کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10802356 | 1055686 | 2013 | 39 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
HtrA2/Omi deficiency causes damage and mutation of mitochondrial DNA
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موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
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چکیده انگلیسی
High-temperature requirement protein A2 (HtrA2), a serine protease, localizes in the mitochondria and has diverse roles, including maintenance of mitochondrial homeostasis and regulation of cellular apoptosis. HtrA2 (also known as Omi) is associated with many neurodegenerative diseases, including Parkinson disease. By employing agarose gel electrophoresis, a fluorescent dye, PicoGreen, intercalation into mtDNA, and long-range PCR (LR-PCR), we showed that mitochondrial DNA conformational stability is related to HtrA2. Nicked forms of mtDNA were produced through reactive oxygen species generated by loss of HtrA2 protease activity, and mtDNA mutations frequently occurred in HtrA2â/â cells, but not in HtrA2+/+ cells. We found conformational changes in mtDNA from the brain tissue of mnd2 mutant mice that lack the serine protease activity of HtrA2. Overexpression of HtrA2 with protease activity targeted to mitochondria only was able to restore mtDNA conformational stability in HtrA2â/â MEF cells. Nuclear-encoded mtDNA repair genes, including POLG2, Twinkle, and APTX1, were significantly upregulated in HtrA2â/â cells. Electron microscopy showed that mitochondrial morphology itself was not affected, even in HtrA2â/â cells. Our results demonstrate that HtrA2 deficiency causes mtDNA damage through ROS generation and mutation, which may lead to mitochondrial dysfunction and consequent triggering of cell death in aging cells.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research - Volume 1833, Issue 8, August 2013, Pages 1866-1875
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research - Volume 1833, Issue 8, August 2013, Pages 1866-1875
نویسندگان
Hui-Gwan Goo, Min Kyo Jung, Sung Sic Han, Hyangshuk Rhim, Seongman Kang,