Adhesion Regulating Molecule 1 Mediates HAP40 Overexpression-Induced Mitochondrial Defects
| Autor: | Lu Shiun Her, Zih Ning Huang, Su Chiung Fang, Her Min Chung |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Dynamins
0301 basic medicine Blotting Western ADRM1 HAP40 Mitochondrion Applied Microbiology and Biotechnology Mice 03 medical and health sciences 0302 clinical medicine Huntington's disease Drp1 medicine Animals Viability assay RNA Small Interfering Molecular Biology Cells Cultured Ecology Evolution Behavior and Systematics Membrane Potential Mitochondrial chemistry.chemical_classification Reactive oxygen species Chemistry Cell adhesion molecule Intracellular Signaling Peptides and Proteins Cell Biology medicine.disease mitochondrial dynamics Mitochondria Cell biology Huntington Disease 030104 developmental biology Microscopy Fluorescence Phosphorylation Mitochondrial fission Carrier Proteins Reactive Oxygen Species Cell Adhesion Molecules 030217 neurology & neurosurgery Research Paper Developmental Biology |
| Zdroj: | International Journal of Biological Sciences |
| ISSN: | 1449-2288 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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