线粒体功能障碍与人类疾病
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• Early-onset 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).
常常
染 色 体 显
染 色 体 隐
X
连 锁
母 系 遗 传
性性
氨
基 糖 甙 类 药
创 伤 感 染
噪其 声他
物
一针致聋 20%
母系遗传
家系
线粒体Hale Waihona Puke Baidu细胞核
数十万线粒体 DNA分子
卵 子
精子
线粒体鞘
数百线粒体DNA分子
3 parents baby
Fatty Acid Oxidation Disorders
• 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.
线粒体功能异常的关键问题
？ 线粒体基因
核基因
遗传缺陷
线粒体功能异常
ATP合成 自由基生成
氧化还原平衡破坏
靶细胞
线粒体相关疾病
Mitochondrial Disorders Examples:
• Electron transport chain subunits
• nuclear encoded, • mtDNA encoded
subunits) • Fatty acid oxidation disorders, carnitine cycle
Respiratory System Digestive System Skeletal System
Circulatory System Muscular System
Cancer and Mitochondria
• mtDNA tRNA and rRNA genes • 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
• 30741 SCI paper
人类线粒体基因组
全长16569bp
编码37个基因
2个rRNA 22个tRNA 13个多肽编码基因
遗传特征
半自主性 母系遗传 阈值效应 高突变率
图2 线粒体基因组图 (源于mitomap网站)
Mutations in Mitochondrial Genome Associated with Human Diseases
• Cardiac: cardiomyopathy, congestive failure
Mitochondrial Genetics
Pyruvate Dehydrogenase Complex Deficiency
• Most commonly reported is the X-linked E1 alpha deficiency.
• Intermediate cases present with neurocognitive disease. • Late onset can appear as carbohydrate-induced ataxia. • Males typically have 3’ point mutations resulting in partial
• Rearrangements • Deletions • Duplications
• Point mutations >350 pathogenic mutations
• 22 tRNA • 2 rRNA • 13 protein encoding genes
聋病的致病原因
遗传因素
相互作用
环境因素
线粒体病 mitochondrial disorders
Genetic defects affecting the body’s ability to make ATP (energy) are termed “mitochondrial disorders”
Mutations can be in the nuclear DNA (chromosomes) or the mitochondrial DNA (mtDNA)
线粒体功能障碍与人类疾病
线粒体是细胞的动力工厂
提供人体细胞~90%ATP 产生95%以上的
活性氧自由基（ROS） 调控细胞凋亡
线粒体
每天消耗ATP量 人体 60kg 心脏 6kg
线粒体功能异常与150多种疾病相关
心血管疾病
糖尿病 耳聋 肿瘤 眼病 神经退行性疾病 脑肌病等
• Treated simply by sugar, either iv or oral (I.e. juices).
• Can present as a myopathy, which is often acute and severe.
• Skeletal: weakness, rhabdomyolysis
• 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 viral infection, especially gastroenteritis. Often other family members have the same viral infection.
常常
染 色 体 显
染 色 体 隐
X
连 锁
母 系 遗 传
性性
氨
基 糖 甙 类 药
创 伤 感 染
噪其 声他
物
一针致聋 20%
母系遗传
家系
线粒体Hale Waihona Puke Baidu细胞核
数十万线粒体 DNA分子
卵 子
精子
线粒体鞘
数百线粒体DNA分子
3 parents baby
Fatty Acid Oxidation Disorders
• 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.
线粒体功能异常的关键问题
？ 线粒体基因
核基因
遗传缺陷
线粒体功能异常
ATP合成 自由基生成
氧化还原平衡破坏
靶细胞
线粒体相关疾病
Mitochondrial Disorders Examples:
• Electron transport chain subunits
• nuclear encoded, • mtDNA encoded
subunits) • Fatty acid oxidation disorders, carnitine cycle
Respiratory System Digestive System Skeletal System
Circulatory System Muscular System
Cancer and Mitochondria
• mtDNA tRNA and rRNA genes • 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
• 30741 SCI paper
人类线粒体基因组
全长16569bp
编码37个基因
2个rRNA 22个tRNA 13个多肽编码基因
遗传特征
半自主性 母系遗传 阈值效应 高突变率
图2 线粒体基因组图 (源于mitomap网站)
Mutations in Mitochondrial Genome Associated with Human Diseases
• Cardiac: cardiomyopathy, congestive failure
Mitochondrial Genetics
Pyruvate Dehydrogenase Complex Deficiency
• Most commonly reported is the X-linked E1 alpha deficiency.
• Intermediate cases present with neurocognitive disease. • Late onset can appear as carbohydrate-induced ataxia. • Males typically have 3’ point mutations resulting in partial
• Rearrangements • Deletions • Duplications
• Point mutations >350 pathogenic mutations
• 22 tRNA • 2 rRNA • 13 protein encoding genes
聋病的致病原因
遗传因素
相互作用
环境因素
线粒体病 mitochondrial disorders
Genetic defects affecting the body’s ability to make ATP (energy) are termed “mitochondrial disorders”
Mutations can be in the nuclear DNA (chromosomes) or the mitochondrial DNA (mtDNA)
线粒体功能障碍与人类疾病
线粒体是细胞的动力工厂
提供人体细胞~90%ATP 产生95%以上的
活性氧自由基（ROS） 调控细胞凋亡
线粒体
每天消耗ATP量 人体 60kg 心脏 6kg
线粒体功能异常与150多种疾病相关
心血管疾病
糖尿病 耳聋 肿瘤 眼病 神经退行性疾病 脑肌病等
• Treated simply by sugar, either iv or oral (I.e. juices).
• Can present as a myopathy, which is often acute and severe.
• Skeletal: weakness, rhabdomyolysis
• 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 viral infection, especially gastroenteritis. Often other family members have the same viral infection.