title: Feast or famine: role of TRPML in preventing cellular amino acid starvation.
abstract: Lysosomal storage diseases are metabolic disorders characterized by the accumulation of acidic vacuoles, and are usually the consequence of the deficiency of an enzyme responsible for the metabolism of vesicular lipids, proteins or carbohydrates. In contrast, mucolipidosis type IV (MLIV), results from the absence of a vesicular Ca ( 2+)  release channel called mucolipin 1/transient receptor potential mucolipin 1 (MCOLN1/TRPML1) which is required for the fusion of amphisomes with lysosomes. In Drosophila, ablation of the MCOLN1 homolog (trpml) leads to diminished viability during pupation when the animals rely on autophagy for nutrients. This pupal lethality results from decreased target of rapamycin complex 1 (TORC1) signaling, and is reversed by reactivating TORC1. Our findings indicate that one of the primary causes of toxicity in the absence of TRPML is cellular amino acid starvation, and the resulting decrease in TORC1 activity. Furthermore, our findings raise the intriguing possibility that the neurological dysfunction in MLIV patients may arise from amino acid deprivation in neurons. Therefore, future studies evaluating the levels of amino acids and TORC1 activity in MLIV neurons may aid in the development of novel therapeutic strategies to combat the severe manifestations of MLIV.
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Sciences Center-Houston; Houston, TX, USA. Kartik.Venkatachalam@uth.tmc.edu
authors.forename: Kartik
authors.initials: K
authors.lastname: Venkatachalam
authors.forename: Ching-On
authors.initials: CO
authors.lastname: Wong
authors.forename: Craig
authors.initials: C
authors.lastname: Montell
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008954:Models, Biological; D009081:Mucolipidoses / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046912:Multiprotein Complexes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology; D050051:Transient Receptor Potential Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D000596:Amino Acids; D029721:Drosophila Proteins; C416674:MCOLN1 protein, human; D046912:Multiprotein Complexes; C570998:TORC1 protein complex, Drosophila; C578373:TRPML protein, Drosophila; D014157:Transcription Factors; D050051:Transient Receptor Potential Channels; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases