Mitochondrial disease 1 and 2 Flashcards
Mitochondrial function
ATP production through ox phos, repirartory chain, regulation of molecules on inner and outer membrane (calcium), control of cystolic ca2+, MOMP crucial for apoptosis
how many genes does the mitochondria encode for oxphos?
37 genes
How do the nuclear encoded mito proteins get into mitocondria?
TIM and TOM
What do we need to have mitochondrial biogenesis and what can we use to drive it?
Exercise drives coordinated
expression of 2 genomes and
mitochondrial biogenesis
What is mitochondrial disease?
- Mutation in mito gene or nuclear gene encoding mito protein that affects organelle function
- Mito disease is multisystem disorder, affecting more than one type of cell/tissue
- Neuromuscular system has high energy needs, thus myopathy/neuropathy common features
What does mitochondrial disease affect?
ns, eyes, heart, liver kidneys, skeletal muscle digestive tract, pancreas
How common is mito disease?
1/5000 (15% mtDNA defects)
what does inhertance look like for mito disease cause by mtDNA?
If mother is affected all kids have, if dad affected no kids are affected
what does inheritance look like for mito disease cause by nDNA?
Mitochondrial diseases caused by nDNA mutations can be due to AR, AD, XAR
Are there sporadic cases with mito diases?
Yes, increases with age
What do we see with Gomori trichrome histochemical stain?
Ragged-red fibers caused by compensating for the dysfunction in mito so there is proliferation of subsarcolemmal
mitochondria (mito under sacrolemma)
What does the Ragged-blue fiber show?
Succinate dehydrogenase (SDH) activity
what does Normal cytochrome c oxidase (COX) histochemical staining show?
Normal cytochrome c oxidase (COX) histochemical staining highlighting
variability of mitochondrial enzyme activity in muscle biopsy (less COX = less mito activity/function)
COX histo from CPEO patient shows?
COX histo from CPEO patient showing COX-deficient fibers, Mosaic pattern of COX activity highly suggestive of mtDNA disorder
How does SDH play a role with decrease in COX and mito activity?
Increases to compensate
Is it possible to have normal COX activity but abnormal mito proflieration?
Yes
How is oxphos performed and how many are there?
OXPHOS performed by five large, multi-subunit supercomplexes (CI-CV) embedded in MIM
What encodes for the complexes of the ETC for ox-phos to occur?
ETC complexes except complex II (SDH) (only nDNA) composed of subunits encoded by mtDNA & nDNA
Describe mito DNA
• mtDNA is circular, contains 37 genes encoding 2 rRNAs, 22 tRNAs, & 13 OXPHOS proteins • mtDNA has ~10-fold greater susceptibility for spontaneous mutagenesis versus nDNA • Fewer DNABPs for protection, coupled with less robust DNA maintenance & repair systems
What affects the severity of mito disease?
Severity of mitochondrial disease in child due to mtDNA mutation
depends on % mutant mtDNA inherited from mother in fertilized egg cell
When all mtDNA molecules are identical?
homoplasmy
When two or more mtDNA types are present?
heteroplasmy
mtDNA mutations affect some but not all mtDNAs within cell?
heteroplasmy
threshold effect?
Minimum % mutant mtDNAs required to cause overt disease = threshold effect
What is the threshold?
impossible to establish universal disease threshold but generally considered ~80%
Heteroplasmic mtDNA mutations cause mutations in respiratory chain when
Heteroplasmic mtDNA mutations only causes respiratory chain (OXPHOS)
dysfunction if present above certain minimal threshold level above 60%
What is EPI-743?
Orally bioavailable synthetic CoQ10 analogue, 1,000-10,000 X more potent antioxidant
How did EPI743 affect individuals with Leigh syndrome?
FDA Expanded Access open label 3 or 6 mo EPI-743 treatment slowed disease progression in kids 1-13 yrs old (x = 6.3) as assessed using various quality of life measurement instruments, taken orally 3 times a day
Where are we know with EPI-743 RESEARCH?
Have not had a case study since 2017 where in Japan they had a patient living after 4 years
what is Asexual healing: mtDNA replacement therapy
making a baby from 3 people, 3 sets of DNA
Purpose of replacement therapy?
Mito genome replacement therapy to prevent next generation transmission of mtDNA mutations
How does the replacement therapy work?
Transfer of nuclear genetic material from oocyte with mutant mtDNA to cytoplasm of donor enucleated oocyte with healthy mtDNA then Reconstructed oocyte fertilized & transplanted
Transmito rhesus monkeys using replacement therapy showed:
Transmito rhesus monkeys display normal growth and
minimal % mtDNA heteroplasmy
When was the first baby born used this technique?
2016: First baby born using “three parent” technique
Asymptomatic carrier of Leigh syndrome (~30% mtDNA mutation load), with four undiagnosed pregnancy losses and deaths of two offspring (~95% load) as result of disease: what did they do?
Spindle transfer from patient’s metaphase II oocyte (~95% mutation load) into cytoplasm of enucleated donor oocyte (arrows indicate spindle), with intent to have male child
What is a drawback with this technique? What did it cause in this case?
Might get some mito DNA still, Heteroplasmy level of maternal mito mutation in biopsied blastocyst = 6%; in son’s tissues
collected within 2 days of birth = ~2.5-9.5%
10 patients with various mtDNA defects following 14 weeks cycle endurance training, what did they see?
improvements in quality of life, peak VO2, & mito function, but mutation load
increased in 6 patients
So is endurance training effective for mito disease?
2 recent studies show similar training benefits, no rise in
mutations or muscle damage so yes Endurance training effective
and appears safe for MM (also resistance)
