Lactate metabolism is associated with mammalian mitochondria

Abstract

It is well established that lactate secreted by fermenting cells can be oxidized or used as a gluconeogenic substrate by other cells and tissues. Within the fermenting cell itself, however, it is generally assumed that lactate is produced to replenish NAD+ and then is secreted. Here we explored the possibility that cytosolic lactate is metabolized by the mitochondria of fermenting mammalian cells. We found that fermenting HeLa and H460 cells utilize exogenous lactate carbon to synthesize a large percentage of their lipids. With high-resolution mass spectrometry, we found that both 13C and 2-2H labels from enriched lactate enter the mitochondria. The lactate dehydrogenase (LDH) inhibitor oxamate decreased respiration of isolated mitochondria incubated in lactate, but not isolated mitochondria incubated in pyruvate. Additionally, transmission electron microscopy (TEM) showed that LDHB localizes to the mitochondria. Taken together, our results demonstrate a link between lactate metabolism and the mitochondria of fermenting mammalian cells.

Lactate is oxidized outside of the mitochondrial matrix in rodent brain

“…This may be due, at least in part, to a heavy reliance on some indirect techniques (e.g., spectrophotometric monitoring of NADH change), and generalizations among species, tissues, and cell types. Recently, the mitochondrial metabolism of lactate in cultured cancer cell lines was investigated more directly, using 13 C-labeled lactate and high-resolution mass spectrometry (Chen et al 2016). The results support the notion of a mitochondrial L-lactate carrier (Taylor 2017) and matrix LDHB in lactate-supported lipogenesis in proliferating, immortalized cells (Chen et al 2016).…”

“…Recently, the mitochondrial metabolism of lactate in cultured cancer cell lines was investigated more directly, using 13 C-labeled lactate and high-resolution mass spectrometry (Chen et al 2016). The results support the notion of a mitochondrial L-lactate carrier (Taylor 2017) and matrix LDHB in lactate-supported lipogenesis in proliferating, immortalized cells (Chen et al 2016). Whether this observation translates to mitochondria in mature, differentiated tissues like skeletal muscle and brain has not, to our knowledge, been reported.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…The ox ida tive path way of lac tate com prises lac tate up take in a process pri mar ily fa cil i tated by MCT1, a mono car boxy late trans porter with a high affin ity for lac tate [72], the con ver sion of lac tate and NAD to lac tate, NADH and H by lac tate de hy dro ge nase B (LDHB), and the mi to chon dr ial use of pyru vate [5] and NADH (im ported into mi to chon dria through the malate as par tate shut tle) [73]. Im por tantly, other au thors have re ported that LDHB can also re side in the mi to chon dria of some can cer cell lines, where they would gen er ate pyru vate and NADH from lac tate to di rectly fuel the TCA cy cle and the elec tron trans port chain, re spec tively [74,75]. The mi to chon dr ial lo cal iza tion of LDHB would be par tic u larly im por tant for gly colytic can cer cells that were re cently shown to use lac tate de rived from gly col y sis as a mi to chon dr ial re source to sup port lipid biosyn the sis [75].…”

“…Im por tantly, other au thors have re ported that LDHB can also re side in the mi to chon dria of some can cer cell lines, where they would gen er ate pyru vate and NADH from lac tate to di rectly fuel the TCA cy cle and the elec tron trans port chain, re spec tively [74,75]. The mi to chon dr ial lo cal iza tion of LDHB would be par tic u larly im por tant for gly colytic can cer cells that were re cently shown to use lac tate de rived from gly col y sis as a mi to chon dr ial re source to sup port lipid biosyn the sis [75]. The ox ida tive path way of lac tate is more con cise and, com par a tively to gly col y sis, does not ne ces si tate ATP in vest ment.…”

The role of mitochondria in cardiac development and protection

“…However, the metabolic signatures of glycolysis might be misleading as fetal cardiomyocytes actually metabolize lactate to pyruvate that is then fed into OXPHOS, a unique feature exploited for selective differentiation of embryonic stem cells into cardiomyocytes [54]. Mitochondria are also otherwise an important sink for lactate as they synthesize a large percentage of their lipids using lactate as a precursor [55].…”