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Role of mitochondrial complex I and protective effect of CoQ10 supplementation in propofol induced cytotoxicity

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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.

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Abbreviations

mPTP:

Mitochondrial permeability transition pore

GA:

General anaesthetics

PRIS:

Propofol infusion Syndrome

CoQ1 :

2,3-Dimethoxy-5-methyl-6-(3-methyl-2-butenyl)-1,4-benzoquinone

DB:

2,3-Dimethoxy-5-methyl--6-decyl-1,4-benzoquinone, oxidized form

DBH2:

2,3-Dimethoxy-5-methyl--6-decyl-1,4-benzoquinol, reduced form

DCIP:

2,6-Dichlorophenolindophenol

ETC:

Electron Transfer Chain

BHM:

Bovine Heart Mitochondria

TMPD:

N,N,N′,N′-Tetramethyl-p-phenylenediamine

FCCP:

Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone

FMN:

Flavin mononucleotide

MTT:

3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide

TMRE:

Tetramethylrhodamine ethyl ester

ECAR:

Extracellular acidification rate

OCR:

Oxygen consumption rate

OXPHOS:

Oxidative phosphorylation

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Acknowledgments

The authors thank Professor Giorgio Lenaz M.D., Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Italy, for the stimulating discussions and for the critical reading of the paper.

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Authors and Affiliations

  1. Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, Bologna, Italy

    Christian Bergamini, Laura Faccioli & Romana Fato

  2. Institute for Diabetes and Regeneration Research, Helmholtz Zentrum Munich, Parkring 11, 85478, Garching, Germany

    Noah Moruzzi, Francesco Volta & Jantje Gerdes

  3. Department of Paediatric Anaesthesia and Intensive Care, S. Orsola-Malpighi Hospital, Bologna University, Bologna, Italy

    Maria Cristina Mondardini

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  1. Christian Bergamini
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  2. Noah Moruzzi
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  6. Maria Cristina Mondardini
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  7. Romana Fato
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Correspondence to Romana Fato.

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Author contributions

C.B., N.M., F.V., and L.F. performed experiments, C.B., M.C.M. and R.F. conceived ideas, designed experiments, analysed results. C.B., N.M., J.G. and R.F. wrote the manuscript. All authors edited and reviewed the final manuscript.

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Bergamini, C., Moruzzi, N., Volta, F. et al. Role of mitochondrial complex I and protective effect of CoQ10 supplementation in propofol induced cytotoxicity. J Bioenerg Biomembr 48, 413–423 (2016). https://doi.org/10.1007/s10863-016-9673-9

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