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

Ida Bager Christensen, Marie-Louise Abrahamsen, Lucas Ribas, Kristian Buch-Larsen, Djordje Marina, Michael Andersson, Steen Larsen, Peter Schwarz, Flemming Dela, Linn Gillberg*

*Corresponding author for this work
2 Citations (Scopus)

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.

Original languageEnglish
JournalCancer Medicine
Volume12
Issue number16
Pages (from-to)16985-16996
Number of pages12
ISSN2045-7634
DOIs
Publication statusPublished - Aug 2023

Keywords

  • Breast Neoplasms/drug therapy
  • DNA, Mitochondrial/genetics
  • Female
  • Humans
  • Leukocytes, Mononuclear/metabolism
  • Mitochondria/metabolism
  • Respiration
  • peripheral blood mononuclear cells
  • mitochondria
  • breast cancer
  • chemotherapy
  • high-resolution respirometry
  • energy metabolism

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