Mitochondrial Mutations in Cholestatic Liver Disease with Biliary Atresia

Hong Koh,Dong-Woo Lee,Chang Eon Park,Seung Kim,Jae-Ho Shin,Sun-Mi Shin,Huy Quang Pham,Gun-Seok Park,Seok Joo Han

doi:10.1038/s41598-017-18958-8

Abstract

Biliary atresia (BA) results in severe bile blockage and is caused by the absence of extrahepatic ducts. Even after successful hepatic portoenterostomy, a considerable number of patients are likely to show progressive deterioration in liver function. Recent studies show that mutations in protein-coding mitochondrial DNA (mtDNA) genes and/or mitochondrial genes in nuclear DNA (nDNA) are associated with hepatocellular dysfunction. This observation led us to investigate whether hepatic dysfunctions in BA is genetically associated with mtDNA mutations. We sequenced the mtDNA protein-coding genes in 14 liver specimens from 14 patients with BA and 5 liver specimens from 5 patients with choledochal cyst using next-generation sequencing. We found 34 common non-synonymous variations in mtDNA protein-coding genes in all patients examined. A systematic 3D structural analysis revealed the presence of several single nucleotide polymorphism-like mutations in critical regions of complexes I to V, that are involved in subunit assembly, proton-pumping activity, and/or supercomplex formation. The parameters of chronic hepatic injury and liver dysfunction in BA patients were also significantly correlated with the extent of hepatic failure, suggesting that the mtDNA mutations may aggravate hepatopathy. Therefore, mitochondrial mutations may underlie the pathological mechanisms associated with BA.

Highlights

Many critical metabolic functions such as gluconeogenesis, triacylglyceride oxidation, fatty acid decomposition, amino acid deamination and transamination, and most plasma protein synthesis are carried out predominantly in hepatocytes[11,12]
Patients with chronic liver diseases caused by Biliary atresia (BA), which is an important cause of liver failure at infancy and childhood, undergo progressive hepatological deterioration[48]
It is known that most chronic liver diseases have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex[20,24]

Summary

Introduction

Many critical metabolic functions such as gluconeogenesis, triacylglyceride oxidation, fatty acid decomposition, amino acid deamination and transamination, and most plasma protein synthesis are carried out predominantly in hepatocytes[11,12]. Mutations in mitochondrial DNA (mtDNA) can alter the efficiency of cellular energy transduction, resulting in mitochondrial dysfunction[19,20]. Liver cirrhosis appears to be associated with hepatocytic mitochondrial dysfunction[25]. It remains unclear whether such dysfunctional hepatic mitochondria are transmitted by nonmendelian inheritance, maternal inheritance, or a sporadic condition. Accumulation of toxic bile acids in the liver, oxidative stress, and systemic circulation negatively affect the mitochondrial function by directly impairing liver respiratory chain activity[33,34]. The specific mechanisms involved in the onset and development of human hepatic mitochondrial dysfunction in liver cholestasis remains unclear. A comparison of clinical, morphologic, biochemical, and genetic features of these patients reveals a remarkable uniformity, suggesting that the mutations in mtDNA protein-coding genes are highly associated with BA without evidence of maternal inheritance

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