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Passarella, S. L-Lactate Transport in Mitochondria. Encyclopedia. Available online: https://encyclopedia.pub/entry/16855 (accessed on 27 July 2024).
Passarella S. L-Lactate Transport in Mitochondria. Encyclopedia. Available at: https://encyclopedia.pub/entry/16855. Accessed July 27, 2024.
Passarella, Salvatore. "L-Lactate Transport in Mitochondria" Encyclopedia, https://encyclopedia.pub/entry/16855 (accessed July 27, 2024).
Passarella, S. (2021, December 07). L-Lactate Transport in Mitochondria. In Encyclopedia. https://encyclopedia.pub/entry/16855
Passarella, Salvatore. "L-Lactate Transport in Mitochondria." Encyclopedia. Web. 07 December, 2021.
L-Lactate Transport in Mitochondria
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This entry is adapted from the peer-reviewed paper 10.3390/ijms222312620

The L-lactate (L-LAC)-mitochondria affair has its closure: that mitochondria can take up and metabolize L-LAC due to the presence of the mitochondrial L-lactate dehydrogenase is shown.

mitochondria L-lactate mitochondrial transport L-lactate dehydrogenase cancer neuronal cells

1. Introduction

Mitochondria play a key role in cell metabolism, and they govern a significant cross talk with the cytosol. This task is achieved by sharing metabolic pathways which rely on both cytosolic and mitochondrial enzymes. Mitochondria export metabolites/ATP for cytosol anaplerosis and import metabolite/ADP for final oxidation and ATP synthesis. Given that mitochondria are “close spaces” within the cytosol, they possess several translocators involved in cytosol communication with the inner mitochondrial compartments. However, as reported by Taylor [1] “the transport selectivities of many carriers remain unknown, and most have not been functionally investigated in mammalian cells”. A review describing “the multifaceted contributions of mitochondria to cellular metabolism” ignored or incompletely reported the transport and metabolism of certain metabolites in mitochondria, including L- and D-lactate and glutamine [2]. Papers describing the role of mitochondria in cancer do not take into consideration key transport processes, e.g., the transport into mitochondria of L-LAC which is the main product of cancer cell energy metabolism [3][4][5][6][7][8].

