mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state

Cell. 2013 Feb 14;152(4):778-790. doi: 10.1016/j.cell.2013.01.023. Epub 2013 Feb 7.

Abstract

Survival in the wild requires organismal adaptations to the availability of nutrients. Endosomes and lysosomes are key intracellular organelles that couple nutrition and metabolic status to cellular responses, but how they detect cytosolic ATP levels is not well understood. Here, we identify an endolysosomal ATP-sensitive Na(+) channel (lysoNa(ATP)). The channel is a complex formed by two-pore channels (TPC1 and TPC2), ion channels previously thought to be gated by nicotinic acid adenine dinucleotide phosphate (NAADP), and the mammalian target of rapamycin (mTOR). The channel complex detects nutrient status, becomes constitutively open upon nutrient removal and mTOR translocation off the lysosomal membrane, and controls the lysosome's membrane potential, pH stability, and amino acid homeostasis. Mutant mice lacking lysoNa(ATP) have much reduced exercise endurance after fasting. Thus, TPCs make up an ion channel family that couples the cell's metabolic state to endolysosomal function and are crucial for physical endurance during food restriction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Adenylate Kinase / metabolism
  • Amino Acids / metabolism
  • Animals
  • Calcium Channels / chemistry
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Fasting
  • Gene Knockout Techniques
  • Homeostasis
  • Humans
  • Hydrogen-Ion Concentration
  • Lysosomes / metabolism*
  • Membrane Potentials
  • Mice
  • Physical Endurance
  • Sodium Channels / metabolism*
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Amino Acids
  • Calcium Channels
  • Sodium Channels
  • TPCN1 protein, mouse
  • TPCN2 protein, mouse
  • Adenosine Triphosphate
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Adenylate Kinase