HtrA2/Omi deficiency causes damage and mutation of mitochondrial DNA

Hui Gwan Goo, Min Kyo Jung, Sung Sik Han, Hyangshuk Rhim, Seong Man Kang

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1866-1875
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1833
Issue number8
DOIs
Publication statusPublished - 2013 Aug 1

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Mitochondrial DNA
varespladib methyl
Mutation
Temperature
Proteins
Serine Proteases
Mitochondria
Peptide Hydrolases
Protein Deficiency
Agar Gel Electrophoresis
Cell Aging
Fluorescent Dyes
Neurodegenerative Diseases
Parkinson Disease
Reactive Oxygen Species
Electron Microscopy
Homeostasis
Cell Death
Maintenance
Apoptosis

Keywords

  • HtrA2
  • Mitochondrial DNA
  • Mutation
  • Omi
  • ROS

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

HtrA2/Omi deficiency causes damage and mutation of mitochondrial DNA. / Goo, Hui Gwan; Jung, Min Kyo; Han, Sung Sik; Rhim, Hyangshuk; Kang, Seong Man.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1833, No. 8, 01.08.2013, p. 1866-1875.

Research output: Contribution to journalArticle

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