title: Insufficient autophagy contributes to mitochondrial dysfunction, organ failure, and adverse outcome in an animal model of critical illness.
abstract: OBJECTIVE
  Increasing evidence implicates mitochondrial dysfunction as an early, important event in the pathogenesis of critical illness-induced multiple organ failure. We previously demonstrated that prevention of hyperglycemia limits damage to mitochondria in vital organs, thereby reducing morbidity and mortality. We now hypothesize that inadequate activation of mitochondrial repair processes (clearance of damaged mitochondria by autophagy, mitochondrial fusion/fission, and biogenesis) may contribute to accumulation of mitochondrial damage, persistence of organ failure, and adverse outcome of critical illness.
  
  
  METHODS
  Prospective, randomized studies in a critically ill rabbit model.
  
  
  METHODS
  University laboratory.
  
  
  METHODS
  Three-month-old male rabbits.
  
  
  METHODS
  We studied whether vital organ mitochondrial repair pathways are differentially affected in surviving and nonsurviving hyperglycemic critically ill animals in relation to mitochondrial and organ damage. Next, we investigated the impact of preventing hyperglycemia over time and of administering rapamycin as an autophagy activator.
  
  
  RESULTS
  In both liver and kidney of hyperglycemic critically ill rabbits, we observed signs of insufficient autophagy, including accumulation of p62 and a concomitant decrease in the microtubule-associated protein light-chain-3-II/microtubule-associated protein light-chain-3-I ratio. The phenotype of insufficient autophagy was more pronounced in nonsurviving than in surviving animals. Molecular markers of insufficient autophagy correlated with impaired mitochondrial function and more severe organ damage. In contrast, key players in mitochondrial fusion/fission or biogenesis were not significantly different regarding survival status. Therefore, we focused on autophagy to study the impact of preventing hyperglycemia. Both after 3 and 7 days of illness, autophagy was better preserved in normoglycemic than in hyperglycemic rabbits, which correlated with improved mitochondrial function and less organ damage. Stimulation of autophagy in kidney with rapamycin correlated with protection of renal function.
  
  
  CONCLUSIONS
  Our findings put forward insufficient autophagy as a potentially important contributor to mitochondrial and organ damage in critical illness and open perspectives for therapies that activate autophagy during critical illness.
authors.affiliation: Clinical Department and Laboratory of Intensive Care Medicine, Division Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Gunst
authors.forename: Inge
authors.initials: I
authors.lastname: Derese
authors.forename: Annelies
authors.initials: A
authors.lastname: Aertgeerts
authors.forename: Eric-Jan
authors.initials: EJ
authors.lastname: Ververs
authors.forename: Andy
authors.initials: A
authors.lastname: Wauters
authors.forename: Greet
authors.initials: G
authors.lastname: Van den Berghe
authors.forename: Ilse
authors.initials: I
authors.lastname: Vanhorebeek
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D016638:Critical Illness; D006943:Hyperglycemia / Q000378:metabolism* / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000473:pathology / Q000503:physiopathology*; D063154:Mitochondrial Dynamics / Q000187:drug effects; D063306:Mitophagy / Q000187:drug effects; D009102:Multiple Organ Failure / Q000503:physiopathology*; D011446:Prospective Studies; D011817:Rabbits; D011897:Random Allocation; D020123:Sirolimus / Q000494:pharmacology; D016019:Survival Analysis
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents; D008869:Microtubule-Associated Proteins; D020123:Sirolimus