title: Changes in Whole-Body Oxygen Consumption and Skeletal Muscle Mitochondria During Linezolid-Induced Lactic Acidosis.
abstract: OBJECTIVE
  To better clarify the pathogenesis of linezolid-induced lactic acidosis.
  
  
  METHODS
  Case report.
  
  
  METHODS
  ICU.
  
  
  METHODS
  A 64-year-old man who died with linezolid-induced lactic acidosis.
  
  
  METHODS
  Skeletal muscle was sampled at autopsy to study mitochondrial function.
  
  
  RESULTS
  Lactic acidosis developed during continuous infusion of linezolid while oxygen consumption and oxygen extraction were diminishing from 172 to 52 mL/min/m and from 0.27 to 0.10, respectively. Activities of skeletal muscle respiratory chain complexes I, III, and IV, encoded by nuclear and mitochondrial DNA, were abnormally low, whereas activity of complex II, entirely encoded by nuclear DNA, was not. Protein studies confirmed stoichiometric imbalance between mitochondrial (cytochrome c oxidase subunits 1 and 2) and nuclear (succinate dehydrogenase A) DNA-encoded respiratory chain subunits. These findings were not explained by defects in mitochondrial DNA or transcription. There were no compensatory mitochondrial biogenesis (no induction of nuclear respiratory factor 1 and mitochondrial transcript factor A) or adaptive unfolded protein response (reduced concentration of heat shock proteins 60 and 70).
  
  
  CONCLUSIONS
  Linezolid-induced lactic acidosis is associated with diminished global oxygen consumption and extraction. These changes reflect selective inhibition of mitochondrial protein synthesis (probably translation) with secondary mitonuclear imbalance. One novel aspect of linezolid toxicity that needs to be confirmed is blunting of reactive mitochondrial biogenesis and unfolded protein response.
authors.affiliation: 1Rianimazione Generale "Emma Vecla," Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy. 2Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy. 3Terapia Intensiva Generale 1, Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Milan, Italy. 4U.O. Anatomia Patologica, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy. 5Dipartimento di Scienze della Salute, Università degli Studi di Milano-Bicocca, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Protti
authors.forename: Dario
authors.initials: D
authors.lastname: Ronchi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Bassi
authors.forename: Francesco
authors.initials: F
authors.lastname: Fortunato
authors.forename: Andreina
authors.initials: A
authors.lastname: Bordoni
authors.forename: Tommaso
authors.initials: T
authors.lastname: Rizzuti
authors.forename: Roberto
authors.initials: R
authors.lastname: Fumagalli
mesh_terms: D000140:Acidosis, Lactic / Q000139:chemically induced* / Q000378:metabolism; D017809:Fatal Outcome; D006801:Humans; D000069349:Linezolid / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects*; D012131:Respiratory Insufficiency / Q000188:drug therapy
chemical_list: D000069349:Linezolid