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Int J Biol Sci 2017; 13(11):1420-1437. doi:10.7150/ijbs.20742

Research Paper

Adhesion Regulating Molecule 1 Mediates HAP40 Overexpression-Induced Mitochondrial Defects

Zih-Ning Huang1, Her Min Chung1, Su-Chiung Fang2,3, Lu-Shiun Her1✉

1. Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan;
2. Biotechnology Center in Southern Taiwan, Academia Sinica, Tainan 741, Taiwan;
3. Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan.

Abstract

Striatal neuron death in Huntington's disease is associated with abnormal mitochondrial dynamics and functions. However, the mechanisms for this mitochondrial dysregulation remain elusive. Increased accumulation of Huntingtin-associated protein 40 (HAP40) has been shown to be associated with Huntington's disease. However, the link between increased HAP40 and Huntington's disease remains largely unknown. Here we show that HAP40 overexpression causes mitochondrial dysfunction and reduces cell viability in the immortalized mouse striatal neurons. HAP40-associated mitochondrial dysfunction is associated with reduction of adhesion regulating molecule 1 (ADRM1) protein. Consistently, depletion of ADRM1 by shRNAs impaired mitochondrial functions and increased mitochondrial fragmentation in mouse striatal cells. Moreover, reducing ADRM1 levels enhanced activity of fission factor dynamin-related GTPase protein 1 (Drp1) via increased phosphorylation at serine 616 of Drp1 (Drp1Ser616). Restoring ADRM1 protein levels was able to reduce HAP40-induced ROS levels and mitochondrial fragmentation and improved mitochondrial functions and cell viability. Moreover, reducing Drp1 activity by Drp1 inhibitor, Mdivi-1, ameliorates both HAP40 overexpression- and ADRM1 depletion-induced mitochondrial dysfunction. Taken together, our studies suggest that HAP40-mediated reduction of ADRM1 alters the mitochondrial fission activity and results in mitochondrial fragmentation and mitochondrial dysfunction.

Keywords: Huntington's disease, mitochondrial dynamics, HAP40, ADRM1, Drp1.

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How to cite this article:
Huang ZN, Chung HM, Fang SC, Her LS. Adhesion Regulating Molecule 1 Mediates HAP40 Overexpression-Induced Mitochondrial Defects. Int J Biol Sci 2017; 13(11):1420-1437. doi:10.7150/ijbs.20742. Available from http://www.ijbs.com/v13p1420.htm