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Metabolic regulation of Drosophila apoptosis through inhibitory phosphorylation of Dronc

Chih-Sheng Yang1, Michael J Thomenius, Eugene C Gan

  • 1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.

The EMBO Journal
|August 12, 2010
PubMed

Insights

Cellular NADPH levels regulate programmed cell death in fruit flies by controlling the phosphorylation of the initiator caspase Dronc. This finding reveals a new link between metabolism and apoptosis, offering insights into cancer cell death regulation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Metabolism

Background:

  • Apoptosis is crucial for maintaining tissue homeostasis and is influenced by metabolic regulators.
  • Previous studies suggested a link between metabolic regulators and caspase activation in Drosophila.

Purpose of the Study:

  • To investigate the previously unrecognized link between cellular metabolism and apoptosis in Drosophila.
  • To elucidate the role of cellular nicotinamide adenine dinucleotide phosphate (NADPH) in modulating programmed cell death.

Main Methods:

  • Utilized genome-wide RNAi screens to identify metabolic regulators of apoptosis.
  • Investigated the phosphorylation of the initiator caspase Dronc (Drosophila melanogaster caspase 9 homolog) at S130.
  • Manipulated cellular NADPH levels and assessed Dronc activation and apoptosis in transgenic flies.

Main Results:

  • Cellular NADPH levels directly modulate Dronc phosphorylation at S130, an inhibitory site.
  • NADPH depletion led to Dronc activation and apoptosis, while NADPH upregulation prevented it.
  • CaMKII-mediated phosphorylation of Dronc by NADPH hinders caspase activation, not catalytic activity.

Conclusions:

  • Established a novel regulatory pathway where NADPH levels control Dronc-mediated apoptosis via phosphorylation.
  • Demonstrated that altered NADPH levels can impact cell death susceptibility in specific neuronal populations.
  • Provides a genetic model to study metabolic alterations in cancer cell apoptosis due to elevated NADPH.

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