Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency Journal Article
| Authors: | Marin-Valencia, I.; Kocabas, A.; Rodriguez-Navas, C.; Miloushev, V. Z.; González-Rodríguez, M.; Lees, H.; Henry, K. E.; Vaynshteyn, J.; Longo, V.; Deh, K.; Eskandari, R.; Mamakhanyan, A.; Berishaj, M.; Keshari, K. R. |
| Article Title: | Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency |
| Abstract: | 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. © 2024 Elsevier Inc. |
| Keywords: | adult; controlled study; survival rate; unclassified drug; nonhuman; neuroimaging; nuclear magnetic resonance imaging; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; glial fibrillary acidic protein; animal experiment; animal model; in vivo study; diagnostic imaging; mice, inbred c57bl; age; c57bl mouse; disease model; brain; fluorodeoxyglucose f 18; citric acid; glia cell; imaging; therapy effect; glucose; upregulation; tracer; alanine; motor dysfunction; motor performance; disease models, animal; glutamic acid; glucose transporter 3; brain function; disease exacerbation; glucose transport; glycolysis; aspartic acid; glutamine; autoradiography; neuropathology; proton nuclear magnetic resonance; glucose transporter 1; carbon nuclear magnetic resonance; lactic acid; pyruvate dehydrogenase; pyruvic acid; citric acid cycle; 2 oxoglutaric acid; glucose metabolism; life extension; 4 aminobutyric acid; multimodal imaging; pyruvate; brain metabolism; malic acid; succinic acid; suxamethonium; male; female; article; isocitric acid; glucose brain level; 3 hydroxybutyric acid; positron emission tomography-computed tomography; succinyl coenzyme a; metabolic phenotype; propionates; propionic acid; propionate; diet, ketogenic; ketogenic diet; fumaric acid; pyruvate dehydrogenase deficiency; pyruvate dehydrogenase complex deficiency disease; 2 deoxyglucose c 14; disorders of glucose metabolism; pyruvate dehydrogenase complex deficiency; step width; stride length |
| Journal Title: | Cell Metabolism |
| Volume: | 36 |
| Issue: | 6 |
| ISSN: | 1550-4131 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2024-06-04 |
| Start Page: | 1394 |
| End Page: | 1410.e12 |
| Language: | English |
| DOI: | 10.1016/j.cmet.2024.05.002 |
| PUBMED: | 38838644 |
| PROVIDER: | scopus |
| PMCID: | PMC11187753 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding authors is MSK author: Kayvan R. Keshari -- Source: Scopus |
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