**7. Aberrant pyruvate transfer**

Altered metabolism of pyruvate resulting from the inability to transfer pyruvate is present in cancer and other metabolic diseases. Pyruvate metabolism and carbon flux are altered in many cancer cells. Metabolic switch to enhanced glycolysis and decreased oxidative phosphorylation (Warburg effect) leads to elevated lactate production, which is advantageous for cancer cells. The first advantage is regeneration of NAD<sup>+</sup> for the continuation of glycolysis. Another is proton-linked transport of lactate out of the cell, increasing the acidity of the extracellular space. Acidification of the extracellular environment provides protection from the immune system [144]. Furthermore, lactic acid appears to influence the activity of matrix metalloproteinases breaking down the extracellular matrix aiding in tumor proliferation and metastasis [145] and can be utilized as fuel source by cancer cells located at the surface of the tumor [146]. Schell et al. [147] found *MPC1* genomic locus as the most frequently deleted region across cancer cells, while *MPC2* locus does not appear to be frequently lost. MPC1 underexpression correlates with poor survival in almost all cancers examined, including colon, kidney, lung, bladder, and brain [147]. The correlation of survival with *MPC2* expression is more variable, but associated with poor prognosis in kidney and colon cancer [147].

Increased pyruvate levels in cerebrospinal fluid reflecting an impaired metabolism of pyruvate have been detected in neurodegenerative disorders including Leigh's syndrome, Alzheimer's disease, and Parkinson's disease [148, 149]. Neuronal metabolism depends upon the uptake of lactate produced by astrocytes (astrocyte-neuron lactate shuttle), its conversion to pyruvate by LDH, and subsequent oxidation in mitochondria to form energy. Glucose is shifted into the pentose phosphate pathway for the NADPH generation to maintain reduced glutathione levels [150]. Due to the lack of pyruvate metabolism in neurodegenerative diseases, synthesis of acetylcholine is also insufficient because it requires acetyl-CoA [143]. To the present, there are not many findings available about MPC inhibition in neuronal cells except for α-cyano-4-hydroxy cinnamate or phenylpyruvate effects. Most likely, MPC efficacy and susceptibility to disease progression are also related to genetic predisposition. Mitochondrial pyruvate supply restriction can also display a neuroprotective effect by increase in glutamate oxidation. Maintaining the levels of synaptic glutamate during glutamatergic neurotransmission comes at energetic cost leading to periods of increased levels of glutamate. High levels of glutamate cause complex I inhibition through receptor-stimulated Ca2+ overload, which is an attribute of acute neuropathologies [151].

MPC1 and MPC2 are highly expressed in brown adipose tissue compared with other tissues [152]. Brown adipocytes use predominantly fatty acids as an energy source for uncoupled respiration and thermogenesis, which requires replenishment of oxaloacetate through pyruvate carboxylation to enter citric acid cycle. MPC is supposed to be important in shifting between formation and oxidation of fatty acids in fat cell metabolism.

Alteration in pyruvate metabolism plays a conspicuous role in heart disease. Heart muscle predominantly metabolizes fatty acids, ketone bodies, lactate, and glucose depending on their availability and neurohormonal signaling. Up to 95% of the heart's ATP generation comes from mitochondrial oxidation, and typically approximately 60–90% of this mitochondrial ATP production comes from fatty acids, whereas 10–40% is from pyruvate oxidation. The myocardium is a significant consumer of lactate even at the maximum load, because of specific expression of LDH-B isoform preferring reaction catalysis toward pyruvate [153]. It was found that acute stress (such as ischemia) and chronic stress (hypertrophy and heart failure) change substrate availability and metabolism [143]. Reduction in pyruvate oxidation leads to increased anaerobic glycolysis and lactate formation. However, age-related decrease in MPC activity was observed [154]. Shift in substrate utilization in order to maintain citric acid cycle can lead to serious states of energy deficiency called "starved heart." The effect was observed in cancer treatment with doxorubicin reducing carnitine transport followed by reduced fatty acid oxidation [155].
