Mitochondrial Inheritance & Disease

Chapter 6 Mitochondrial inheritance & disease

郑 大 基 础 医 学 院 ： 程 晓 丽

Segment 1 mitochondrial DNA mutation and disease

Segment 2

genetic character of mitochondrial DNA

郑 大 基 础 医 学 院 ： 程 晓 丽

History

In 1894,first discovered it in animal In 1897,named it for the first time In 1963,first discover the 郑 mtDNA 大 In 1981,the whole sequence 基 础 was done In 1988,confirmed the first kind 医 学 院 of disease caused by mtDNA ： 程 mutation 晓 丽

郑 大 基 础 医 学 院 ： 程 晓 丽

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　 Mitochondria are responsible for producing most of the energy that's needed for our cells to function. In fact, they provide such an important source of energy that a typical human cell contains hundreds of them. A mitochondrial disease can shut down some or all the mitochondria, cutting off this 郑 essential energy supply. 　 Because muscle cells and nerve cells have especially high energy needs, muscular and neurological problems are common features of mitochondrial disease.

大 基 础 医 学 院 ： 程 晓 丽

郑 大 基 础 医 学 院 ： 程 晓 丽

Here are some "Rules of Thumb" of when to think mitochondria: 1. A “common disease” (i.e. autism( 孤独症 ), cerebral palsy （瘫痪） , lots of others) has atypical features that set it apart from the pack. 2. Three or more organ systems are involved. 郑 3. Recurrent setbacks （复发） or flares in a chronic大 基 disease occur with infections. 础 医 4. Credit for above "rules of thumb" to 学 Mitochondrial News, Spring 2000 Issue by Dr. 院 ： Robert K. Navaiaux. 程 

晓 丽

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Organ Systems Possible Problems

Brain developmental delays, mental retardation, dementia （痴呆） , seizures, neuropsychiatric disturbances, atypical cerebral palsy, migraines （偏头痛） , strokes  Nerves weakness (which may be intermittent), neuropathic pain, absent reflexes, dysautonomia （家族性自主神经异常） , gastrointestinal 郑 （胃与肠的） problems (ge reflux, dysmotility, 大 基 diarrhea （腹泻） , irritable bowel syndrome, 础 constipation, pseudo-obstruction), fainting, 医 absent or excessive sweating resulting in 学 院 temperature regulation problems ：  Muscles weakness, hypotonia （张力减退） , 程 晓 cramping, muscle pain 

丽

Kidneys renal tubular acidosis or wasting resulting in loss of protein, magnesium, phosphorous, calcium and other electrolytes.  Heart cardiac conduction defects (heart blocks), cardiomyopathy （心肌症）  Liver hypoglycemia (low blood sugar), liver failure  Eyes visual loss and blindness  Ears hearing loss and deafness 郑 大  Pancreas and Other Glands diabetes and 基 exocrine pancreatic failure (inability to make 础 医 digestive enzymes), parathyroid （副甲状腺的） 学 failure (low calcium) 院  Systemic failure to gain weight, short stature, ： 程 fatigue, respiratory problems including 晓 丽 intermittent air hunger, vomitting 

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Diagnostic Testing for Mitochondrial Disease

1. Blood

for mtDNA (PCR and Southern) 2. Blood and CSF for Lactate （乳酸盐） and Pyruvate （丙酮酸盐） , or Brain MR Spectroscopy 3. Urine Organic Acids (by GC/MS) 4. Plasma and Urine Amino Acids 郑 5. Blood and Urine Carnitine （肉毒碱） 大 基 6. Brain MRI 础 医 7. Muscle Biopsy and Skin Biopsy, 学 Neuropathology and Electron Microscopy, 院 ： Mitochondrial Electron Transport Studies, Fresh (coupled) mitochondrial Polarography, Muscle 程 晓 mtDNA (PCR and Southern) 丽

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Carnitine: An essential thing to check in children with low muscle tone, frequent infections, slow weight gain.

Carnitine plays an important role in cellular energy metabolism!  The mitochondria is the "furnace" of the cell. Fatty acids (fuel) must bind with carnitine to enter the mitochondria. Once inside, fatty acids are burned for energy. Carnitine then binds with the toxic waste by-郑 products of metabolism, removing them from the 大 mitochondria. The inner mitochondrial membrane is 基 impermeable to fatty acids. Transport of fatty acids 础 医 across this membrane can occur only when the fatty学 acids are attached to carnitine. 院 

： 程 晓 丽

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Toxic waste products resulting from energy production are removed from the mitochondria by binding to carnitine. If they are not removed, toxic build-up occurs.

