Restoring the balance

Nat. Biotechnol. https://doi.org/10.1038/s41587-019-0377-7 (2020)

Reductive stress in mitochondrial disease results from an abundance of reducing equivalents in the cell, such as an elevated NADH:NAD⁺ ratio, which impairs NAD⁺-dependent pathways and generates reactive oxygen species. Decreasing the extracellular lactate:pyruvate ratio can lower the intracellular NADH:NAD⁺ ratio, but directly adding stoichiometric amounts of pyruvate to achieve this is not a feasible clinical treatment for mitochondrial disorders. To target the lactate:pyruvate ratio enzymatically, Patgiri et al. constructed LOXCAT, a fusion of lactate oxidase, which converts lactate and O₂ to pyruvate and H₂O₂, with catalase to detoxify the H₂O₂ byproduct by converting it to water and O₂. In vitro, LOXCAT indeed converted lactate to pyruvate without detectable H₂O₂ leakage. In cells, under antimycin-induced reductive stress, media-supplemented LOXCAT lowered both the extracellular lactate:pyruvate ratio and the intracellular NADH:NAD⁺ ratio and rescued impaired glycolysis and proliferative defects. When injected into blood, LOXCAT was able to restore heart and brain NADH:NAD⁺ balance in a mouse model of mitochondrial drug toxicity. By demonstrating the successful catalytic modulation of lactate:pyruvate ratios, LOXCAT provides a tool for the study and potential treatment of redox dysregulation.

Credit: Nat. Biotechnol.