Discover how scientists are decoding the complex system that powers every cell in your body
Within each of your 37 trillion cells, a sophisticated energy management system operates continuously—one that scientists have only recently begun to map.
This system, dubbed the "ATPome," represents the complete network of genes, proteins, and pathways that regulate our cellular energy currency, adenosine triphosphate (ATP). When this system fails, the consequences can be devastating, contributing to diseases ranging from cancer to neurodegeneration 1 . Recent breakthroughs in mapping the ATPome are opening revolutionary avenues for therapeutic interventions.
Like a city's electrical system, the ATPome dynamically routes energy where it's needed most.
ATP powers virtually every cellular process, from muscle contraction to DNA synthesis.
The ATPome represents the comprehensive inventory of all cellular components that produce, consume, or regulate ATP—the molecular "currency" that powers virtually every cellular process. Maintaining adequate ATP levels is critical to health, and disruptions to this delicate balance underlie a wide spectrum of diseases 1 .
The ATPome constantly adapts to changing conditions—when oxygen is scarce, it shifts toward glycolysis; when energy demands spike, it activates backup systems.
Researchers devised an ingenious approach integrating CRISPR gene-editing technology and a biosensor that glows when ATP binds to it to conduct a genome-wide hunt for ATP regulators 1 .
Human K562 cells were equipped with a special fluorescent ATP biosensor that changes color based on ATP levels.
Using CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa), researchers switched individual genes off and on across the entire genome.
Fluorescence-activated cell sorting (FACS) separated cells with unusually high or low ATP levels.
DNA sequencing of sorted cells revealed which genetic manipulations caused ATP levels to rise or fall.
| Condition Name | Energy Pathway Available | Substrate Provided | Pathway Blocker Used |
|---|---|---|---|
| Respiratory | Mitochondria only | Pyruvate | 2-deoxyglucose |
| Glycolytic | Glycolysis only | Glucose | Oligomycin |
| Basal | Both pathways | Standard media | None |
The findings challenged long-held assumptions about cellular energy management and revealed a landscape of remarkable complexity.
Key genes regulating ATP in respiratory conditions
Genes regulating ATP in glycolytic or basal conditions
HK2 enzyme identified as greatest ATP consumer
Researchers discovered that glycolytic enzymes actively suppress mitochondrial respiration—and vice versa—even when the suppressed pathway isn't actively producing ATP 1 . This helps explain the Warburg effect in cancer cells.
When cells are physically squeezed, mitochondria rush to the nucleus within seconds, forming "nucleus-associated mitochondria" (NAMs) that create a localized ATP surge for DNA repair 2 .
| Pathway | Role in ATP Regulation | Key Genes Identified | Effect When Suppressed |
|---|---|---|---|
| HIF1 pathway | Promotes glycolysis under low oxygen | HIF1α, ARNT, CHCHD4 | Increases ATP in respiratory conditions |
| Mitochondrial translation | Produces respiratory chain components | Mitochondrial ribosomal proteins | Decreases ATP in respiratory conditions |
| COP9 signalosome | Regulates HIF1 stability | COPS4, COPS8 | Increases ATP in respiratory conditions |
| HK2-VDAC1 interaction | Links glycolysis to mitochondria | HK2, VDAC1 | Increases ATP when disrupted |
The revolution in understanding cellular energy has been propelled by innovative technologies that allow researchers to observe processes once invisible.
Genetically engineered proteins that change fluorescence when bound to ATP, allowing real-time monitoring in living cells.
Gene-editing technology adapted to systematically turn genes on and off across the entire genome.
Using isotopically labeled nutrients to track molecular flow through metabolic pathways.
Devices that gently squeeze cells to mimic tissue pressures and observe organelle movements.
The mapping of the ATPome promises to reshape how we understand and treat a wide range of diseases.
Discovery of HK2 enzyme as major ATP consumer suggests new approaches to starve tumors. Targeting mitochondrial repositioning could block cancer metastasis.
Blocking P2RX4 receptor that senses ATP in lupus models decreased autoantibody levels and improved symptoms 5 .
Identification of microproteins reveals new players in metabolic regulation, opening avenues for treating obesity and related disorders 3 .
HSD17B10, a mitochondrial enzyme, was identified as crucial ATP regulator. Mutations cause neurodegeneration, suggesting new therapeutic targets 1 .
The mapping of the ATPome represents far more than just a new list of cellular components—it offers a revolutionary new framework for understanding how life manages the energy that powers its most fundamental processes.
As technologies advance, scientists can ask increasingly sophisticated questions: How does the ATPome differ between tissue types? How does it change with aging? Can we develop drugs that specifically target pathological energy regulation without disrupting normal function?
Warburg effect explained by reciprocal inhibition; HK2 targeting potential
ATP signaling to plasma cells; P2RX4 receptor as target
HSD17B10 mutations disrupt ATP regulation
Microproteins identified as new regulators
Genome-wide ATPome mapping published
Microprotein regulation discovered
Mitochondrial repositioning under stress revealed