title: mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state.
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.
authors: Department of Biology, University of Pennsylvania, 415 S. University Ave., Philadelphia, Pennsylvania 19104, USA.
authors: Chunlei
authors: C
authors: Cang
authors: Department of Biology, University of Pennsylvania, 415 S. University Ave., Philadelphia, Pennsylvania 19104, USA.
authors: Yandong
authors: Y
authors: Zhou
authors: Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital, Boston, Massachusetts 02115, USA.
authors: Betsy
authors: B
authors: Navarro
authors: Department of Biology, University of Pennsylvania, 415 S. University Ave., Philadelphia, Pennsylvania 19104, USA.
authors: Young-Jun
authors: YJ
authors: Seo
authors: Department of Biology, University of Pennsylvania, 415 S. University Ave., Philadelphia, Pennsylvania 19104, USA.
authors: Kimberly
authors: K
authors: Aranda
authors: Department of Biology, University of Pennsylvania, 415 S. University Ave., Philadelphia, Pennsylvania 19104, USA.
authors: Lucy
authors: L
authors: Shi
authors: INSERM U954, Nutrition Génétique et exposition aux risques environnementaux Faculté de Médecine - BP 184, Université de Lorraine, 54505 VANDOEUVRE LES NANCY CEDEX, FRANCE.
authors: Shyuefang
authors: S
authors: Battaglia-Hsu
authors: Division of Child Development and Metabolic Disease, Children's Hospital of Philadelphia, Department of Pediatrics, Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors: Itzhak
authors: I
authors: Nissim
authors: Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital, Boston, Massachusetts 02115, USA.
authors: David E
authors: DE
authors: Clapham
authors: Department of Biology, University of Pennsylvania, 415 S. University Ave., Philadelphia, Pennsylvania 19104, USA.
authors: Dejian
authors: D
authors: Ren
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000263:Adenylate Kinase / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005215:Fasting; D055786:Gene Knockout Techniques; D006706:Homeostasis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism*; D008564:Membrane Potentials; D051379:Mice; D010807:Physical Endurance; D015222:Sodium Channels / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000097903:Two-Pore Channels
chemical_list: D000255:Adenosine Triphosphate; D000263:Adenylate Kinase; D000596:Amino Acids; D015220:Calcium Channels; D015222:Sodium Channels; D058570:TOR Serine-Threonine Kinases; C546784:TPCN1 protein, mouse; D000097903:Two-Pore Channels; C546785:TPCN2 protein, mouse; C546843:mTOR protein, mouse
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