Your browser doesn't support javascript.
loading
Upregulation of the AMPK-FOXO1-PDK4 pathway is a primary mechanism of pyruvate dehydrogenase activity reduction in tafazzin-deficient cells.
Liang, Zhuqing; Ralph-Epps, Tyler; Schmidtke, Michael W; Lazcano, Pablo; Denis, Simone W; Balázová, Mária; Teixeira da Rosa, Nevton; Chakkour, Mohamed; Hazime, Sanaa; Ren, Mindong; Schlame, Michael; Houtkooper, Riekelt H; Greenberg, Miriam L.
Afiliación
  • Liang Z; Department of Biological Sciences, Wayne State University, Detroit, MI, USA.
  • Ralph-Epps T; Department of Biological Sciences, Wayne State University, Detroit, MI, USA.
  • Schmidtke MW; Department of Biological Sciences, Wayne State University, Detroit, MI, USA.
  • Lazcano P; Department of Biological Sciences, Wayne State University, Detroit, MI, USA.
  • Denis SW; Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • Balázová M; Amsterdam Gastroenterology Endocrinology and Metabolism Institute, Amsterdam, The Netherlands.
  • Teixeira da Rosa N; Amsterdam Cardiovascular Sciences Institute, Amsterdam, The Netherlands.
  • Chakkour M; Emma Center for Personalized Medicine, Amsterdam UMC, Amsterdam, The Netherlands.
  • Hazime S; Department of Membrane Biochemistry, Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, 84005, Bratislava, Slovakia.
  • Ren M; Department of Biological Sciences, Wayne State University, Detroit, MI, USA.
  • Schlame M; Department of Biological Sciences, Wayne State University, Detroit, MI, USA.
  • Houtkooper RH; Department of Biological Sciences, Wayne State University, Detroit, MI, USA.
  • Greenberg ML; Department of Anesthesiology, Perioperative Care, and Pain Medicine, Grossman School of Medicine, New York University, New York, NY, USA.
Sci Rep ; 14(1): 11497, 2024 05 20.
Article en En | MEDLINE | ID: mdl-38769106
ABSTRACT
Barth syndrome (BTHS) is a rare disorder caused by mutations in the TAFAZZIN gene. Previous studies from both patients and model systems have established metabolic dysregulation as a core component of BTHS pathology. In particular, features such as lactic acidosis, pyruvate dehydrogenase (PDH) deficiency, and aberrant fatty acid and glucose oxidation have been identified. However, the lack of a mechanistic understanding of what causes these conditions in the context of BTHS remains a significant knowledge gap, and this has hindered the development of effective therapeutic strategies for treating the associated metabolic problems. In the current study, we utilized tafazzin-knockout C2C12 mouse myoblasts (TAZ-KO) and cardiac and skeletal muscle tissue from tafazzin-knockout mice to identify an upstream mechanism underlying impaired PDH activity in BTHS. This mechanism centers around robust upregulation of pyruvate dehydrogenase kinase 4 (PDK4), resulting from hyperactivation of AMP-activated protein kinase (AMPK) and subsequent transcriptional upregulation by forkhead box protein O1 (FOXO1). Upregulation of PDK4 in tafazzin-deficient cells causes direct phospho-inhibition of PDH activity accompanied by increased glucose uptake and elevated intracellular glucose concentration. Collectively, our findings provide a novel mechanistic framework whereby impaired tafazzin function ultimately results in robust PDK4 upregulation, leading to impaired PDH activity and likely linked to dysregulated metabolic substrate utilization. This mechanism may underlie previously reported findings of BTHS-associated metabolic dysregulation.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Ratones Noqueados / Proteínas Quinasas Activadas por AMP / Proteína Forkhead Box O1 / Piruvato Deshidrogenasa Quinasa Acetil-Transferidora Límite: Animals Idioma: En Revista: Sci Rep / Sci. rep. (Nat. Publ. Group) / Scientific reports (Nature Publishing Group) Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Ratones Noqueados / Proteínas Quinasas Activadas por AMP / Proteína Forkhead Box O1 / Piruvato Deshidrogenasa Quinasa Acetil-Transferidora Límite: Animals Idioma: En Revista: Sci Rep / Sci. rep. (Nat. Publ. Group) / Scientific reports (Nature Publishing Group) Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos