Person: Puigserver, Pere
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Puigserver
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Puigserver, Pere
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Publication Tetracyclines Promote Survival and Fitness in Mitochondrial Disease Models(Springer Science and Business Media LLC, 2021-01-18) Perry, Elizabeth; Bennett, Christopher; Luo, Chi; Balsa Martinez, Eduardo; Jedrychowski, Mark; O'Malley, Katherine; Latorre Muro, Pedro Antonio; Ladley, Richard Porter; Reda, Kamar; Wright, Peter; Gygi, Steven; Myers, Andrew; Puigserver, PereMitochondrial diseases (MD) are a heterogeneous group of disorders resulting from genetic mutations in nuclear or mitochondrial DNA (mtDNA) genes encoding for mitochondrial proteins 1,2. MD cause pathologies with severe tissue damage and ultimately death 3,4. There are no cures for MD and current treatments are only palliative 5–7. To search for new drug-targeted therapies, we designed a chemical high-throughput screen using cells carrying human MD mutations to identify small molecules that prevent cellular damage and death under nutrient stress conditions. Top hits in the screen were a series of antibiotics that maintain survival of different human MD mutant cells. A sub-library of tetracycline analogs, including doxycycline, rescued cell death and inflammatory signatures in mutant cells through partial and selective mitochondrial translation inhibition, causing a mitohormetic response that was ATF4 independent. Remarkably, doxycycline treatment strongly promoted fitness and survival of Ndufs4-/- mice, a pre-clinical Leigh syndrome mouse model 8. Brain proteomic analysis showed that doxycycline treatment largely prevented neuronal death and the increases of neuroimmune and inflammatory proteins in Ndufs4-/- mice, indicating a potential causality of these proteins in this brain pathology. These findings implicate tetracyclines as a potential therapeutic treatment for MD.Publication Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylationa(Elsevier, 2014) Chow, Jenny D.Y.; Lawrence, Robert T.; Healy, Marin E.; Dominy, John E.; Liao, Jason A.; Breen, David S.; Byrne, Frances L.; Kenwood, Brandon M.; Lackner, Carolin; Okutsu, Saeko; Mas, Valeria R.; Caldwell, Stephen H.; Tomsig, Jose L.; Cooney, Gregory J.; Puigserver, Pere; Turner, Nigel; James, David E.; Villén, Judit; Hoehn, Kyle L.Lipid deposition in the liver is associated with metabolic disorders including fatty liver disease, type II diabetes, and hepatocellular cancer. The enzymes acetyl-CoA carboxylase 1 (ACC1) and ACC2 are powerful regulators of hepatic fat storage; therefore, their inhibition is expected to prevent the development of fatty liver. In this study we generated liver-specific ACC1 and ACC2 double knockout (LDKO) mice to determine how the loss of ACC activity affects liver fat metabolism and whole-body physiology. Characterization of LDKO mice revealed unexpected phenotypes of increased hepatic triglyceride and decreased fat oxidation. We also observed that chronic ACC inhibition led to hyper-acetylation of proteins in the extra-mitochondrial space. In sum, these data reveal the existence of a compensatory pathway that protects hepatic fat stores when ACC enzymes are inhibited. Furthermore, we identified an important role for ACC enzymes in the regulation of protein acetylation in the extra-mitochondrial space.Publication Cyclin D1-CDK4 Controls Glucose Metabolism Independently of Cell Cycle Progression(2014) Lee, Yoonjin; Dominy, John E.; Choi, Yoon Jong; Jurczak, Michael; Tolliday, Nicola; Camporez, Joao Paulo; Chim, Helen; Lim, Ji-Hong; Ruan, Hai-Bin; Yang, Xiaoyong; Vazquez, Francisca; Sicinski, Piotr; Shulman, Gerald I.; Puigserver, PereInsulin constitutes a major evolutionarily conserved hormonal axis for maintaining glucose homeostasis1-3; dysregulation of this axis causes diabetes2,4. PGC-1α links insulin signaling to the expression of glucose and lipid metabolic genes5-7. GCN5 acetylates PGC-1α and suppresses its transcriptional activity, whereas SIRT1 deacetylates and activates PGC-1α8,9. Although insulin is a mitogenic signal in proliferative cells10,11, whether components of the cell cycle machinery contribute to insulin’s metabolic action is poorly understood. Herein, we report that insulin activates cyclin D1-CDK4, which, in turn, increases GCN5 acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high throughput chemical screen, we identified a CDK4 inhibitor that potently decreases PGC-1α acetylation. Insulin/GSK3β signaling induces cyclin D1 protein stability via sequestering cyclin D1 in the nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 mRNA transcripts. Activated cyclin D1-CDK4 kinase phosphorylates and activates GCN5, which then acetylates and inhibits PGC-1α activity on gluconeogenic genes. Loss of hepatic cyclin D1 results in increased gluconeogenesis and hyperglycemia. In diabetic models, cyclin D1-CDK4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless further activation of this kinase normalizes glycemia. Our findings show that insulin uses components of the cell cycle machinery in post-mitotic cells to control glucose homeostasis independently of cell division.Publication Oxidative Dimerization of PHD2 is Responsible for its Inactivation and Contributes to Metabolic Reprogramming via HIF-1α Activation(Nature Publishing Group, 2016) Lee, Gibok; Won, Hyung-Sik; Lee, Yoon-Mi; Choi, Jae-Wan; Oh, Taek-In; Jang, Jeong-Hwa; Choi, Dong-Kug; Lim, Beong-Ou; Kim, Young Jun; Park, Jong-Wan; Puigserver, Pere; Lim, Ji-HongProlyl hydroxylase domain protein 2 (PHD2) belongs to an evolutionarily conserved superfamily of 2-oxoglutarate and Fe(II)-dependent dioxygenases that mediates homeostatic responses to oxygen deprivation by mediating hypoxia-inducible factor-1α (HIF-1α) hydroxylation and degradation. Although oxidative stress contributes to the inactivation of PHD2, the precise molecular mechanism of PHD2 inactivation independent of the levels of co-factors is not understood. Here, we identified disulfide bond-mediated PHD2 homo-dimer formation in response to oxidative stress caused by oxidizing agents and oncogenic H-rasV12 signalling. Cysteine residues in the double-stranded β-helix fold that constitutes the catalytic site of PHD isoforms appeared responsible for the oxidative dimerization. Furthermore, we demonstrated that disulfide bond-mediated PHD2 dimerization is associated with the stabilization and activation of HIF-1α under oxidative stress. Oncogenic H-rasV12 signalling facilitates the accumulation of HIF-1α in the nucleus and promotes aerobic glycolysis and lactate production. Moreover, oncogenic H-rasV12 does not trigger aerobic glycolysis in antioxidant-treated or PHD2 knocked-down cells, suggesting the participation of the ROS-mediated PHD2 inactivation in the oncogenic H-rasV12-mediated metabolic reprogramming. We provide here a better understanding of the mechanism by which disulfide bond-mediated PHD2 dimerization and inactivation result in the activation of HIF-1α and aerobic glycolysis in response to oxidative stress.