老人性難聴へのアプローチ : 酸化ストレスとミトコンドリア障害説  [in Japanese] The role of oxidative stress and mitochondrial DNA mutation in the age-related hearing loss  [in Japanese]

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Abstract

酸化ストレス、ミトコンドリア遺伝子障害と老化の関連が示唆されている。我々はPolgおよびゲルマニウム慢性摂取マウスという2つのミトコンドリア障害モデルで、聴覚系の変化を検討し、加齢に伴う有意な聴力閾値上昇・蝸牛組織の変性を確認した。ゲルマニウム摂取モデルでは蝸牛でミトコンドリア関連遺伝子発現低下を認め、その機能低下が蝸牛組織変性・難聴につながると考えられた。次に抗酸化剤であるビタミンC合成能欠損マウス(SMP30/GNL KOマウス)を用い、ビタミンCの投与量による聴覚系の変化を検討した。ビタミンC制限は蝸牛内ビタミンC濃度低下、聴力閾値上昇とラセン神経節細胞の減少を来たした。しかし、ビタミンC補充は野生型マウスでも蝸牛内ビタミンC 濃度の上昇はなく、聴力・ラセン神経節の保護効果はなかった。ビタミンCの欠乏は老化に伴う難聴を加速させるが、補充は難聴の進行を予防できないことが示唆された。

Increased oxidative stress due to reactive oxygen species (ROS) and accumulation of mitochondrial DNA (mtDNA) mutations are thought to be important factors in aging. We assessed the role played by accumulation of mtDNA mutations in the development of age-related hearing loss (AHL) by using Polg (D257A) knockin mice, which exhibit increased spontaneous mtDNA mutation rates during aging. These mice exhibited hearing loss and degeneration of hair cells, spiral ganglion cells, and stria vascularis by the age of 9 months, whereas wild-type (WT) animals did not. Next, we examined whether mitochondrial damage induced by systemic application of germanium dioxide caused progressive hearing loss and cochlear damage. The mice developed accelerated hearing loss due to degeneration of supporting cells, stria vascularis, and spiral ganglion cells by the age of 3 months. Microarray and quantitative real time polymerase chain reaction (QRTPCR) analyses showed that the expressions of mitochondrial function-associated genes were significantly decreased in the cochleae of germanium-treated mice. These findings indicate that the accumulation of mtDNA mutations can induce damage to the cochlear cells and cause hearing loss. Many ROS are endogenously generated in our body as byproducts of energy metabolism. Noise exposure, hypoperfusion, and other environmental factors can also generate ROS. In addition, age-associated reduction in endogenous enzymes that protect from ROS enhances the generation of ROS. Mitochondria are a major source of ROS, and ROS production increases with age. Vitamin C (VC) is a well-known ROS scavenger. Using senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice, which cannot synthesize VC, we examined whether modulation of the VC level affects AHL. KO and WT C57BL/6 mice were administered VC-rich water or VC-restricted water. At 10 months of age, KO VC(−) mice showed significant reduction in the VC level in the inner ear, increase in the auditory brainstem response (ABR) thresholds, and decrease in the number of spiral ganglion cells as compared with that observed in WT VC(−), WT VC(+), and KO VC(+) mice. There were no differences in the VC level in the inner ear, ABR thresholds, or the number of spiral ganglion cells among WT VC(−), WT VC(+), and KO VC(+) mice. These findings suggest that VC depletion can accelerate AHL but that VC supplementation may not increase the VC level in the inner ear or slow AHL in mice.

Journal

  • Otology Japan

    Otology Japan 20(3), 191-196, 2010-07-25

    THE JAPAN OTOLOGICAL SOCIETY

References:  16

Codes

  • NII Article ID (NAID)
    10029699056
  • NII NACSIS-CAT ID (NCID)
    AN10358085
  • Text Lang
    JPN
  • Article Type
    REV
  • ISSN
    09172025
  • Data Source
    CJP  J-STAGE 
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