MODULATION OF MITOCHONDRIAL BIOENERGETICS AND CELL METABOLISM BY CARBON MONOXIDE IN INFLAMMATORY CELLS

Carbon monoxide-releasing molecules (CO-RMs) uncouple respiration in isolated mitochondria1, which may serve as crucial organelles to transduce the anti-inflammatory properties of CO. Here we investigated in detail how CORM-4012, a manganese-based compound, modulates mitochondrial function in BV2 and primary microglia cells using a Seahorse XF analyzer. CORM-401 caused a concentration- and time-dependent increase in oxygen consumption rate (OCR) up to 100 µM, while higher concentrations were inhibitory. The increase in OCR was associated with a decrease in mitochondrial membrane potential and occurred when CORM-401 was added either before or after oligomycin, indicating an activity independent from ATP turnover, i.e. uncoupling (see Figure). Maximal respiration induced by FCCP was decreased by CORM-401, thus diminishing the spare respiratory capacity of cells. The uncoupling effect of CORM-401 was confirmed in permeabilized cells3 with a concentration-dependent increase in state 4 OCR at the level of complex I and III and a mild stimulation of state 3 OCR of complex II. Interestingly, CORM-401 increased glycolysis and prevented the depression of respiration as well as the decrease in ATP levels elicited by lipopolysaccharide in BV2 cells. These findings suggest that the anti-inflammatory activity of CO may be linked to modulation of mitochondrial bioenergetics and metabolism.