Diverse cytopathologies in mitochondrial disease are caused by AMP-activated protein kinase signaling
Diverse cytopathologies in mitochondrial disease are caused by AMP-activated protein kinase signaling
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DOI：
10.1091/mbc.e06-09-0881
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发表时间：
2007-05-01
影响因子：
3.3
通讯作者：
Fisher, Paul R.
中科院分区：
文献类型：
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作者：
Bokko, Paul B.;Francione, Lisa;Fisher, Paul R.
线粒体疾病的复杂细胞病理学通常归因于ATP不足。腺苷酸活化蛋白激酶（AMPK）是一种高度敏感的细胞能量传感器，可被ATP耗竭应激刺激。通过反义抑制伴侣蛋白60的表达，我们产生了在趋光性、生长和多细胞形态发生方面具有基因剂量依赖性缺陷的尿道疾病菌株。线粒体疾病是通过过度表达组成型活性AMPK α亚基（AMPK α T）以基因剂量依赖性方式表型复制的。通过反义抑制AMPK α表达，完全抑制了尿道病变菌株中的异常表型。吞噬作用和巨胞饮作用虽然消耗能量，但不受线粒体疾病和AMPK α表达水平的影响。与AMPK在能量稳态中的作用一致，AMPK α反义抑制降低了线粒体“质量”和ATP水平，AMPK α T过表达增加了线粒体“质量”和ATP水平，但它们在肾脏病变细胞中接近正常。我们还发现，5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷，一种哺乳动物细胞中的药理学AMPK激活剂，在损害网骨藻趋光性方面模拟线粒体疾病，并且AMPK α反义抑制细胞对这种作用具有抗性。结果表明，网骨藻线粒体疾病中的多种细胞病理学是由慢性AMPK信号传导而不是ATP不足引起的。
The complex cytopathology of mitochondrial diseases is usually attributed to insufficient ATP. AMP-activated protein kinase (AMPK) is a highly sensitive cellular energy sensor that is stimulated by ATP-depleting stresses. By antisense-inhibiting chaperonin 60 expression, we produced mitochondrially diseased strains with gene dose-dependent defects in phototaxis, growth, and multicellular morphogenesis. Mitochondrial disease was phenocopied in a gene dose-dependent manner by overexpressing a constitutively active AMPK alpha subunit (AMPK alpha T). The aberrant phenotypes in mitochondrially diseased strains were suppressed completely by antisense-inhibiting AMPK alpha expression. Phagocytosis and macropinocytosis, although energy consuming, were unaffected by mitochondrial disease and AMPK alpha expression levels. Consistent with the role of AMPK in energy homeostasis, mitochondrial "mass" and ATP levels were reduced by AMPK alpha antisense inhibition and increased by AMPK alpha T overexpression, but they were near normal in mitochondrially diseased cells. We also found that 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, a pharmacological AMPK activator in mammalian cells, mimics mitochondrial disease in impairing Dictyostelium phototaxis and that AMPK alpha antisense-inhibited cells were resistant to this effect. The results show that diverse cytopathologies in Dictyostelium mitochondrial disease are caused by chronic AMPK signaling not by insufficient ATP.