Microenvironmental Stimulation Modulates Mitochondrial Bioenergetics and Redox Responses in Chronic Lymphocytic Leukemia
Abstract
Background: /Objectives: Microenvironmental signals shape chronic lymphocytic leukemia (CLL) cell biology, but their effects on mitochondrial bioenergetics and redox-associated readouts remain incompletely characterized when assessed in parallel with normal B cells under matched activation conditions. Methods: Primary B cells from 18 CLL treatment-naïve patients and normal B cells from 10 age-matched healthy donors were exposed for 72 h to CpG with or without IL-15, CD40L-expressing feeder cells, or B-cell receptor (BCR) engagement combined with IL-4. Mitochondrial ATP synthesis, oxygen consumption, oxidative phosphorylation efficiency (P/O), and extracellular lactate accumulation were assessed. Reactive oxygen species (ROS), malondialdehyde (MDA), and catalase activity were evaluated following CpG+IL-15 stimulation. Results: Microenvironment-associated stimulation enhanced mitochondrial ATP synthesis and oxygen consumption in both cohorts. CpG-based stimulation produced the most consistent increase in extracellular lactate. CLL cells generally exhibited greater absolute mitochondrial output, whereas the P/O ratio did not change significantly across activation conditions, indicating increased bioenergetic capacity without detectable loss of apparent OxPhos coupling under these assay conditions. CpG+IL-15 increased ROS in both cohorts; in CLL cells, this was accompanied by increased catalase activity without a significant increase in MDA, whereas normal B cells exhibited increased lipid peroxidation without significant catalase induction. Conclusions: Under the substrate-supported assay conditions used, microenvironment-associated stimulation amplifies mitochondrial bioenergetic output in CLL without detectable impairment of oxidative phosphorylation coupling. The redox findings are compatible with different downstream responses to CpG+IL-15 in CLL and normal B cells, but they remain exploratory because they were obtained in a small subset and do not establish a causal antioxidant mechanism or a therapeutic vulnerability.
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