title: Calcium channel regulator Mid1 links TORC2-mediated changes in mitochondrial respiration to autophagy.
abstract: Autophagy is a catabolic process that recycles cytoplasmic contents and is crucial for cell survival during stress. The target of rapamycin (TOR) kinase regulates autophagy as part of two distinct protein complexes, TORC1 and TORC2. TORC1 negatively regulates autophagy according to nitrogen availability. In contrast, TORC2 functions as a positive regulator of autophagy during amino acid starvation, via its target kinase Ypk1, by repressing the activity of the calcium-dependent phosphatase calcineurin and promoting the general amino acid control (GAAC) response. Precisely how TORC2-Ypk1 signaling regulates calcineurin within this pathway remains unknown. Here we demonstrate that activation of calcineurin requires Mid1, an endoplasmic reticulum-localized calcium channel regulatory protein implicated in the oxidative stress response. We find that normal mitochondrial respiration is perturbed in TORC2-Ypk1-deficient cells, which results in the accumulation of mitochondrial-derived reactive oxygen species that signal to Mid1 to activate calcineurin, thereby inhibiting the GAAC response and autophagy. These findings describe a novel pathway involving TORC2, mitochondrial oxidative stress, and calcium homeostasis for autophagy regulation.
authors.affiliation: Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, CA 95616.
authors.forename: Ariadne
authors.identifier: http://orcid.org/0000-0003-3452-9925
authors.initials: A
authors.lastname: Vlahakis
authors.affiliation: Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, CA 95616.
authors.forename: Nerea
authors.initials: N
authors.lastname: Lopez Muniozguren
authors.affiliation: Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, CA 95616 tpowers@ucdavis.edu.
authors.forename: Ted
authors.identifier: http://orcid.org/0000-0002-2007-3819
authors.initials: T
authors.lastname: Powers
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D001343:Autophagy; D019703:Calcineurin / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D019069:Cell Respiration; D000076225:Mechanistic Target of Rapamycin Complex 2; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D015220:Calcium Channels; C090463:MID1 protein, S cerevisiae; D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; D029701:Saccharomyces cerevisiae Proteins; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin