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A Web Tool for Generating High Quality Machine-readable Biological Pathways
Published on: February 8, 2017
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Defining the ATPome reveals cross-optimization of metabolic pathways
Neal K Bennett1, Mai K Nguyen1, Maxwell A Darch1
1Gladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA.
Nature Communications
|August 30, 2020
Summary
Cellular ATP levels are regulated by energy production and consumption. This study reveals that inhibiting alternative metabolism paradoxically boosts energy, identifying targets for treating energy failure.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolic Engineering
Background:
- Disrupted cellular energy metabolism is implicated in various diseases.
- Current therapeutic strategies to modulate ATP levels are limited.
Purpose of the Study:
- To create a comprehensive map of genes and pathways regulating cellular ATP (the ATPome).
- To identify mechanisms controlling cellular energy homeostasis and potential therapeutic targets.
Main Methods:
- Genome-wide CRISPR interference/activation screening.
- Integration with a cellular ATP biosensor.
- Analysis of metabolic pathway regulation.
Main Results:
- Identified Hexokinase 2 (HK2) as a major ATP consumer, suggesting energy failure may stem from inefficient glycolysis rather than production deficits.
- Revealed reciprocal inhibition between the HIF1 pathway and mitochondrial respiration.
- Demonstrated that suppressing alternative metabolic pathways can paradoxically increase ATP levels under substrate-limited conditions.
Conclusions:
- Cellular ATP levels are controlled by a balance between energy production and consumption mechanisms.
- Therapeutic strategies targeting metabolic pathway regulation, particularly HK2 and the interplay between glycolysis and respiration, hold promise for treating energy failure-related diseases.
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