Rajasekaran 2018 FASEB J

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Rajasekaran R, Felser A, Nuoffer JM, Dufour JF, St-Pierre MV (2018) The histidine triad nucleotide-binding protein 2 (HINT-2) positively regulates hepatocellular energy metabolism. FASEB J 32:5143-61.

» PMID: 29913563

Rajasekaran R, Felser A, Nuoffer JM, Dufour JF, St-Pierre MV (2018) FASEB J

Abstract: The histidine triad nucleotide-binding protein 2 (HINT-2) is a mitochondrial adenosine phosphoramidase expressed in hepatocytes. The phenotype of Hint2 knockout (Hint2^-/-) mice includes progressive hepatic steatosis and lysine hyperacetylation of mitochondrial proteins, which are features of respiratory chain malfunctions. We postulated that the absence of HINT-2 induces a defect in mitochondria bioenergetics. Isolated Hint2^-/- hepatocytes produced less ATP and generated a lower mitochondrial membrane potential than did Hint2^+/+ hepatocytes. In extracellular flux analyses with glucose, the basal, ATP-linked, and maximum oxygen consumption rates (OCRs) were decreased in Hint2^-/- hepatocytes and in HepG2 cells lacking HINT-2. Conversely, in HINT-2 overexpressing SNU-449 and HepG2 cells, the basal, ATP-linked, and maximum OCRs were increased. Similarly, with palmitate, basal and maximum OCRs were decreased in Hint2^-/- hepatocytes, but they were increased in HINT-2 overexpressing HepG2 cells. When assayed with radiolabeled substrate, palmitate oxidation was reduced by 25% in Hint2^-/- mitochondria. In respirometry assays, complex I- and II-driven, coupled and uncoupled respirations and complex IV KCN-sensitive respiration were reduced in Hint2^-/- mitochondria. Furthermore, HINT-2 associated with cardiolipin and glucose-regulated protein 75 kDa. Our study shows decreased electron transfer and oxidative phosphorylation capacity in the absence of HINT-2. The bioenergetics deficit accumulated over time in hepatocytes lacking HINT-2 likely leads to the secondary outcome of steatosis. • Keywords: Bioenergetics, Hepatic steatosis, Lysine hyperacetylation, Mitochondrial respiration • Bioblast editor: Plangger M • O2k-Network Lab: CH Bern Nuoffer JM

Labels: MiParea: Respiration, Genetic knockout;overexpression

Organism: Mouse Tissue;cell: Liver Preparation: Isolated mitochondria

Coupling state: LEAK, OXPHOS, ET Pathway: N, S, CIV, ROX HRR: Oxygraph-2k

Labels, 2018-09