Mice deficient in pyruvate dehydrogenase kinase 4 are protected against acetaminophen-induced hepatotoxicity

• Published in: Toxicology and applied pharmacology Vol. 387; p. 114849
• Main Authors: Duan, Luqi, Ramachandran, Anup, Akakpo, Jephte Y., Woolbright, Benjamin L., Zhang, Yuxia, Jaeschke, Hartmut
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.01.2020
• Subjects: Acetaminophen - poisoning; Acetaminophen, drug-induced liver injury; Animals; Bioenergetics; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - pathology; Disease Models, Animal; Drug Overdose - complications; Drug Overdose - etiology; Energy Metabolism - drug effects; Female; Humans; Liver - cytology; Liver - drug effects; Liver - pathology; Male; Mice; Mice, Knockout; Mitochondria; Mitochondria - drug effects; Oxidant stress; Oxidative Stress - drug effects; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - genetics; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - metabolism; UCP2; Uncoupling Protein 2 - metabolism; APAP; GSSG; JNK; MT; SOD; HO-1; MAPK; PDC; Acetaminophen, drug-induced liver injury; SHP1; LDH; NAC; Mitochondria; GCLC; TUNEL; Bioenergetics; UCP2; PDK4; GCLM; NAPQI; Oxidant stress; AIF; OCR
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2019.114849

Though mitochondrial oxidant stress plays a critical role in the progression of acetaminophen (APAP) overdose-induced liver damage, the influence of mitochondrial bioenergetics on this is not well characterized. This is important, since lifestyle and diet alter hepatic mitochondrial bioenergetics and an understanding of its effects on APAP-induced liver injury is clinically relevant. Pyruvate dehydrogenase (PDH) is critical to mitochondrial bioenergetics, since it controls the rate of generation of reducing equivalents driving respiration, and pyruvate dehydrogenase kinase 4 (PDK4) regulates (inhibits) PDH by phosphorylation. We examined APAP-induced liver injury in PDK4-deficient (PDK4−/−) mice, which would have constitutively active PDH and hence elevated flux through the mitochondrial electron transport chain. PDK4−/− mice showed significant protection against APAP-induced liver injury when compared to wild type (WT) mice as measured by ALT levels and histology. Deficiency of PDK4 did not alter APAP metabolism, with similar APAP-adduct levels in PDK4−/− and WT mice, and no difference in JNK activation and translocation to mitochondria. However, subsequent amplification of mitochondrial dysfunction with release of mitochondrial AIF, peroxynitrite formation and DNA fragmentation were prevented. Interestingly, APAP induced a rapid decline in UCP2 protein levels in PDK4-deficient mice. These data suggest that adaptive changes in mitochondrial bioenergetics induced by enhanced respiratory chain flux in PDK4−/− mice render them highly efficient in handling APAP-induced oxidant stress, probably through modulation of UCP2 levels. Further investigation of these specific adaptive mechanisms would provide better insight into the control exerted by mitochondrial bioenergetics on cellular responses to an APAP overdose. •PDK4-deficient mice were protected against acetaminophen hepatotoxicity•The protection did not involve inhibition of drug metabolism or JNK activation•PDK4-deficient mice showed less mitochondrial oxidant stress and dysfunction•Early mitochondrial oxidant stress is distinct from late amplification mechanisms