title: Inhibiting cytosolic translation and autophagy improves health in mitochondrial disease.
abstract: Mitochondrial respiratory chain (RC) disease therapies directed at intra-mitochondrial pathology are largely ineffective. Recognizing that RC dysfunction invokes pronounced extra-mitochondrial transcriptional adaptations, particularly involving dysregulated translation, we hypothesized that translational dysregulation is itself contributing to the pathophysiology of RC disease. Here, we investigated the activities, and effects from direct inhibition, of a central translational regulator (mTORC1) and its downstream biological processes in diverse genetic and pharmacological models of RC disease. Our data identify novel mechanisms underlying the cellular pathogenesis of RC dysfunction, including the combined induction of proteotoxic stress, the ER stress response and autophagy. mTORC1 inhibition with rapamycin partially ameliorated renal disease in B6.Pdss2(kd/kd) mice with complexes I-III/II-III deficiencies, improved viability and mitochondrial physiology in gas-1(fc21) nematodes with complex I deficiency, and rescued viability across a variety of RC-inhibited human cells. Even more effective was probucol, a PPAR-activating anti-lipid drug that we show also inhibits mTORC1. However, directly inhibiting mTORC1-regulated downstream activities yielded the most pronounced and sustained benefit. Partial inhibition of translation by cycloheximide, or of autophagy by lithium chloride, rescued viability, preserved cellular respiratory capacity and induced mitochondrial translation and biogenesis. Cycloheximide also ameliorated proteotoxic stress via a uniquely selective reduction of cytosolic protein translation. RNAseq-based transcriptome profiling of treatment effects in gas-1(fc21) mutants provide further evidence that these therapies effectively restored altered translation and autophagy pathways toward that of wild-type animals. Overall, partially inhibiting cytosolic translation and autophagy offer novel treatment strategies to improve health across the diverse array of human diseases whose pathogenesis involves RC dysfunction.
authors.affiliation: Division of Human Genetics, Department of Pediatrics and Department of Genetics and.
authors.forename: Min
authors.initials: M
authors.lastname: Peng
authors.affiliation: Division of Human Genetics, Department of Pediatrics and.
authors.forename: Julian
authors.initials: J
authors.lastname: Ostrovsky
authors.affiliation: Division of Human Genetics, Department of Pediatrics and.
authors.forename: Young Joon
authors.initials: YJ
authors.lastname: Kwon
authors.affiliation: Division of Human Genetics, Department of Pediatrics and.
authors.forename: Erzsebet
authors.initials: E
authors.lastname: Polyak
authors.affiliation: Division of Human Genetics, Department of Pediatrics and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Licata
authors.affiliation: Division of Human Genetics, Department of Pediatrics and.
authors.forename: Mai
authors.initials: M
authors.lastname: Tsukikawa
authors.affiliation: Division of Human Genetics, Department of Pediatrics and.
authors.forename: Eric
authors.initials: E
authors.lastname: Marty
authors.affiliation: Division of Cell Pathology, Department of Pathology, The Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA and.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Division of Oncology, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Felix
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Xiao
authors.affiliation: Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Genetics and.
authors.forename: David L
authors.initials: DL
authors.lastname: Gasser
authors.affiliation: Division of Cell Pathology, Department of Pathology, The Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA and.
authors.forename: Yair
authors.initials: Y
authors.lastname: Argon
authors.affiliation: Division of Human Genetics, Department of Pediatrics and falkm@email.chop.edu.
authors.forename: Marni J
authors.initials: MJ
authors.lastname: Falk
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D003600:Cytosol; D004195:Disease Models, Animal; D004579:Electron Transport; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation; D011341:Probucol / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059467:Transcriptome
chemical_list: D046912:Multiprotein Complexes; D003513:Cycloheximide; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D011341:Probucol; D020123:Sirolimus