Peroxiredoxin 3 (PRX3), a typical 2-Cys
peroxiredoxin located exclusively in the mitochondrial matrix, is the principal
peroxidase responsible for metabolizing mitochondrial
hydrogen peroxide, a byproduct of cellular respiration originating from the mitochondrial electron transport chain. Mitochondrial
oxidants are produced in excess in
cancer cells due to oncogenic transformation and metabolic reorganization, and signals through FOXM1 and other redox-responsive factors to support a hyper-proliferative state. Over-expression of PRX3 in
cancer cells has been shown to counteract oncogene-induced senescence and support
tumor cell growth and survival making PRX3 a credible therapeutic target. Using
malignant mesothelioma (MM) cells stably expressing shRNAs to PRX3 we show that decreased expression of PRX3 alters mitochondrial structure, function and cell cycle kinetics. As compared to control cells, knockdown of PRX3 expression increased mitochondrial membrane potential, basal
ATP production, oxygen consumption and extracellular acidification rates. shPRX3 MM cells failed to progress through the cell cycle compared to wild type controls, with increased numbers of cells in G2/M phase. Diminished PRX3 expression also induced mitochondrial hyperfusion similar to the DRP1 inhibitor
mdivi-1. Cell cycle progression and changes in mitochondrial networking were rescued by transient expression of either
catalase or mitochondrial-targeted
catalase, indicating high levels of
hydrogen peroxide contribute to perturbations in mitochondrial structure and function in shPRX3 MM cells. Our results indicate that PRX3 levels establish a redox set point that permits MM cells to thrive in response to increased levels of mROS, and that perturbing the redox status governed by PRX3 impairs proliferation by altering cell cycle-dependent dynamics between mitochondrial networking and energy metabolism.