Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and represents the hepatic expression of several metabolic abnormalities of high epidemiologic relevance. Fat accumulation in the hepatocytes results in cellular fragility and risk of progression toward necroinflammation, i.e., nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Several pathways contribute to fat accumulation and damage in the liver and can also involve the mitochondria, whose functional integrity is essential to maintain liver bioenergetics. In NAFLD/NASH, both structural and functional mitochondrial abnormalities occur and can involve mitochondrial electron transport chain, decreased mitochondrial β-oxidation of free fatty acids, excessive generation of reactive oxygen species, and lipid peroxidation. NASH is a major target of therapy, but there is no established single or combined treatment so far. Notably, translational and clinical studies point to mitochondria as future therapeutic targets in NAFLD since the prevention of mitochondrial damage could improve liver bioenergetics.

Some metabolic pathways involve two different cell components, for instance, cytosol and mitochondria, with metabolites traffic occurring from cytosol to mitochondria and vice versa, as seen in both glycolysis and gluconeogenesis. However, the knowledge on the role of mitochondrial transport within these two glucose metabolic pathways remains poorly understood, due to controversial information available in published literature. In what follows, we discuss achievements, knowledge gaps, and perspectives on the role of mitochondrial transport in glycolysis and gluconeogenesis. We firstly describe the experimental approaches for quick and easy investigation of mitochondrial transport, with respect to cell metabolic diversity. In addition, we depict the mitochondrial shuttles by which NADH formed in glycolysis is oxidized, the mitochondrial transport of phosphoenolpyruvate in the light of the occurrence of the mitochondrial pyruvate kinase, and the mitochondrial transport and metabolism of L-lactate due to the L-lactate translocators and to the mitochondrial L-lactate dehydrogenase located in the inner mitochondrial compartment.

L-Lactate Transport and Metabolism in Mitochondria of Hep G2 Cells—The Cori Cycle Revisited

The term ‘aerobic glycolysis’ has been in use ever since Warburg conducted his research on cancer cells’ proliferation and discovered that cells use glycolysis to produce adenosine triphosphate (ATP) rather than the more efficient oxidative phosphorylation (oxphos) pathway, despite an abundance of oxygen. When measurements of glucose and oxygen utilization by activated neural tissue indicated that glucose was consumed without an accompanied oxygen consumption, the investigators who performed those measurements also termed their discovery ‘aerobic glycolysis’. Red blood cells do not contain mitochondria and, therefore, produce their energy needs via glycolysis alone. Other processes within the central nervous system (CNS) and additional organs and tissues (heart, muscle, and so on), such as ion pumps, are also known to utilize glycolysis only for the production of ATP necessary to support their function. Unfortunately, the phenomenon of ‘aerobic glycolysis’ is an enigma wherever it is encountered, thus several hypotheses have been produced in attempts to explain it; that is, whether it occurs in cancer cells, in activated neural tissue, or during postprandial or exercise metabolism. Here, it is argued that, where the phenomenon in neural tissue is concerned, the prefix ‘aerobic’ in the term ‘aerobic glycolysis’ should be removed. Data collected over the past three decades indicate that L-lactate, the end product of the glycolytic pathway, plays an essential role in brain energy metabolism, justifying the elimination of the prefix ‘aerobic’. Similar justification is probably appropriate for other tissues as well.

One of the outstanding problems in biochemistry as well as in biological sciences is whether and how each research paper and in particular each review paper reports up-to date information on a specific topic. We suggest to resort to available data bases that sort publications by relevance (i.e. WEB of Sciences and SCOPUS) or by best match (i.e. PubMed). For instance, when searching for “lactate metabolism and cancer mitochondria” on July 9th2018, one finds more than 950 results that includes in the first 6, three publications from the Passarella Lab showing that cancer mitochondria can take up and metabolize externally added D and L-lactate [1-3]. This finding is further confirmed in the 14th and 15th papers on the list [4,5]. Surprisingly, the mitochondrial lactate metabolism in cancer cells is essentially ignored in all listed papers including the one published by the Gladden’s lab, which is listed at 43th place [6].

Mitochondria serve as central hubs of cellular metabolism, integrating catabolic and anabolic pathways through the controlled exchange of metabolites across their membranes. Although mitochondrial transport of several metabolites has been well documented, the mechanisms underlying the trafficking of fumarate, glutamine, and phosphoenolpyruvate as well as the role of the mitochondrial pyruvate kinase remain insufficiently represented in modern biochemistry textbooks. Here, we revisit the biochemical evidence supporting specific transport systems for these metabolites, discuss their physiological roles in major metabolic pathways, and highlight how foundational experimental studies have been overlooked in contemporary literature. Re-examining these mechanisms provides new insight into the dynamic interplay between mitochondrial function, cytosolic metabolism, and overall cellular homeostasis.