SELECTIVE-INHIBITION OF MITOCHONDRIAL RESPIRATION AND GLYCOLYSIS IN HUMAN LEUKEMIC LEUKOCYTES BY METHYLGLYOXAL

The effect of methylglyoxal an the oxygen consumption of mitochondria of both normal and leukaemic leucocytes was tested by using different respiratory substrates and complex specific artificial electron donors and inhibitors. The results indicate that methylglyoxal strongly inhi bits mitochondrial respiration in leukaemic leucocytes, whereas, at a much higher concentration, methylglyoxal fails to inhibit mitochondria l respiration in normal leucocytes. Methylglyoxal strongly inhibits AD P-stimulated a-oxoglutarate and malate plus NAD(+)-dependent respirati on, whereas, at a higher concentration, methylglyoxal fails to inhibit succinate and alpha-glycerophosphate-dependent respiration. Methylgly oxal also fails to inhibit respiration which is initiated by duroquino ne and cannot inhibit oxygen consumption when the N,N,N',N'-tetramethy l-p-phenylenediamine by-pass is used. NADH oxidation by sub-mitochondr ial particles of leukaemic leucocytes is also inhibited by methylglyox al. Lactaldehyde, a catabolite of methylglyoxal, can exert a protectiv e effect on the inhibition of leukaemic leucocyte mitochondrial respir ation by methylglyoxal. Methylglyoxal also inhibits L-lactic acid form ation by intact leukaemic leucocytes and critically reduces the ATP le vel of these cells, whereas methylglyoxal has no effect on normal leuc ocytes. We conclude that methylglyoxal inhibits glycolysis and the ele ctron flow through mitochondrial complex I of leukaemic leucocytes. Th is is strikingly similar to our previous studies on mitochondrial resp iration, glycolysis and ATP levels in Ehrlich ascites carcinoma cells [Ray, Dutta, Halder and Ray (1994) Biochem. J. 303, 69-72; Halder, Ray and Ray (1993) Int. J. Cancer 54, 443-449], which strongly suggests t hat the inhibition of electron flow through complex I of the mitochond rial respiratory chain and inhibition of glycolysis by methylglyoxal m ay be common characteristics of all malignant cells.