Anthracyclines effect on mitochondrial function and biogenesis in normal blood cells of hodgkin lymphoma patients.

The preferential accumulation of anthracyclines in the mitochondrial matrix has been proposed to trigger a self-perpetuating vicious cycle with mitochondrial DNA (mtDNA) alteration and redox stress enhancing one each other to lead to a progressive mitochondrial impairment. To test this hypothesis, we monitored oxygen consumption rate (OCR) and mt-DNA copy number (mtDNA-CN) of peripheral blood mononuclear cells (PBMCs) harvested from 23 patients with Hodgkin lymphoma (HL) submitted to adriamycin-bleomycin-vinblastine-dacarbazine (ABVD) for the whole treatment, according to a Deauville score ≤ 3 after two cycles of chemotherapy at the interim PET/CT. PBMCs were isolated before treatment (baseline), at interim and one month after End of Therapy (EoT). Baseline data were compared with 23 healthy subjects selected according to a case-control criterion. OCR was estimated under control condition, after blockade of ATP-synthase, and of mitochondrial Complexes I and III. mtDNA-CN was assayed by droplet digital PCR and normalized against nuclear DNA. Mitochondrial DNA mutational status was assayed by next generation sequencing and alignment to reference genome after sequencing depth equalization. At diagnosis, mitochondrial OCR was lower in HL PBMCs than in controls, despite a preserved mitochondrial asset, testified by the mtDNA-CN. In the 18 subjects with complete remission at EoT PET/CT, both variables decreased back to the baseline values. By contrast, in the 5 patients with persistent disease, both mitochondrial OCR and mtDNA-CN remained elevated. ABVD therapy alters mitochondrial function and biogenesis of normal PBMCs whose metabolic pattern might represent a possible marker of treatment effectiveness.