FUNCTIONAL ALTERATIONS OF THE MITOCHONDRIALLY ENCODED ND4 SUBUNIT ASSOCIATED WITH LEBERS HEREDITARY OPTIC NEUROPATHY
FUNCTIONAL ALTERATIONS OF THE MITOCHONDRIALLY ENCODED ND4 SUBUNIT ASSOCIATED WITH LEBERS HEREDITARY OPTIC NEUROPATHY
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DOI：
10.1016/0014-5793(94)00971-6
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发表时间：
1994-10-03
期刊：
影响因子：
3.5
通讯作者：
CORTELLI, P
中科院分区：
文献类型：
--
作者：
ESPOSTI, MD;CARELLI, V;CORTELLI, P
Leber遗传性视神经病变（LHON）是一种与线粒体DNA点突变相关的母系遗传性疾病。这些突变中最常见的是核苷酸位置11，778处的G至A取代，其将NADH：泛醌还原酶（呼吸复合物I）的亚基ND 4中位置340处的组氨酸与进化上保守的精氨酸改变。我们报告说，这种氨基酸取代改变了复合物I对泛醌底物的亲和力，并诱导LHON患者线粒体对其有效抑制剂鱼藤酮的抗性。这种变化可能反映了NADH：泛醌还原酶的能量保存功能的实质性丧失，从而解释了ND 4/11，778突变的病理作用。
Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease associated with point mutations in mitochondrial DNA. The most frequent of these mutations is the G-to-A substitution at nucleotide position 11,778 which changes an evolutionarily conserved arginine with a histidine at position 340 in subunit ND4 of NADH:ubiquinone reductase (respiratory complex I). We report that this amino acid substitution alters the affinity of complex I for the ubiquinone substrate and induces resistance towards its potent inhibitor rotenone in mitochondria of LHON patients. Such changes could reflect a substantial loss in the energy conserving function of NADH:ubiquinone reductase and thus explain the pathological effect of the ND4/11,778 mutation.