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1、线粒体功能障碍与人类疾病 管敏鑫管敏鑫MinMin- -XinXin GuanGuan 浙江大学浙江大学医医学院学院 管敏鑫管敏鑫 1979197919831983：杭州大学（现浙江大学）生物系：杭州大学（现浙江大学）生物系 1989198919931993：澳大利亚国立大学：澳大利亚国立大学 博士博士 1993199319991999：加州理工学院生物系：加州理工学院生物系 Research Fellow Research Fellow 、Senior Research Fellow Senior Research Fellow 1999199920112011：美国辛辛那提大学儿童医院医
2、学中心：美国辛辛那提大学儿童医院医学中心 助理教授、副教授、教授助理教授、副教授、教授 20112011至今：浙江大学（全职回国工作）至今：浙江大学（全职回国工作） 国家国家 “”特聘专家“”特聘专家, , 973973项目首席科学家项目首席科学家 管敏鑫团队的研究工作 非综合征型耳聋与药物性耳聋非综合征型耳聋与药物性耳聋 Leber遗传性视神经病变（遗传性视神经病变（LHON） 高血压等心血管疾病高血压等心血管疾病 糖尿病糖尿病 线粒体是细胞的动力工厂线粒体是细胞的动力工厂 提供人体提供人体细胞细胞90%ATP 产生产生95%以上的以上的 活性氧自由基（活性氧自由基（ROS） 调控细胞凋亡调
3、控细胞凋亡 每天消耗每天消耗ATP量量 人体人体 60kg 心脏心脏 6kg 线粒体线粒体 线粒体功能异常与线粒体功能异常与150多种疾病相关多种疾病相关 糖尿病糖尿病 耳聋耳聋 肿瘤肿瘤 眼病眼病 神经退行性疾病神经退行性疾病 脑肌病等脑肌病等 心血管疾病心血管疾病 Genetic defects affecting the bodys ability to make ATP (energy) are termed “mitochondrial disorders” Mutations can be in the nuclear DNA (chromosomes) or the mitoch
4、ondrial DNA (mtDNA) 线粒体病线粒体病 mitochondrial disorders 线粒体功能异常线粒体功能异常 靶细胞靶细胞 线粒体相关疾病线粒体相关疾病 ATP合成合成 自由基生成自由基生成 氧化还原平衡破坏氧化还原平衡破坏 线粒体功能异常的关键问题线粒体功能异常的关键问题 ？ 线粒体基因线粒体基因 核基因核基因 遗传缺陷遗传缺陷 Mitochondrial Disorders Examples: Electron transport chain subunits nuclear encoded, mtDNA encoded mtDNA tRNA and rRNA g
5、enes Electron transport chain assembly factors, co-factors (Menkes) mtDNA regulatory factors (most are AR, AD KSS) Mitochondrial membrane transporters Krebs cycle enzymes Pyruvate dehydrogenase complex (E1 alpha, other subunits) Fatty acid oxidation disorders, carnitine cycle Digestive System Respir
6、atory System Circulatory System Muscular System Skeletal System Cancer and Mitochondria 30741 SCI paper 人类线粒体基因组人类线粒体基因组 2个个rRNA 22个个tRNA 13个多肽编码基因个多肽编码基因 半自主性半自主性 母系遗传母系遗传 阈值效应阈值效应 高突变率高突变率 图图2 线粒体基因组图线粒体基因组图 (源于源于mitomap网站网站) 全长全长16569bp 编码编码37个基因个基因 遗传特征遗传特征 Mutations in Mitochondrial Genome Asso
7、ciated with Human Diseases Rearrangements Deletions Duplications Point mutations 350 pathogenic mutations 22 tRNA 2 rRNA 13 protein encoding genes 聋病的致病聋病的致病原因原因 遗传因素遗传因素 环境因素环境因素 相互作用相互作用 常常 染染 色色 体体 显显 性性 常常 染染 色色 体体 隐隐 性性 X X 连连 锁锁 母母 系系 遗遗 传传 氨氨 基基 糖糖 甙甙 类类 药药 物物 创创 伤伤 感感 染染 噪噪 声声 其其 他他 20% 一一针致
8、聋针致聋 精子精子 卵卵 子子 线粒体线粒体 细胞核细胞核 线粒体鞘线粒体鞘 母系遗传母系遗传 数百线粒体数百线粒体DNA分子分子 家系家系 数十万线粒体数十万线粒体 DNA分子分子 3 parents baby Fatty Acid Oxidation Disorders All can present as disorders of fasting metabolism. Can present at any age, nursery to adults. However, the toddler years is common. Usually present during a vira
9、l infection, especially gastroenteritis. Often other family members have the same viral infection. Vomiting, but may be unnoticed because of current illness. Increasing lethargy, leading to confusion and coma Fatal if untreated, can be rapidly fatal. May mimic SIDS. Treated simply by sugar, either i
10、v or oral (I.e. juices). Can present as a myopathy, which is often acute and severe. Skeletal: weakness, rhabdomyolysis Cardiac: cardiomyopathy, congestive failure Mitochondrial Genetics Pyruvate Dehydrogenase Complex Deficiency Most commonly reported is the X-linked E1 alpha deficiency. Early-onset
11、 variety presents with “overwhelming” lactic acidosis in the first hours after birth; leading to multi-system failure and death. Often has congenital anomalies, especially brain and kidneys (cysts). Intermediate cases present with neurocognitive disease. Late onset can appear as carbohydrate-induced
12、 ataxia. Males typically have 3 point mutations resulting in partial deficiency. Inheritance is X-linked recessive. Females typically have rearrangements with null activity. Inheritance is X-linked dominant with lethality in hemizygous males. Autosomal recessive deficiencies of other subunits Mitoch
13、ondrial Genetics Electron Transport Chain Complex 1 converts NADH to NAD+. Complex 2 converts FADH2 to FAD. Complexes 1, 3 and 4 pump protons across the mitochondrial inner membrane. Complex 5 uses the protein gradient to make ATP from ADP and Pi. Complex 2 is entirely nuclear-encoded. The other com
14、plexes have both mtDNA and nDNA-encoded subunits (most are nDNA) Mitochondrial Genetics Most Likely Mode of Inheritance Infantile onset, severe Autosomal recessive X-linked recessive Maternal Late onset, less severe Maternal Autosomal dominant Autosomal Recessive Mitochondrial Disorders Common Sever
15、e Infantile onset Affected siblings have very similar manifestations In most cases, the family history is non- contributory mtDNA 16.6 kb 37 genes 13 proteins 22 t-RNAs 2 r-RNAs 1 kb control region Mitochondrial Genetics Principles of Maternal Inheritance Asexual Inherited from mothers only High recurrence risk Heteroplasmy Varies from cell to cell, mutation and tissue dependent Bottleneck Heteroplasmy is unstable Threshold Some tissues need more energy than others Maternal Inheritance All relatives shown in red have exactly the same mtDNA sequence in the absence of a new mutation.