2. L-Lactate Transport in Mitochondria

2.1. The L-Lactate History

Although the L-LAC history begins more than a century ago, the role of mitochondria in L-LAC metabolism has received recognition only at the outset of the third millennium. Notably, in the past two decades, authors writing the L-LAC history have come from different scientific backgrounds. Physiologists consider L-LAC as a major product of exercise, neuroscientists approach L-LAC as an important oxidative substrate for brain energy metabolism, while others are experts in mitochondrial research involved in the role of mitochondria in the L-LAC metabolism. The consideration of L-LAC biochemistry, when approached from different perspectives, explains why limited knowledge of mitochondrial bioenergetics could lead to potential misunderstandings (see ref. [7]).
Until the mid-1980s, L-LAC was considered to be a waste product rather than an energy source for a variety of cells, and was postulated to be taken up and oxidized (see [9]). Thereafter, the role of mitochondria in L-LAC metabolism has been demonstrated in spermatozoa, liver, heart, skeletal muscle, brain, plant, and yeast mitochondria. As for the latter, the history of the L-LAC–mitochondrial affair up to 2008 has been outlined in a mini-review by Passarella et al. [9]. Figure 1 describes the status of the L-LAC–mitochondria affair in 2008.
Ijms 22 12620 g011 550
Figure 1. The mitochondrial metabolism of L-lactate. From Passarella et al. From [9]. With permission from John Wiley and Sons, 2021.
(A) The mitochondrial metabolism of L-lactate in potato tuber. The sequence of events involved in mitochondrial metabolism of L-lactate (L-LAC) is envisaged as: uptake into mitochondria of L-LAC, synthesized in the cytosol by anaerobic glycolysis, perhaps via the L-LAC/H+ symporter; oxidation of the L-LAC to PYR by the mL-LDH located in the inner mitochondrial compartment; activation of alternative oxidase (AOX) by the newly synthesized PYR, oxidation of the intramitochondrial NAD(P)H via AOX with efflux of PYR via a putative L-LAC/PYR antiporter and the oxidation of cytosolic NADH in a non-energy-competent L-LAC/PYR shuttle. PYR conversion could also occur to AcetylCoA and malate via pyruvate dehydrogenase and malic enzyme, respectively.
(B) The mitochondrial metabolism of L-lactate in the liver. Externally added L-LAC can enter RLM where it is oxidized by the mitochondrial L-LDH. L-lactate can cause efflux in the extramitochondrial phase of PYR and OAA newly synthesized in the mitochondrial matrix via mL-LDH and pyruvate carboxylase. The metabolite efflux occurs by virtue of the occurrence of three carriers for L-LAC transport in mitochondria: the L-LAC/H+ symporter and the L-LAC/PYR and L-LAC/OAA antiporters. The LAC/PYR antiporter accounts for the LAC/PYR shuttle which transfers reducing equivalents from the cytoplasm to the mitochondrial respiratory chain. The L-LAC/OAA antiporter accounts for novel gluconeogenesis. OAA and PYR (via the pyruvate dehydrogenase) could also fill up the Krebs cycle intermediate pool.
(C) The mitochondrial metabolism of L-lactate in Saccharomyces cerevisiae. Externally added L-LAC can enter mitochondria via a putative L-LAC/H+ symporter. In mitochondria, an NAD-dependent mL-LDH exists. Moreover, in the intermembrane space L-LAC is oxidized to PYR with reduction in cytochrome c by a flavin mitochondrial L-lactate:cytochrome c oxidoreductase in an energy competent manner. Abbreviations: AcCoA, acetyl-CoA; AOX, alternative oxidase; GNG, gluconeogenesis; L-LAC, L-lactate; MAL, malate; OAA, oxaloacetate; PYR, pyruvate; R.C., respiratory chain; transport and oxidation processes the existence of which has not yet been confirmed. Enzymes: a, cytosolic L-LDH; b, mitochondrial L-LDH; c, malic enzyme; d, pyruvate dehydrogenase; e, pyruvate carboxylase; f, L-lactate:cytochrome c oxidoreductase (Cyb2p). Mitochondrial carriers: 1, L-LAC/H+ symporter; 2, L-LAC/PYR antiporter; 3, L-LAC/OAA antiporter.
Interestingly, de Bari et al. [10] provided evidence for the presence of an intermembrane L-lactate oxidase that generates H2O2 sufficient to activate the known ROS response elements, signaling mitochondrial and other adaptations to exercise. That work provides a possible mechanism by which L-LAC generation in muscle exercise participates in the feedback loop. L-LAC generation in exercise leads to adaptations facilitating high rates of lactate disposal in exercise. It is worth noticing that the putative L-LAC oxidase could be a candidate to the new role proposed for L-LAC as “lactormone”, i.e., in Brooks’ term [11] as a cell-signaling molecule that is involved in the adaptive response to exercise. In 2015, Paventi, Lessard, Bailey, and Passarella [12] found that in boar sperm capacitation L-LAC, but not PYR can contribute to mitochondrial membrane potential increase as monitored via safranine fluorescence, this both strongly suggesting that L-LAC is the ultimate product of glycolysis and confirming that L-LAC must enter mitochondria to be oxidized by the mL-LDH (see also [9]).
We will consider some aspects of the mitochondrial L-LAC transport and metabolism in neuronal and cancer cells not already considered in [9].

