title: Role of mitochondrial complex I and protective effect of CoQ10 supplementation in propofol induced cytotoxicity.
abstract: Propofol (2,6-diisopropylphenol) is an anaesthetic widely used for human sedation. Due to its intrinsic antioxidant properties, rapid induction of anaesthesia and fast recovery, it is employed in paediatric anaesthesia and in the intensive care of premature infants. Recent studies have pointed out that exposure to anaesthesia in the early stage of life might be responsible of long-lasting cognitive impairment. The apoptotic neurodegeneration induced by general anaesthetics (GA) involves mitochondrial impairment due to the inhibition of the OXPHOS machinery. In the present work, we aim to identify the main mitochondrial respiratory chain target of propofol toxicity and to evaluate the possible protective effect of CoQ10 supplementation. The propofol effect on the mitochondrial functionality was assayed in isolated mitochondria and in two cell lines (HeLa and T67) by measuring oxygen consumption rate. The protective effect of CoQ10 was assessed by measuring cells viability, NADH-oxidase activity and ATP/ADP ratio in cells treated with propofol. Our results show that propofol reduces cellular oxygen consumption rate acting mainly on mitochondrial Complex I. The kinetic analysis of Complex I inhibition indicates that propofol interferes with the Q module acting as a non-competitive inhibitor with higher affinity for the free form of the enzyme. Cells supplemented with CoQ10 are more resistant to propofol toxicity. Propofol exposure induces cellular damages due to mitochondrial impairment. The site of propofol inhibition on Complex I is the Q module. CoQ10 supplementation protects cells against the loss of energy suggesting its possible therapeutic role to minimizing the detrimental effects of general anaesthesia.
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, Bologna, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Bergamini
authors.affiliation: Institute for Diabetes and Regeneration Research, Helmholtz Zentrum Munich, Parkring 11, 85478, Garching, Germany.
authors.forename: Noah
authors.initials: N
authors.lastname: Moruzzi
authors.affiliation: Institute for Diabetes and Regeneration Research, Helmholtz Zentrum Munich, Parkring 11, 85478, Garching, Germany.
authors.forename: Francesco
authors.initials: F
authors.lastname: Volta
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, Bologna, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Faccioli
authors.affiliation: Institute for Diabetes and Regeneration Research, Helmholtz Zentrum Munich, Parkring 11, 85478, Garching, Germany.
authors.forename: Jantje
authors.initials: J
authors.lastname: Gerdes
authors.affiliation: Department of Paediatric Anaesthesia and Intensive Care, S. Orsola-Malpighi Hospital, Bologna University, Bologna, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mondardini
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, Bologna, Italy. romana.fato@unibo.it.
authors.forename: Romana
authors.initials: R
authors.lastname: Fato
mesh_terms: D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019587:Dietary Supplements; D042967:Electron Transport Complex I / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D006993:Hypnotics and Sedatives / Q000633:toxicity; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D015742:Propofol / Q000633:toxicity*; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000187:drug effects / Q000494:pharmacology
chemical_list: D006993:Hypnotics and Sedatives; D014451:Ubiquinone; D042967:Electron Transport Complex I; C024989:coenzyme Q10; D015742:Propofol
keywords: Anaesthesia; Complex I; Mitochondria; Oxygen consumption; Propofol