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Bioenergetics
Published in Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan, Strength and Conditioning in Sports, 2023
Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan
Although blood glucose is preferentially used, slow glycolysis can use either blood glucose or muscle glycogen as an energy source. Aerobic or slow glycolysis is a result of mitochondria activity being sufficient to accept the two NADH produced during glycolysis (Pasteur effect (161, 187) (Figure 2.5). An additional six ATP can be created resulting from the entrance of the two NADH into the electron transport system. During slow (aerobic) glycolysis, pyruvate can enter the mitochondrial matrix via a localized carrier mechanism in the outer and inner membranes (35, 51, 186). Two proteins are believed to be involved in pyruvate mitochondrial transport, mitochondrial pyruvate carriers MPC1 and MPC2 form a hetero-oligomeric complex in the inner mitochondrial membrane to facilitate pyruvate transport (186). In this manner, pyruvate can lose a carboxyl group (as CO2) and be made available for oxidation.
Mitochondrial dysfunction and mitochondrion-targeted therapeutics in liver diseases
Published in Journal of Drug Targeting, 2021
Li Xiang, Yaru Shao, Yuping Chen
The Tricarboxylic acid (TCA) cycle activity has been proven to be enhanced in NAFLD/NASH patients and animal models while the respiratory coupling is impaired. Inhibiting the transport of pyruvate via the mitochondrial pyruvate carriers (MPCs) on the IMM into mitochondrion matrix for oxidisation was seen to reduce the TCA cycle function and its mutual transformations among carbohydrates, lipids and amino acids [34]. Thiazolidinedione compounds were seen to inhibit MPC2 in hepatocytes, alter mitochondrial pyruvate metabolism and effectively act against NASH and liver fibrosis [35]. Besides, MPC2 inactivation either by the suppression with thiazolidinedione drug (MSDC-0602) or by the hepatocyte-specific deletion affected the secretion of exosomes from hepatocytes, or probably lowered the availability of glutamine for HSCs, indirectly inhibiting HSC activation in vitro and in vivo and attenuating NASH and fibrosis scoring in high trans-fat, fructose and cholesterol diet mice [36]. Accordingly, inhibiting PDH kinase with dichloroacetic acid increased the mitochondrial utilisation of pyruvate, improved levels of the reducing cofactors in OXPHOS and enhanced energy production [37]; while blocking mitochondrial translocation of pyruvate by PUMA, a pro-apoptotic Bcl-2 family protein, was reported to promote glycolytic metabolism and contribute to HCC progression [38,39]. All these studies underline the significance of mitochondrial pyruvate metabolism in liver diseases.
MSDC-0602K, a metabolic modulator directed at the core pathology of non-alcoholic steatohepatitis
Published in Expert Opinion on Investigational Drugs, 2018
Jerry R. Colca, William G McDonald, Wade J. Adams
Recently, a new binding site for the anti-diabetic TZDs was discovered to be the mitochondrial pyruvate carrier (MPC) [9,10]. The MPC is composed of two major subunits known as mpc1 and mpc2, it serves as the main connection between non-oxidative and oxidative metabolism, and it is well-conserved from yeast to man [11–14]. The expression of the MPC proteins are increased in animals given a high fat diet [15], and elimination (selective knockout) of either mpc1 [16] or mpc2 [17] in the liver parenchymal cells protects against the liver damage produced by a high fat diet. Thus, there is strong evidence that the MPC plays a role in animal models of fatty liver disease.
Current and emerging gluconeogenesis inhibitors for the treatment of Type 2 diabetes
Published in Expert Opinion on Pharmacotherapy, 2021
Mitochondrial processes are key to cellular energetics, and there has been progress in understanding the organization of these processes. The mitochondrial pyruvate carriers (MPC1, MPC2) transport pyruvate across the mitochondrial membrane thus promoting gluconeogenesis [105]. They are downregulated by the PPAR-γ agonist pioglitazone.