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
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
HtrA2/Omi deficiency causes damage and mutation of mitochondrial DNA
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 HtrA2−/− 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 HtrA2−/− MEF cells. Nuclear-encoded mtDNA repair genes, including POLG2, Twinkle, and APTX1, were significantly upregulated in HtrA2−/− cells. Electron microscopy showed that mitochondrial morphology itself was not affected, even in HtrA2−/− 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
نویسندگان
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