title: The atypical cadherin fat directly regulates mitochondrial function and metabolic state.
abstract: Fat (Ft) cadherins are enormous cell adhesion molecules that function at the cell surface to regulate the tumor-suppressive Hippo signaling pathway and planar cell polarity (PCP) tissue organization. Mutations in Ft cadherins are found in a variety of tumors, and it is presumed that this is due to defects in either Hippo signaling or PCP. Here, we show Drosophila Ft functions in mitochondria to directly regulate mitochondrial electron transport chain integrity and promote oxidative phosphorylation. Proteolytic cleavage releases a soluble 68 kDa fragment (Ft(mito)) that is imported into mitochondria. Ft(mito) binds directly to NADH dehydrogenase ubiquinone flavoprotein 2 (Ndufv2), a core component of complex I, stabilizing the holoenzyme. Loss of Ft leads to loss of complex I activity, increases in reactive oxygen species, and a switch to aerobic glycolysis. Defects in mitochondrial activity in ft mutants are independent of Hippo and PCP signaling and are reminiscent of the Warburg effect.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Anson
authors.initials: A
authors.lastname: Sing
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Yonit
authors.initials: Y
authors.lastname: Tsatskis
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G OA4, Canada.
authors.forename: Lacramioara
authors.initials: L
authors.lastname: Fabian
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Hester
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Robyn
authors.initials: R
authors.lastname: Rosenfeld
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Mauro
authors.initials: M
authors.lastname: Serricchio
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Norman
authors.initials: N
authors.lastname: Yau
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Maïlis
authors.initials: M
authors.lastname: Bietenhader
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Riya
authors.initials: R
authors.lastname: Shanbhag
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Jurisicova
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G OA4, Canada.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Brill
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: angus.mcquibban@utoronto.ca.
authors.forename: G Angus
authors.initials: GA
authors.lastname: McQuibban
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: mcneill@lunenfeld.ca.
authors.forename: Helen
authors.initials: H
authors.lastname: McNeill
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D016764:Cell Polarity; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism; D005123:Eye / Q000254:growth & development; D016147:Genes, Tumor Suppressor; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D014921:Wings, Animal / Q000254:growth & development
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; D029721:Drosophila Proteins; D045222:Electron Transport Chain Complex Proteins; D017382:Reactive Oxygen Species; C472307:ft protein, Drosophila; D048670:MAP Kinase Kinase 4; D042967:Electron Transport Complex I