Organization of a functional glycolytic metabolon on mitochondria for metabolic efficiency.

Autor: Wang H; Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA., Vant JW; Biodesign Institute, The School of Molecular Sciences, Arizona State University, Tempe, AZ, USA., Zhang A; Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA., Sanchez RG; Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA., Wu Y; Department of Genetics and Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA., Micou ML; Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA.; Thomas Jefferson University, Philadelphia, PA, USA., Luczak V; Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA.; Neurocrine Biosciences, San Diego, CA, USA., Whiddon Z; Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA., Carlson NM; Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA., Yu SB; Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA.; Denali Therapeutics Inc., South San Francisco, CA, USA., Jabbo M; Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA., Yoon S; Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA.; University of Southern California, Los Angeles, CA, USA., Abushawish AA; Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA., Ghassemian M; Biomolecular and Proteomics Mass Spectrometry Facility, University of California San Diego, La Jolla, CA, USA., Masubuchi T; Cell and Developmental Biology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA., Gan Q; Department of Cell Biology, Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USA., Watanabe S; Department of Cell Biology, Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USA., Griffis ER; Nikon Imaging Center, University of California San Diego, La Jolla, CA, USA.; Altos Labs, San Diego, CA, USA., Hammarlund M; Department of Genetics and Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA., Singharoy A; Biodesign Institute, The School of Molecular Sciences, Arizona State University, Tempe, AZ, USA., Pekkurnaz G; Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA. gpekkurnaz@ucsd.edu.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2024 Sep; Vol. 6 (9), pp. 1712-1735. Date of Electronic Publication: 2024 Sep 11.
DOI: 10.1038/s42255-024-01121-9
Abstrakt: Glucose, the primary cellular energy source, is metabolized through glycolysis initiated by the rate-limiting enzyme hexokinase (HK). In energy-demanding tissues like the brain, HK1 is the dominant isoform, primarily localized on mitochondria, and is crucial for efficient glycolysis-oxidative phosphorylation coupling and optimal energy generation. This study unveils a unique mechanism regulating HK1 activity, glycolysis and the dynamics of mitochondrial coupling, mediated by the metabolic sensor enzyme O-GlcNAc transferase (OGT). OGT catalyses reversible O-GlcNAcylation, a post-translational modification influenced by glucose flux. Elevated OGT activity induces dynamic O-GlcNAcylation of the regulatory domain of HK1, subsequently promoting the assembly of the glycolytic metabolon on the outer mitochondrial membrane. This modification enhances the mitochondrial association with HK1, orchestrating glycolytic and mitochondrial ATP production. Mutation in HK1's O-GlcNAcylation site reduces ATP generation in multiple cell types, specifically affecting metabolic efficiency in neurons. This study reveals a previously unappreciated pathway that links neuronal metabolism and mitochondrial function through OGT and the formation of the glycolytic metabolon, providing potential strategies for tackling metabolic and neurological disorders.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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