Non-Canonical Control of Neuronal Energy Status by the Na + Pump

Cell Metab. 2019 Mar 5;29(3):668-680.e4. doi: 10.1016/j.cmet.2018.11.005. Epub 2018 Dec 6.


Neurons have limited intracellular energy stores but experience acute and unpredictable increases in energy demand. To better understand how these cells repeatedly transit from a resting to active state without undergoing metabolic stress, we monitored their early metabolic response to neurotransmission using ion-sensitive probes and FRET sensors in vitro and in vivo. A short theta burst triggered immediate Na+ entry, followed by a delayed stimulation of the Na+/K+ ATPase pump. Unexpectedly, cytosolic ATP and ADP levels were unperturbed across a wide range of physiological workloads, revealing strict flux coupling between the Na+ pump and mitochondria. Metabolic flux measurements revealed a "priming" phase of mitochondrial energization by pyruvate, whereas glucose consumption coincided with delayed Na+ pump stimulation. Experiments revealed that the Na+ pump plays a permissive role for mitochondrial ATP production and glycolysis. We conclude that neuronal energy homeostasis is not mediated by adenine nucleotides or by Ca2+, but by a mechanism commanded by the Na+ pump.

Keywords: ATP:ADP; ATeam 1.03; FLII12Pglu700μΔ6; Na(+)/K(+) ATPase; glucose; laconic; lactate; perceval HR; pyronic; pyruvate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • Astrocytes / cytology
  • Astrocytes / metabolism*
  • Energy Metabolism
  • Glucose / metabolism
  • Glycolysis
  • Homeostasis
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Sodium-Potassium-Exchanging ATPase / metabolism*


  • Adenosine Triphosphate
  • Sodium-Potassium-Exchanging ATPase
  • Glucose