Glucose-1,6-bisphosphate: A new gatekeeper of cerebral mitochondrial pyruvate uptake

Glucose-1,6-bisphosphate (G-1,6-BP), a byproduct of glycolysis that is synthesized by phosphoglucomutase 2 like 1 (PGM2L1), is particularly abundant in neurons. G-1,6-BP is sensitive to the glycolytic flux, due to its dependence on 1,3-bisphosphoglycerate as phosphate donor, and the energy state, du...

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Published in:	Molecular metabolism (Germany) Vol. 88; p. 102018
Main Authors:	Safari, Motahareh Solina, Woerl, Priska, Garmsiri, Carolin, Weber, Dido, Kwiatkowski, Marcel, Hotze, Madlen, Kuenkel, Louisa, Lang, Luisa, Erlacher, Matthias, Gelpi, Ellen, Hainfellner, Johannes A., Baier, Gottfried, Baier-Bitterlich, Gabriele, zur Nedden, Stephanie
Format:	Journal Article
Language:	English
Published:	Germany Elsevier GmbH 01-10-2024 Elsevier
Subjects:	Brief Communication Energy metabolism Glucose-1,6-bisphosphate Ischemia Mitochondrial pyruvate carrier Phosphoglucomutase 2 like 1 Protein kinase N1 BRET MPC Energy metabolism PMM1 G-1,6-BP Mitochondrial pyruvate carrier ADP DARTS assay IMP OGD G-6-P PGM2L1 PCA TCA Phosphoglucomutase 2 like 1 Ischemia Glucose-1,6-bisphosphate wwt aCSF Protein kinase N1 PKN1 Rep ATP OCR mitochondrial pyruvate carrier phosphoglucomutase 2 like 1 glucose-1,6-bisphosphate protein kinase N1 ischemia
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Summary:	Glucose-1,6-bisphosphate (G-1,6-BP), a byproduct of glycolysis that is synthesized by phosphoglucomutase 2 like 1 (PGM2L1), is particularly abundant in neurons. G-1,6-BP is sensitive to the glycolytic flux, due to its dependence on 1,3-bisphosphoglycerate as phosphate donor, and the energy state, due to its degradation by inosine monophosphate-activated phosphomannomutase 1. Since the exact role of this metabolite remains unclear, our aim was to elucidate the specific function of G-1,6-BP in the brain. The effect of PGM2L1 on neuronal post-ischemic viability was assessed by siRNA-mediated knockdown of PGM2L1 in primary mouse neurons. Acute mouse brain slices were used to correlate the reduction in G-1,6-BP upon ischemia to changes in carbon metabolism by 13C6-glucose tracing. A drug affinity responsive target stability assay was used to test if G-1,6-BP interacts with the mitochondrial pyruvate carrier (MPC) subunits in mouse brain protein extracts. Human embryonic kidney cells expressing a MPC bioluminescence resonance energy transfer sensor were used to analyze how PGM2L1 overexpression affects MPC activity. The effect of G-1,6-BP on mitochondrial pyruvate uptake and oxygen consumption rates was analyzed in isolated mouse brain mitochondria. PGM2L1 and a predicted upstream kinase were overexpressed in a human neuroblastoma cell line and G-1,6-BP levels were measured. We found that G-1,6-BP in mouse brain slices was quickly degraded upon ischemia and reperfusion. Knockdown of PGM2L1 in mouse neurons reduced post-ischemic viability, indicating that PGM2L1 plays a neuroprotective role. The reduction in G-1,6-BP upon ischemia was not accompanied by alterations in glycolytic rates but we did see a reduced 13C6-glucose incorporation into citrate, suggesting a potential role in mitochondrial pyruvate uptake or metabolism. Indeed, G-1,6-BP interacted with both MPC subunits and overexpression of PGM2L1 increased MPC activity. G-1,6-BP, at concentrations found in the brain, enhanced mitochondrial pyruvate uptake and pyruvate-induced oxygen consumption rates. Overexpression of a predicted upstream kinase inhibited PGM2L1 activity, showing that besides metabolism, also signaling pathways can regulate G-1,6-BP levels. We provide evidence that G-1,6-BP positively regulates mitochondrial pyruvate uptake and post-ischemic neuronal viability. These compelling data reveal a novel mechanism by which neurons can couple glycolysis-derived pyruvate to the tricarboxylic acid cycle. This process is sensitive to the glycolytic flux, the cell's energetic state, and upstream signaling cascades, offering many regulatory means to fine-tune this critical metabolic step. •Glucose-1,6-bisphosphate (G-1,6-BP) is specifically elevated in the brain and quickly degraded upon energetic stress.•The G-1,6-BP synthase Phosphoglucomutase 2 like 1 (PGM2L1) is important for post-ischemic neuronal survival.•G-1,6-BP enhances mitochondrial pyruvate uptake and oxygen consumption rates.•PGM2L1 activity and G-1,6-BP levels can be inhibited by Protein Kinase N1.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Motahareh Solina Safari, Priska Woerl and Carolin Garmsiri contributed equally to this work.
ISSN:	2212-8778 2212-8778
DOI:	10.1016/j.molmet.2024.102018