title: Mitochondrial dysfunction in steatotic rat livers occurs because a defect in complex i makes the liver susceptible to prolonged cold ischemia.
abstract: Steatotic livers are susceptible to cold ischemia, which is thought to be secondary to mitochondrial dysfunction. Ischemic preconditioning (IPC) has been reported to improve liver function in the setting of warm ischemia/reperfusion injury, but the effect of IPC on steatotic liver mitochondrial function (MF) with cold ischemia has not been previously evaluated. We aimed to evaluate MF with various severities of hepatic steatosis after various durations of cold ischemia storage with or without IPC. Male Sprague-Dawley rats were fed a normal diet or a high-fat/high-sucrose diet for 1, 2, or 4 weeks to induce mild (<30%), moderate (30%-60%), or severe (>60%) macrovesicular steatosis, respectively. Liver MF was tested with high-resolution respirometry after 1.5, 4, 8, 12, 18, and 24 hours of cold ischemia. Rats in each group (n = 10) underwent 10 minutes of IPC or no IPC before cold ischemia. The baseline (time 0) respiration was similar for lean and severely steatotic livers despite decreased mitochondrial complex I (C-I) activity in severely steatotic livers. Hepatic steatosis was associated with increased C-I-mediated leaks and decreased respiratory control ratios (RCRs) after cold ischemia. Mildly, moderately, and severely steatotic livers showed significantly lower RCRs after 8, 1.5, and 1.5 hours of cold ischemia, respectively, in comparison with lean livers. IPC restored RCRs in mildly steatotic livers to levels comparable to those in lean livers for up to 24 hours of cold ischemia via the attenuation of C-I-mediated leaks, but it had no beneficial effect on moderately and severely steatotic livers. In conclusion, steatotic livers exhibited apparent mitochondrial dysfunction through an alteration in C-I activity, and this made them more susceptible to prolonged cold ischemia. The clinically based IPC protocol used here restored MF in cases of mild hepatic steatosis by attenuating C-I-mediated leaks after prolonged cold ischemia, but it did work not in livers with moderate or severe steatosis.
authors.affiliation: Department of Surgery, University of Auckland, Auckland, New Zealand.
authors.forename: Michael J J
authors.initials: MJ
authors.lastname: Chu
authors.forename: Anthony J R
authors.initials: AJ
authors.lastname: Hickey
authors.forename: Yannan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Amorita
authors.initials: A
authors.lastname: Petzer
authors.forename: Adam S J R
authors.initials: AS
authors.lastname: Bartlett
authors.forename: Anthony R J
authors.initials: AR
authors.lastname: Phillips
mesh_terms: D000818:Animals; D050377:Cold Ischemia / Q000009:adverse effects*; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism*; D019194:Ischemic Preconditioning / Q000379:methods; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology*; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000175:diagnosis / Q000201:enzymology; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000175:diagnosis / Q000201:enzymology / Q000209:etiology* / Q000517:prevention & control; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D042967:Electron Transport Complex I