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Abstract
Disrupted energy metabolism drives cell dysfunction and disease, but approaches to increase or preserve ATP are lacking. To generate a comprehensive metabolic map of genes and pathways that regulate cellular ATP—the ATPome—we conducted a genome-wide CRISPR interference/activation screen integrated with an ATP biosensor. We show that ATP level is modulated by distinct mechanisms that promote energy production or inhibit consumption. In our system HK2 is the greatest ATP consumer, indicating energy failure may not be a general deficiency in producing ATP, but rather failure to recoup the ATP cost of glycolysis and diversion of glucose metabolites to the pentose phosphate pathway. We identify systems-level reciprocal inhibition between the HIF1 pathway and mitochondria; glycolysis-promoting enzymes inhibit respiration even when there is no glycolytic ATP production, and vice versa. Consequently, suppressing alternative metabolism modes paradoxically increases energy levels under substrate restriction. This work reveals mechanisms of metabolic control, and identifies therapeutic targets to correct energy failure.
Energy metabolism and ATP levels are controlled by an interlocking network of pathways. Here, the authors apply a genome-wide CRISPR screen to define genes that increase or decrease ATP levels to define the “ATPome”, a map of pathways that contribute to cellular ATP regulation.
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1 Gladstone Institute of Neurological Disease, San Francisco, USA (GRID:grid.249878.8) (ISNI:0000 0004 0572 7110)
2 University of California, Department of Radiation Oncology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
3 UCLA Metabolomics Center, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718)
4 NeuroCure Clinical Research Center, Charité–Universitätsmedizin Berlin, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662); Charité–Universitätsmedizin Berlin, Department of Neuropediatrics, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662)
5 University of California, Department of Pediatrics, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
6 University of California, Department of Biochemistry and Biophysics and Institute for Neurodegenerative Diseases, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); Chan Zuckerberg Biohub, San Francisco, USA (GRID:grid.266102.1)
7 Gladstone Institute of Neurological Disease, San Francisco, USA (GRID:grid.249878.8) (ISNI:0000 0004 0572 7110); University of California, Department of Neurology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Graduate Program in Biomedical Sciences, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); Graduate Program in Neuroscience, University of California, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)