Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.

Autor:	Marin-Valencia I; The Abimael Laboratory of Neurometabolism, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY, USA. Electronic address: isaac.marin-valencia@mssm.edu., Kocabas A; The Abimael Laboratory of Neurometabolism, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Rodriguez-Navas C; The Abimael Laboratory of Neurometabolism, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Miloushev VZ; Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., González-Rodríguez M; The Abimael Laboratory of Neurometabolism, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Lees H; Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Henry KE; Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Vaynshteyn J; The Abimael Laboratory of Neurometabolism, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Longo V; Small Animal Imaging Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Deh K; Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Eskandari R; Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA., Mamakhanyan A; Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Berishaj M; Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Keshari KR; Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address: rahimikk@mskcc.org.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2024 Jun 04; Vol. 36 (6), pp. 1394-1410.e12.
DOI:	10.1016/j.cmet.2024.05.002
Abstrakt:	A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain-it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition. Competing Interests: Declaration of interests K.R.K. is a founder with equity interest of Atish Technologies, Inc. and a member of the scientific advisory boards of NVision Imaging Technologies, Imaginostics, and Mi2. K.R.K. holds patents related to imaging and modulation of cellular metabolism. I.M.-V., K.R.K., C.R.-N., M.G.R., and A.K. are in the process of a patent application for the use of propionate as a therapeutic agent for PDHD and other neurometabolic diseases. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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