemo- and radiotherapy in postmenopausal patients with EBC. Besides the increased mtDNA content, a shift in PBMC subpopulation proportions towards cells relying on oxidative phosphorylation, who may be less sensitive to chemotherapy, might influence the increased mitochondrial respiration observed iafter chemotherapy.

Trial registration: ClinicalTrials.gov NCT03784651.

Keywords: breast cancer; chemotherapy; energy metabolism; high-resolution respirometry; mitochondria; peripheral blood mononuclear cells.