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Aspartate β-hydroxylase disrupts mitochondrial DNA stability and function in hepatocellular carcinoma.
Oncogenesis 2017 July 18
The mechanism of aberrant mitochondrial genome and function in hepatocellular carcinoma (HCC) remains largely unknown. Our previous study demonstrated an increased expression of aspartate β-hydroxylase (ASPH) in HCC tissues, which was associated with tumor invasiveness and a worse prognosis. Currently, we unexpectedly observed the presence of ASPH in purified mitochondrial protein fraction. In addition, immunostaining of both exogenously and endogenously expressed ASPH showed a colocalization with mitochondrial biomarkers. This study aimed to investigate whether the mitochondrial ASPH is involved in mitochondrial malfunction in HCC. Our results showed that ASPH overexpression in HCC tissues was correlated with decreased copy numbers of displacement loop (D-loop) and NADH dehydrogenase subunit 1 (ND-1) and enhanced D-loop mutation, suggesting the disrupted mitochondrial DNA (mtDNA) stability. The reduced mtDNA copy numbers were associated with aggressive clinicopathological features of HCC. The loss of mtDNA integrity induced by enforced expression of ASPH was accompanied with mitochondrial dysfunction, which was characterized by the aberrant mitochondrial membrane potential, decreased ATP generation and enhanced reactive oxygen species. In contrast, knocking down ASPH by siRNA in HCC cell lines showed the opposite impact on mtDNA integrity and function. Mass spectrometry and co-immunoprecipitation further identified that ASPH interacted with histone H2A member X (H2AX). ASPH overexpression diminished the interaction between H2AX and mitochondrial transcription factor A (mtTFA), an important DNA-binding protein for mtDNA replication, which then reduced the binding of mtTFA to D-loop region. Collectively, our results demonstrate that ASPH overexpression disrupts the mtDNA integrity through H2AX-mtTFA signal, thereby affecting mitochondrial functions in HCC.
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