L-lactate metabolism can occur in normal and cancer prostate cells via the novel mitochondrial L-lactate dehydrogenase

Abstract

Abstract. Both normal (PTN1A) and cancer (PC3) prostate cells produce high levels of L-lactate because of a low energy supply via the citric cycle and oxidative phosphorylation. Since some mammalian mitochondria possess a mitochondrial L-lactate dehydrogenase (mLDH), we investigated whether prostate cells can take up L-lactate and metabolize it in the mitochondria. We report here that externally added L-lactate can enter both normal and cancer cells and mitochondria, as shown by both the oxygen consumption and by the increase in fluorescence of NAD(P)H which occur as a result of L-lactate addition. In both cell types L-lactate enters mitochondria in a carrier-mediated manner, as shown by the inhibition of swelling measurements due to the non-penetrant thiol reagent mersalyl. An L-lactate dehydrogenase exists in mitochondria of both cell types located in the inner compartment, as shown by kinetic investigation and by immunological analysis. The mLDHs proved to differ from the cytosolic enzymes (which themselves differ from one another) as functionally investigated with respect to kinetic features and pH profile. Normal and cancer cells were found to differ from one another with respect to mLDH protein level and activity, being the enzyme more highly expressed and of higher activity in PC3 cells. Moreover, the kinetic features and pH profiles of the PC3 mLDH also differ from those of the PNT1A enzyme, this suggesting the occurrence of separate isoenzymes.

Functional inhibition of lactate dehydrogenase suppresses pancreatic adenocarcinoma progression

“…57,58,59,60 Furthermore, the elevated catalytic efficiency of glycolytic enzyme promoted L-lactate secretion and formed an autocrine lactate loop promoting malignant transformation. 57,61,62 The possible role of llactate metabolism and transport in cancer biochemistry has long been ignored in cancer research 63 and future research is warranted.…”

“…It was observed that berberine potently suppressed LDHA-OE pancreatic cancer cell growth. We identified half-maximal inhibitory concentration (IC50) approximately equal to 62 5E). Functionally, exposure of L-lactate to berberine-treated cancer cells attenuated the growth and invasion suppression by berberine (Figure 5F and G), suggesting the restoration of LDHA attenuated the suppressive effect of berberine on PAAD.…”

Mitochondrial Transport in Glycolysis and Gluconeogenesis: Achievements and Perspectives

“…Surprisingly, such a simple procedure has not been appreciated and accepted in a recent paper [ 7 ] stating that “Unfortunately, some studies which have concluded the existence or absence of mitochondrial LDH, and implied the physiological relevance thereof, base such claims on experiments involving the continuous monitoring of added NADH autofluorescence in isolated mitochondria [ 14 , 18 , 19 , 20 , 21 , 22 , 23 ]”. We believe that the authors misinterpreted the cited papers since NADH was not added to mitochondria.…”

“…We believe that the authors misinterpreted the cited papers since NADH was not added to mitochondria. Rather, the authors monitored only the fluorescence of the mitochondrial NAD(P)H [ 14 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review

“…This is further evidenced by LDHB localizing to the mitochondria at greater densities than to other locations, and LDHA not localizing to the mitochondria (Chen et al, 2016). Additionally, mitochondrial LDH is highly expressed and more active in cancerous prostate cells than normal ones, contributing to the anaplerosis of TCA cycle intermediates to help fuel cancer progression (De Bari et al, 2010). However, some have demonstrated that lactate must be first converted to pyruvate before it can enter the mitochondrial matrix and have challenged the hypothesis that lactate can be directly oxidized by mitochondria (Jacobs et al, 2013;Passarella et al, 2014).…”