Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice.
Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice.
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DOI：
10.1093/hmg/ddn309
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发表时间：
2009-01-01
影响因子：
3.5
通讯作者：
Zeviani M
中科院分区：
文献类型：
--
作者：
Viscomi C;Spinazzola A;Maggioni M;Fernandez-Vizarra E;Massa V;Pagano C;Vettor R;Mora M;Zeviani M
在人类中，MPV17 突变会导致严重的线粒体耗竭综合征，主要影响肝脏和神经系统。为了深入了解 MPV17 相关疾病的病理生理学，我们研究了可用的 Mpv17 敲除动物模型。我们发现肝脏中线粒体 DNA 严重缺失，骨骼肌中线粒体 DNA 严重缺失（尽管程度较轻），而在出生后 1 年内，大脑和肾脏中几乎未检测到任何线粒体 DNA 缺失。小鼠胚胎成纤维细胞确实表现出线粒体 DNA 耗尽，但仅在几次培养传代后或在无血清培养基中。尽管线粒体DNA严重缺失，但在Mpv17−/−肝脏中仅观察到呼吸链酶活性中度下降和轻度细胞结构改变，但该器官在任何年龄都没有发生肝硬化或衰竭。肝脏中 mtDNA 转录率显着增加，这可能有助于补偿严重的 mtDNA 损耗。这种现象与 mtDNA 转录负调节因子 Mterf1 的特异性下调有关。最相关的临床特征涉及皮肤、内耳和肾脏。 Mpv17−/− 小鼠的皮毛在成年早期就变成灰色，18 个月或以上的小鼠出现局灶节段性肾小球硬化症 (FSGS) 并伴有大量蛋白尿。还报道了耳蜗感觉上皮的伴随退化。这些症状与寿命显着缩短有关。与 FSGS 发生同时，肾小球簇中几乎没有留下任何线粒体 DNA。这些结果表明 Mpv17 通过高度组织特异性和可能的细胞型特异性机制控制 mtDNA 拷贝数。
In humans, MPV17 mutations are responsible for severe mitochondrial depletion syndrome, mainly affecting the liver and the nervous system. To gain insight into physiopathology of MPV17-related disease, we investigated an available Mpv17 knockout animal model. We found severe mtDNA depletion in liver and, albeit to a lesser extent, in skeletal muscle, whereas hardly any depletion was detected in brain and kidney, up to 1 year after birth. Mouse embryonic fibroblasts did show mtDNA depletion, but only after several culturing passages, or in a serumless culturing medium. In spite of severe mtDNA depletion, only moderate decrease in respiratory chain enzymatic activities, and mild cytoarchitectural alterations, were observed in the Mpv17−/− livers, but neither cirrhosis nor failure ever occurred in this organ at any age. The mtDNA transcription rate was markedly increased in liver, which could contribute to compensate the severe mtDNA depletion. This phenomenon was associated with specific downregulation of Mterf1, a negative modulator of mtDNA transcription. The most relevant clinical features involved skin, inner ear and kidney. The coat of the Mpv17−/− mice turned gray early in adulthood, and 18-month or older mice developed focal segmental glomerulosclerosis (FSGS) with massive proteinuria. Concomitant degeneration of cochlear sensory epithelia was reported as well. These symptoms were associated with significantly shorter lifespan. Coincidental with the onset of FSGS, there was hardly any mtDNA left in the glomerular tufts. These results demonstrate that Mpv17 controls mtDNA copy number by a highly tissue- and possibly cytotype-specific mechanism.
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影响因子：
30.8
作者：
Bourdon, Alice;Minai, Limor;Rotig, Agnes
通讯作者：
Rotig, Agnes
影响因子：
2.5
作者：
Fernandez-Vizarra, Erika;Enriquez, Jose A.;Fernandez-Silva, Patricio
通讯作者：
Fernandez-Silva, Patricio
影响因子：
30.8
作者：
Irwin, WA;Bergamin, N;Bonaldo, P
通讯作者：
Bonaldo, P
影响因子：
9.8
作者：
Karadimas, Charalampos L.;Vu, Tuan H.;Hirano, Michio
通讯作者：
Hirano, Michio
影响因子：
6
作者：
Binder, CJ;Weiher, H;Kerjaschki, D
通讯作者：
Kerjaschki, D