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Carnitine is a small molecule found in animal foods. There is little in a strictly vegetarian diet. This transport via the carnitine is the first step in turning fat into energy for driving 郑 muscle contraction or nerve cell firing. When 大 carnitine is in short supply production of ATP 基 础 is slowed. 医

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Only the L (levo) form of carnitine is safe for humans; the D form, which does not occur in nature, can be toxic.

学 院 ： 程 晓 丽

Segment 1 mtDNA mutation and disease

tRN A rRN point A mRN mtDNA A deletionprotei n

Shortage of the enzymes The function of the protein郑 大 基 Function础 医 of the ATP 学 tissue 院 loss and ： organ 程 晓 丽

Leber hereditary optic neuropathy

sympto m mai n othe r

examp le

Visual loss caused by atrophy and putrescence of bilateral optic neuropathy Neural conduction disorder, fremitus,sarcous hypotonicity.

The incidence of males is 5 times high than females,the reason is unclear.

郑 大 基 础 医 学 院 ： 程 晓 丽

mechanism

A variety of mtDNA mutation that associated with LHON have been discovered. First discovery

Arginine

G

The 11778th bp point mutation

A

Energy production is blocked

郑 大 基 础 医 学 院 ： NADHⅠabnor 程 mal 晓 丽

histidine

Parkinson disease

examp le

is a chronic, progressive neurodegenerative movement disorder. Tremors, rigidity, slow movement (bradykinesia), poor balance, and difficulty walking (called parkinsonian gait) are characteristic primary symptoms 郑 大 of Parkinson disease. 基 础 医 学 院 ： 程 晓 丽

Parkinson results from the degeneration of dopamine-producing nerve cells in the brain, specifically in the substantia nigra and the locus coeruleus. Dopamine is a neurotransmitter that stimulates motor neurons, those nerve cells that control the muscles. When dopamine production is depleted, the motor system nerves are unable to control movement and coordination. 郑 Parkinson's disease patients have lost 80% or 大 基 more of their dopamine-producing cells by the 础 医 time symptoms appear. 学 院 ： 程 晓 丽

Other disease Cerebric muscle disease Cardiac muscle disease Familial deafness caused by mtDNA mutation 郑 大 基 础 医 学 院 ： 程 晓 丽

Segment 2

The characteristics of the mtDNA 1. maternal inheritance

Most of the mtDNA come from the egg, to contrast, the sperm have few mtDNA.

郑 大 基 础 医 学 院 ： 程 晓 丽

郑 大 基 础 医 学 院 ： 程 晓 丽

2. high mutation rate Bareness of mtDNA No mechanism of repair

The reasons

rate

nDNA10 ～ 20 times 郑 大 基 础 医 学 院 ： 程 晓 丽

郑 大 基 础 医 学 院 ： 程 晓 丽

3. Heteroplasmy/homoplasmy mutati on

Somatic cell Germ cell

Abnorm al mtDNA

Norma l mtDN A

Heteroplasmy both normal and abnormal mtDNA are contained in the same cell or tissue. Homoplasmy either normal or abnormal mtDNA is contained in the same cell or tissue.

郑 大 基 础 医 学 院 ： 程 晓 丽

4. semiautomous organelle Mitochondria has its own genetic material, and has the capability of duplication, transcription and translation. The mtDNA is called the 25th chromosome.

郑 大 基 础 医 学 院 ： 程 晓 丽

郑 大 基 础 医 学 院 ： 程 晓 丽

5. effect of threshold The energy supply is not impacted seriously when there is only little mutation mitochondria in the cell or tissues. When there is large mount of abnormal mitochondria existed, the energy supply will be impacted seriously enough to cause the cell out of function. T 郑 20

15 10 a

发 病

5

low

high mtDNAmutationrate

大 基 础 医 学 院 ： 程 晓 丽

effect of threshold

郑 大 基 础 医 学 院 ： 程 晓 丽

Genetic bottleneck the process of the number of the mitochondria reduce from thousands to less than one hundred during the maturing of the egg. 郑 大 基 础 医 学 院 ： 程 晓 丽

6. MtDNA can reproduce itself by duplication during the cell mitosis and mieosis 7.different genetic codon

codon nuclear amino acid mitochondrial amino 郑 acid 大 UGA stop condon tryptophan 基 础 AGA,AGG arginine stop condon 医 AUA isoleucine methionine 学 AUU

isoleucine

methionine

院 ： 程 晓 丽

郑 大 基 础 医 学 院 ： 程 晓 丽

Mitochondrial disease caused by nucleus gene mutation Target sequence A sequence consist of 15-30 amino acids usually exist at the N-terminal of the protein produced by nuclear gene. 郑 　　 大 基 How these protein enter the mitochondria? 础 医 学 院 ： 程 晓 丽

Key point 1. The characteristics of mtDNA ？ 2. Heteroplasmy, homoplasmy, 3. Bottleneck effect

郑 大 基 础 医 学 院 ： 程 晓 丽