Biochem 7 - Mitochondrial Diseases

Front 1

complex 5

Back 1

ATP synthase

Front 2

where does NADH enter the ETC

Back 2

Complex 1

Front 3

where does FADH2 enter the ETC

Back 3

complex 2 --> CoQ

Front 4

what does pyruvate dehydrogenase do

Back 4

converts pyruvate into acetyl coA

Front 5

regulation of pyruvate dehydrogenase complex

Back 5

phosphorylation --> inhibits activity

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GTP stands for

Back 6

guanine tri-phosphate

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diagnostic measures of mitochondrial energy-generating system

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1. 14C labelled pyruvate, succinate, malate

2. measure O2 consumption in the presence of different substrates

3. measure rate of ATP synthesis in the presence of different substrates

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4 results of mitochondrial myopathies

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1. exercise intolerance
2. lactic acidosis
3. stroke/seizure
4. headache

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define mitochondrial myopathy

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genetic defect in mitochondrial structure leading to defective aerobic energy transduction

Front 10

what is:
genetic defect in mitochondrial structure leading to defective aerobic energy transduction

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mitochondrial myopathy

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4 main categories of causes of plasma lactate elevation

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1. erroneous
2. physiological
3. systemic diseases that increase blood lactate
4. metabolic diseases

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2 examples of erroneous elevations

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1. poor collection technique
2. poor sample handling

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physiological cause of plasma lactate elevation

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anaerobic exercise

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systemic diseases that increase plasma lactate (6)

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1. hypoxia
2. hypotension
3. shock
4. sepsis
5. cardiac failure
6. renal failure

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metabolic diseases that increase plasma lactate (4)

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1. amino acid disorders
2. pyruvate metabolism disorders
3. OXPHOS disorders
4. citric acid cycle defects

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official diagnosis of mitochondrial disorder

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<30% normal function

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disorder in which mitochondrial dysfunction is normal

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autis

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clinical abnormalities in mitochondrial disease and ASD (10)

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1. developmental delay
2. loss of skills
3. seizures
4. muscle weakness
5. peripheral neuropathy
6. abnormal endocrine/growth
7. abnormal GI
8. abnormal lactate
9. abnormal pyruvate
10. abnormal alanine

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physiological consequence of mitochondrial dysfunction (4)

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1. ROS
2. reduced GABA interneuron activity (GABA = inhibitory)
3. abnormal Ca regulation (Can can cause apoptosis)
4. reduced synaptic plasticity

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clinical abnormalities found in mitochondrial disease that are not typically clinically abnormal in ASD (5)

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1. ophthalmoplegia
2. facies myopathica
3. cortical blindness
4. migraine
5. stroke like episodes

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3 things autistic kids were more likely to have than other kids

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1. mitochondrial dysfunction
2. mtDNA overreplication
3. mtDNA deletion

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2 most common deficiencies in autism

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1. NADH oxidase
2. succinate oxidase (oxidizes succinate to fumarate)

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problem with the fact that (in autism) more anaerobic metabolism occurs

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sucks for the brain because the brain relies on mitochondrial oxphos

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fun fact about autism

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lower oxphos
increase in oxidative stress

Front 25

3 types of insults that cause mitochondrial stress

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environmental (radiation, toxic chemicals)
genetic (mutations in mito pathways)
spontaneous (ROS)

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3 types of problems caused by mito stress

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1. loss of metabolic functions
2. more ROS
3. ATPase any consume ATP to generate membrane potential instead of vice versa

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6 cellular responses to mitochondrial damage

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1. DNA repair
2. proteases
3. lipases
4. mitochondrial unfolded protein response
5. mitophagy
6. apoptosis

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unfolded protein response

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stops protein translation
increases production of molecular chaperones involved in protein folding
apoptosis if this fails

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what tags proteins for degradation

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ubiquitin

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2 pathological features of parkinsons disease

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1. mitochondrial dysfunction
2. protein inclusions in Lewy-bodies in dopaminergic neurons

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disease in which there are Lewy bodies

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PD

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what cell type contains Lewy bodies

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dopaminergic neurons

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what could cause mitochondrial dysfunction and protein inclusions in Lewy-bodies

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impairment in quality control systems for mitochondria

impairment in mitochondrial fission/fusion dynamics

impairment in ubiquitin proteasome system

impairment in autophagy pathway

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autophagy

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lysosomal degradation pathway

for long-lived, misfolded or aggregated proteins, damaged or excess organelles

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what accumulates and aggregates in PD

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a-synuclein

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overexpression of alpha synuclein causes

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impaired autophagy

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a-synnuclein is degraded by

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chaperone mediated autophagy

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neurotoxins that affect humans and that are used in animal models of PD

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MPTP
6-hydroxy-dopamine
rotenone
paraquat

Front 39

mechanism of action of MPTP

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inhibits complex 1

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animal models of PD with MPTP, 6-hydroxydopamine, etc. suggest pathogenic mechanisms for parkinsons

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mitochondrial dysfunction
oxidative stress

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what do Lewy bodies contain

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ubiquitin
a-synnuclein

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most common cause of recessive parkinsons

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Parkin mutation

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role of Parkin

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mediates clearance of abnormal mitochondria through autophagy

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general role of Parkin and PINK1

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regulate mitochondrial morphology and maintenance
These functions are also abnormal in idiopathic forms which are more common than the autosomal recessive forms

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Note about autosomal recessive PD forms

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they lack characterisic Lewy-body pathology

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2 types of PD

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autosomal recessive mutation (ex. PINK1, Parkin mutations)
idiopathic (more common)

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pink parkin and mitophagy

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1. unhealthy part of mito undergoes fission
2. pink is constantly being produced and degraded
3. PINK recognizes mito membrane potential
4. PINK associates with the outer membrane
5. then it is brought inside for cleavage

BUT in times of abnormal mitochondrial potential
1. PINK is not brought inside for cleavage
2. accumulates on the surface
3. Parkin is recruited
4. this tags the mitochondria for ubiquination and degradation

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role of mitochondrial fusion

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facilitates interchange of internal components such as:
mitochondrial genome
resp proteins
metabolic products

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role of mitochondrial fission

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removal of dysfunctional mitochondria with reduced membrane potential via mitophagy in lysosomes