2.2 The L-Lactate Mitochondrial Metabolism Plays a Major Role in Neuronal Cells

A better understanding of the role of L-LAC in neuronal energy metabolism and in particular in mitochondrial energy metabolism (see [9]) requires some attention. In fact, for almost a century this molecule was considered just a waste product of the brain during hypoxia. The lactic acidosis hypothesis of delayed neuronal damage post cerebral ischemia was proposed in 1981 [13], and the researchers quickly explained the cellular mechanism that leads to this phenomenon, i.e., the fall in pH post-ischemia leads to delayed neuronal damage and this drop is due to the ischemic production of L-LAC. Upon attempting to establish an in vitro model of cerebral ischemia by showing that lactic acidosis would worsen ischemic neuronal damage, the investigators were surprised to find out that acidic pH provided slight protection, while L-LAC provided dramatically better protection [14].
Consequently, a seminal paper demonstrated the ability of neuronal tissue to utilize L-LAC as its sole oxidative energy substrate to maintain neuronal function [15]. This finding did not sit well with the prevailing dogma of the time regarding glycolysis, L-LAC, and oxidative energy metabolism leading to a long-lasting debate that has not subsided to this day. Nevertheless, the above-mentioned in vitro model system allowed further exploration of the role of L-LAC as neuronal tissue main substrate for oxidative energy metabolism. By 1994, Izumi et al. [16] confirmed this finding. Similarly, Larrabee [17][18] provided further support for neuronal oxidative utilization of L-LAC. L-LAC was shown to be the obligatory energy substrate for the recovery of neuronal function from hypoxic/ischemic insult [19][20]. Using in vivo recording in the rat brain, Hu and Wilson [21] demonstrated that fluctuations in the levels of extracellular L-LAC and oxygen levels are coupled to neuronal activity. An increase in L-LAC output upon neuronal excitation in vitro was shown to serve the need for increased energy demands of excited neurons [22]. In contrast, the blockade of L-LAC transport via the monocarboxylate transporter 1 (MCT1) exacerbates delayed neuronal damage in a rat model of cerebral ischemia [23]. This finding established L-LAC as the preferential oxidative energy substrate when ATP stores dwindle to the point that glycolytic glucose phosphorylation is unattainable or possibly even under normal physiological conditions. In 2003, Smith et al. [24] showed that L-LAC is the preferred fuel for human brain metabolism in vivo and Dalsgaard et al. [25] demonstrated that reduced cerebral metabolic ratio in exercise reflects L-LAC metabolism rather than accumulation in the human brain. Thus, in 2006 L-LAC was suggested to be the ultimate cerebral oxidative energy substrate [26]. By 2007, it was demonstrated that L-LAC, not PYR, is the neuronal aerobic glycolysis end product in vitro [26][27]. In that study relatively specific LDH inhibitors were used to inhibit either the L-LAC-to-PYR reaction or the PYR-to-L-LAC one, enabling the investigators to determine that L-LAC, rather than PYR, is the substrate that is being oxidized intra-mitochondrially by LDH.
During the preparation of the 2006 review [26], a thorough search of older literature from the 1920s and 1930s, rediscovered a throve of studies, most of which were performed by one group of biochemists. Those investigators demonstrated and were aware of the ability of brain tissue preparation to make lactic acid disappear in the presence of oxygen, a process the investigators interpreted as a mechanism of lactic acid clearance [28][29][30][31][32][33][34][35][36][37].
The prevailing dogma at the time had been that lactic acid is a waste product to be cleared. It is important to clarify that Krebs and Johnson were not sure about their suggestion that PYR is the mitochondrial substrate of the TCA cycle [38][39][40], but that suggestion was the one responsible for the decision by the elucidators of the glycolytic pathway to place PYR as its final aerobic product. This digging might suggest that biochemical archeology could still be a source of inspiration.
That L-LAC can be a neuronal energy source was also shown by O’Brien et al. [40] and Wyss et al. [41].
A short commentary [42] weighed in on the results published by Larsen et al. [43]. These investigators described their attempts to elucidate the mechanism behind the observed exercise-induced reduction in the cerebral metabolic ratio (CMR) as measured in healthy human subjects. They no longer used the accepted definition of CMR as O2/glucose, but rather focus instead on the more accurate definition of CMR, i.e., O2/(glucose + ½ L-LAC), to make their estimates. They clearly show that as their subjects approached the maximal work load and exhaustion under control conditions, the CMR [O2/(glucose + ½ L-LAC)] fell from the expected value of approximately 6 to about 3. When the same measurement was done for CMR (O2/glucose), its value did not change significantly throughout the experimental period. Concomitantly, the a–v differences for glucose and oxygen, even at the maximum workload, increased only slightly in comparison to the values at rest. In contrast, the a–v differences for total carbohydrates (CHO) at maximal workload were significantly higher than the values at rest, an increase that could be attributed almost entirely to the significantly higher a–v difference for L-LAC. Based on the results of Larsen and colleagues, Schurr concluded that L-LAC is a major and crucial player in the normal function of both brain and muscle [42]. In 2012, it was shown that aerobic production and utilization of L-LAC satisfy increased energy demands upon neuronal activation in hippocampal slices and provide neuroprotection against oxidative stress [44]. The authors analyzed, among others, the results of the study by Hu and Wilson [21] who measured glucose, L-LAC, and oxygen level in brain tissue in vivo during rest and stimulation. The analysis demonstrated that, during continuous stimulation, brain tissue consumes, oxidatively, gradually more L-LAC and less glucose, a process that allows for a more efficient ATP production to support neuronal activation induced by such stimulation. Moreover, in vitro experiments carried out by Schurr and Gozal [44] indicated that the production of reactive oxygen species (ROS) in response to the presence of the excitotoxic neurotransmitter, glutamate was reduced significantly when L-LAC was the sole energy substrate. PYR—as the sole energy substrate—could not reduce ROS production. Despite the continuous accumulation of studies supporting L-LAC’s major role in brain energy metabolism, doubts about their validity are persisting, even today. In a review [45] the authors opined on the persistence of doubt among scientists regarding L-LAC’s role as a major oxidative substrate for energy metabolism in the brain and elsewhere and offered that a “habit of mind” may explain the persistence of that doubt. Considering the proposed function of L-LAC in energy metabolism, the accuracy of current methods and techniques used to measure brain tissue metabolic rates of glucose only, not taking into account the contribution of L-LAC to these measurements is questioned.
Clearly, there is ample evidence to support the concept that brain L-LAC is the glycolytic end product, both aerobically and anaerobically, and hence the main oxidative substrate for mitochondrial TCA.
Evidence that L-LAC transport and metabolism can occur in brain mitochondria was demonstrated for the first time in 2007 when mitochondria from cerebellar granule cells were shown to metabolize externally added L-LAC [46]. This has been confirmed [40] and where the occurrence of LDH in the mitochondria of an astrocytic cell line was shown. In 2008 Hashimoto et al. [11] proposed that neurons contain a mitochondrial lactate oxidation complex that has the potential to facilitate both intracellular and cell–cell lactate shuttles in the brain (see below).

