Chapter 6

Mitochondrial
inheritance & disease 郑
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Segment 1

mitochondrial DNA
mutation and disease

Segment 2 郑
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genetic character of
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mitochondrial DNA 学
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 History
In 1894,first discovered it in animals
In 1897,named it for the first time
In 1963,first discover the mtDNA
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In 1981,the whole sequence was done 大
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In 1988,confirmed the first kind of 医
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disease caused by mtDNA mutation 院
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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
essential energy supply. 郑
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 　 Because muscle cells and nerve cells have 础
especially high energy needs, muscular and 医
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neurological problems are common features 院
of mitochondrial disease. ：
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 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 大
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chronic disease occur with infections. 础
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4. Credit for above "rules of thumb" to 学
Mitochondrial News, Spring 2000 Issue by Dr.院：
Robert K. Navaiaux. 程
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 Organ Systems Possible Problems
 Brain developmental delays, mental
retardation, dementia （痴呆） , seizures, neuro-
psychiatric 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
diarrhea （腹泻） , irritable bowel syndrome, 基
constipation, pseudo-obstruction), fainting, 础
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absent or excessive sweating resulting in 学
temperature regulation problems 院
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 Muscles weakness, hypotonia （张力减退） , 程
cramping, muscle pain 晓
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 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
 Pancreas and Other Glands diabetes and 大
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exocrine pancreatic failure (inability to make 础
digestive enzymes), parathyroid （副甲状腺的） 医
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failure (low calcium) 院
 Systemic failure to gain weight, short stature, ：
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fatigue, respiratory problems including 晓
intermittent air hunger, vomitting 丽
 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
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5. Blood and Urine Carnitine （肉毒碱） 大
6. Brain MRI
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7. Muscle Biopsy and Skin Biopsy, Neuropathology 医
and Electron Microscopy, Mitochondrial Electron学
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Transport Studies, Fresh (coupled) ：
mitochondrial Polarography, Muscle mtDNA 程
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(PCR and Southern) 丽
 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 郑
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waste by-products of metabolism, removing them基
from the mitochondria. The inner mitochondrial 础
membrane is impermeable to fatty acids. 医
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Transport of fatty acids across this membrane can院
occur only when the fatty acids are attached to ：
carnitine. 程
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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.
 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
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is slowed. 医
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 Only the L (levo) form of carnitine is safe for 院
humans; the D form, which does not occur in ：
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nature, can be toxic. 晓
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Segment 1
mtDNA mutation and disease

tRNA Shortage of
rRNA the enzymes
point
The function of
mtDNA mRNA the protein 郑 大
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deletion Function础
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protein ATP of the 学
loss tissue and
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organ 程
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 Leber hereditary optic neuropathy example
symptom
Visual loss caused by atrophy
main and putrescence of bilateral
optic neuropathy

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other Neural conduction disorder, 大
fremitus,sarcous hypotonicity. 基
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The incidence of males is 5 院
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times high than females,the 程
reason is unclear. 晓
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 mechanism
A variety of mtDNA mutation that associated
with LHON have been discovered.

First
discovery G Arginine
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A histidine 础
The 11778th bp 医
point mutation 学
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Energy production is NADHⅠabnormal 程
blocked 晓
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Parkinson disease example
is a chronic, progressive neurodegenerative
movement disorder. Tremors, rigidity, slow
movement (bradykinesia), poor balance,
and difficulty walking (called parkinsonian
gait) are characteristic primary symptoms
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of Parkinson disease. 大
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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
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more of their dopamine-producing cells by the 础
time symptoms appear. 医
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 Other disease
Cerebric  muscle disease
Cardiac muscle disease 
Familial deafness caused by mtDNA mutation 

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Segment 2
The characteristics of the mtDNA

1. maternal inheritance

Most of the mtDNA come from the egg, to 郑

contrast, the sperm have few mtDNA. 大
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2. high mutation rate

Bareness
of mtDNA
rate ＞ nDNA10 ～ 20 times
No mechanism
of repair
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The reasons 基
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 3. Heteroplasmy/homoplasmy

Somatic cell Abnormal Normal

mutation
mtDNA ＋ mtDNA
Germ cell

Heteroplasmy both normal and abnormal mtDNA are 郑

contained in the same cell or tissue. 大
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Homoplasmy either normal or abnormal mtDNA is 学
contained in the same cell or tissue. 院
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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.
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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.
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low high
mtDNA mutation rate 丽
effect of threshold

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Genetic bottleneck
the process of the number of the mitochondria
reduce from thousands to less than one
hundred during the maturing of the egg.

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 6. MtDNA can reproduce itself by
duplication during the cell mitosis
and mieosis

7.different genetic codon

codon nuclear amino acid mitochondrial amino acid郑

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UGA stop condon tryptophan 基
AGA,AGG arginine stop condon 础
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AUA isoleucine methionine 学
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AUU isoleucine methionine ：
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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.
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How these protein enter the mitochondria? 础
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 Key point
1. The characteristics of
mtDNA ？

2. Heteroplasmy, homoplasmy,

3. Bottleneck effect 郑
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