title: Transaldolase inhibition impairs mitochondrial respiration and induces a starvation-like longevity response in Caenorhabditis elegans.
abstract: Mitochondrial dysfunction can increase oxidative stress and extend lifespan in Caenorhabditis elegans. Homeostatic mechanisms exist to cope with disruptions to mitochondrial function that promote cellular health and organismal longevity. Previously, we determined that decreased expression of the cytosolic pentose phosphate pathway (PPP) enzyme transaldolase activates the mitochondrial unfolded protein response (UPRmt) and extends lifespan. Here we report that transaldolase (tald-1) deficiency impairs mitochondrial function in vivo, as evidenced by altered mitochondrial morphology, decreased respiration, and increased cellular H2O2 levels. Lifespan extension from knockdown of tald-1 is associated with an oxidative stress response involving p38 and c-Jun N-terminal kinase (JNK) MAPKs and a starvation-like response regulated by the transcription factor EB (TFEB) homolog HLH-30. The latter response promotes autophagy and increases expression of the flavin-containing monooxygenase 2 (fmo-2). We conclude that cytosolic redox established through the PPP is a key regulator of mitochondrial function and defines a new mechanism for mitochondrial regulation of longevity.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.|Molecular and Cellular Biology Program, University of Washington, Seattle, WA, United States of America.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Bennett
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Kwon
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Christine
authors.identifier: 0000-0003-0354-4583
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Russell
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Kathlyn
authors.identifier: 0000-0001-8998-4541
authors.initials: K
authors.lastname: Acosta
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Nikolay
authors.identifier: 0000-0003-1885-8999
authors.initials: N
authors.lastname: Burnaevskiy
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Crane
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bitto
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Helen
authors.initials: H
authors.lastname: Vander Wende
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Marissa
authors.initials: M
authors.lastname: Simko
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Victor
authors.initials: V
authors.lastname: Pineda
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.|Molecular Medicine and Mechanisms of Disease Program, University of Washington, Seattle, WA, United States of America.
authors.forename: Ryan
authors.initials: R
authors.lastname: Rossner
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wasko
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Haeri
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Shiwen
authors.identifier: 0000-0002-8889-9094
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Shirley
authors.identifier: 0000-0001-5724-4063
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Gholamali
authors.identifier: 0000-0001-7647-9351
authors.initials: G
authors.lastname: Jafari
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
authors.forename: Bryan
authors.identifier: 0000-0001-9971-0472
authors.initials: B
authors.lastname: Sands
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
authors.forename: Carissa
authors.identifier: 0000-0003-1261-9364
authors.initials: C
authors.lastname: Perez Olsen
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Mendenhall
authors.affiliation: Center for Integrated Brain Research, Seattle Children's Research Institute, Seattle, WA, United States of America.|Department of Anesthesiology, University of Washington School of Medicine, Seattle, WA, United States of America.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Morgan
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, United States of America.|Molecular and Cellular Biology Program, University of Washington, Seattle, WA, United States of America.|Molecular Medicine and Mechanisms of Disease Program, University of Washington, Seattle, WA, United States of America.
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D008136:Longevity / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010105:Oxygenases / Q000096:biosynthesis / Q000235:genetics*; D013217:Starvation; D014153:Transaldolase / Q000037:antagonists & inhibitors / Q000235:genetics*; D056811:Unfolded Protein Response / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D029742:Caenorhabditis elegans Proteins; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D010105:Oxygenases; D014153:Transaldolase; D048051:p38 Mitogen-Activated Protein Kinases; C583069:HLH-30 protein, C elegans; C020066:dimethylaniline monooxygenase (N-oxide forming)