RegB/A-dependent redox regulation links iron uptake to methanol metabolism in Methylomonas sp. DH-1

ABSTRACT Methanotrophs primarily use methane as a carbon and energy source, but they can also grow on methanol. However, methanol assimilation in the absence of methane oxidation results in a redox imbalance due to the accumulation of NADH. In Methylomonas sp. DH-1, a type I methanotroph, we show that this methanol-induced redox stress activates the RegB/RegA two-component system, a global redox sensor. Methanol triggers the RegB-to-RegA phosphotransfer cascade, resulting in RegA-dependent expression of the feo operon and increased ferrous iron uptake. This iron acquisition is essential for methanol growth, as it supports the function of Na + -transporting NADH:ubiquinone reductase (Na + -NQR), an iron-sulfur cluster-containing enzyme required for NADH oxidation. The operon encoding Na + -NQR complex is upregulated independently of RegA. Together, these findings reveal a redox-sensitive …