CcpA regulation of aerobic and respiration growth in Lactococcus lactis

The catabolic control protein CcpA is the highly conserved regulator of carbon metabolism in Gram-positive bacteria. We recently showed that Lactococcus lactis, a fermenting bacterium in the family of Streptococcaceae, is capable of respiration late in growth when haem is added to aerated cultures. As the start of respiration coincides with glucose depletion from the medium, we hypothesized that CcpA is involved in this metabolic switch and investigated its role in lactococcal growth under aeration and respiration conditions. Compared with modest changes observed in fermentation growth, inactivation of ccpA shifts metabolism to mixed acid fermentation under aeration conditions. This shift is due to a modification of the redox balance via derepression of NADH oxidase, which eliminates oxygen and decreases the NADH pool. CcpA also plays a decisive role in respiration metabolism. Haem addition to lag phase ccpA cells results in growth arrest and cell mortality. Toxicity is due to oxidative stress provoked by precocious haem uptake. We identify the repressor of the haem transport system and show that it is a target of CcpA activation. We propose that CcpA-mediated repression of haem uptake is a means of preventing oxidative damage at the start of exponential growth. CcpA thus appears to govern a regulatory network that coordinates oxygen, iron and carbon metabolism.