Mitochondrial Disorders Flashcards
Where does oxidative phosphorylation occur?
Matrix
Where is the ETC and where are protons being pumped
ETC is on the inner mitochondrial membrane
Protons are being pumped into the intermembrane space
Functions of the mitochondria
- Form ATP by oxidative phosphorylation
- Signaling center of cells
- Regulation of apoptosis
- Major source of reactive oxygen species
Most mitochondrial disorders are the result of mutations in ___ genomes
Nuclear genomes -> can be AD, AR, X-linked
(More genes in the nuclear genome support ETC than genes in mitochondrial genome)
Which is more efficient - aerobic or anaerobic respiration? Why does aerobic respiration need oxygen?
Aerobic respiration is more efficient (38ATP per glucose vs 2ATP)
Oxygen is the final electron acceptor of the ETC
Copies of mtDNA vs nuclear DNA
There are mutliple copies of mtDNA in each mitochondrion and multiple mitochondria per cell; whereas, there’s only one complete copy of nuclear DNA per cell
Which contains more noncoding DNA - mtDNA or nuclear DNA?
Nuclear DNA; it’s 93% noncoding DNA
structure of mtDNA
Double-stranded closed circle w limited mtDNA repair
Replicative segregation
Multiple copies of mtDNA in each mitochondrion replicate and sort randomly among newly synthesized mitochondria, which are in turn distributed randomly between daughter cells
–> a mother can have mild/no symptoms, but can produce egg cells with a lot of abnormal mitochondria (bottle neck)
Homoplasmy
A cell contains a pure population of normal mTDNA or a pure population of mtDNA
Heteroplasmy
Mixture of mutant and normal mtDNA within a cell
If Mom is homoplasmic for a mutation, then
all her children will inherit the mutation
Whereas, children of males carrying a mutation will never get it.
If Mom is heteroplasmic for point mutations and duplications, then
she will pass them on to all of her children, but the fraction of mutant mitochondria in the offspring will vary (due to random chance + ho wmany mutants the mom had) –> risk and severity of disease will vary
Heterplasmic ___ are generally not inherited
Deletions
Why is there a “spectrum o fidsease” among family members in which there is heteroplasmy for a mitochondrial mutation?
The fraction o fmutant mitochondria in different tissues for a heteroplasmic individual can vary tremendously
Pleiotropy
Pleiotropy: Disorders where multiple, unrelated organ systems are affected
Ex) One person has cardiac arrhythmia, but someone else with the same disorder in the same or a different pedigree has deafness.
Variable expressivity
Differing clinical features or phenotype among individuals with the same gene allele or genotype
When to consider mitochondrial disease, since it can affect any organ system with any symptom at any time with any form of inheritance
- Unexplained association of neuromuscular and non-neuromuscular symptoms
- Rapid progression
- Unrelated organs (brain, liver, muscle)
Diagnostic tools
No single diagnostic tool - Screening, gene sequencing, muscle biopsy
If there’s no lactic acidosis, may not be mitochondrial disease.
Two disorders associated with mutation to nuclear DNA
POLG-related disorders
Leigh syndrome
POLG-related disorders
POLG is the DNA polymerase for mtDNA replication, so when this is affected there’s a significant drop in mtDNA in affected tissues –> many overlapping phenotypes
- Mostly AR, but some are AD
- Hypotonia
- Failure to thrive
- Mental retardation
- Seizures
- Regression
- brain, liver, muscle
Leigh syndrome can be due to nuclear (80%) or mtDNA mutations (20%) - what is it?
Abnormal lesions in the basal ganglia and midline brainstem caused by mitochondrial deletions.
- Progressive neurological disease
- Psychomotor retardation
- Cerebellar ataxia
- Epilepsy
KSS, Pearson syndrome, and LEigh syndrome are all caused by
mitochondrial deletion
MERRF and MELAS are both __plasmic and caused by mutations in __ DNA
Heteroplasmic; caused by mutations in mtDNA