2.3. The L-Lactate Mitochondrial Metabolism Plays a Major Role in Cancer Cells

In cancer, L-LAC is the ultimate product of glycolysis (Warburg effect), however, until 2010 its metabolism has not been investigated in detail: in the words of Kennedy and Dewhirst [47] “The implications and consequences of L-LAC utilization by tumors are currently unknown; therefore, future research is needed on the intricacies of tumor metabolism”. No mitochondrial metabolism was proposed until 2010 when de Bari et al. [48] published a paper in which showed that “L-LAC metabolism can occur in normal and cancer prostate cells via the novel mitochondrial L-LAC dehydrogenase”. They showed that L-LAC can be transported into mitochondria isolated from both normal (PTNA) and cancer cells (PC3 cells) in a carrier-mediated manner via the putative L-LAC/H+ symporter, inhibited by the thiol reagent mersalyl. Inside mitochondria L-LAC is oxidized by the mL-LDH, producing PYR. Normal and cancer cells were found to differ from one another with respect to mL-LDH protein level and activity, being the enzyme more highly expressed and of higher activity in cancer cells. Such a conclusion was confirmed by Hussien and Brooks who found differences in mitochondrial LDH and MCT isoform expression in normal breast cancer and breast cancer cells [49]. Moreover, the kinetic features and pH profiles of the PC3 mL-LDH also differ from those of the PNT1A enzyme, this suggesting the occurrence of separate isoenzymes. Considering the poor oxygen consumption and since fatty acid oxidation is the bioenergetic dominant pathway in the prostate, L-LAC metabolism was suggested to lead to citric cycle anaplerosis to give OAA via pyruvate carboxylase, activated by acetyl-CoA. Citrate could be then formed to be used essentially in fatty acid synthesis in PC3 cells and exported in the extracellular fluid in the PNT1 cells. Two years later, confirmation that L-LAC uptake can trigger metabolic traffic from cytosol to mitochondria and vice versa was found in Hep G2 cells: occurrence of the L-LAC/PYR shuttle (see [50][9]) and the appearance outside mitochondria of OAA, malate and citrate arising from L-LAC uptake and metabolism together with the low oxygen consumption and membrane potential generation were found thus establishing an anaplerotic role for L-Lactate in Hep G2-M for instance in fatty acid synthesis [51]. It was found that Hep G2 cell mitochondria (Hep G2-M) possess an mL-LDH restricted to the inner mitochondrial compartments as shown by immunological analysis, confocal microscopy and by assaying mL-LDH activity in solubilized mitochondria [51]. Cytosolic and mitochondrial L-LDHs were found to differ from one another in their saturation kinetics. The capability of L-LAC to enter mitochondria was shown by measuring the increase in NAD(P)H fluorescence which takes place as a result of L-LAC addition and by monitoring the mitochondrial swelling in ammonium L-LAC solution. Interestingly, in the same experiment, PYR proved to be a non-penetrant metabolite, this suggesting the impossibility that the Cori cycle could occur in these cells. Accordingly, Passarella and Schurr [52] published “L-lactate transport and metabolism in mitochondria of Hep G2 cells-the Cori Cycle revisited”, in which, due to the lack of the PYR carrier activity in cancer mitochondria, it is proposed that gluconeogenesis in Hep G2 cells depends on L-LAC mitochondrial transport, where OAA is formed and exported for gluconeogenesis likely via the L-LAC/OAA antiporter. Recently, it was proposed to include the mitochondrial metabolism of L-LAC in cancer metabolic reprogramming [53].

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