Mito Flashcards
Roles of Mitochondria
- Energy production
- Calcium homeostasis
- Apoptosis
- Radical species generation
- Radical species scavenging
- Steroid biosynthesis
- Orchestrate Metabolism
Complex _ is comprised of only nuclear subunits
II
Jobs of nuclear genes in mitochondria:
- Structural subunits of enzyme complexes
- Cofactors
- Assembly factors
- Translation factors
- Mitochondrial DNA maintenance
- Fission/fusion
mtDNA
- Mitochondrial genome has 16,569 base pairs
- Double-stranded
mtDNA contains 37 genes: •13 polypeptides • Complex I: 7/45 subunits • Complex II: 0/4 subunits • Complex III: 1/11 subunits • Complex IV: 3/13 subunits • Complex V: 2/12-13 subunits
- 22 tRNAs
- 2 rRNAs (12S and 16S )
Key features of mtDNA genome
- No introns
- No homologous recombination or meiosis
- Replication is continuous, not synchronized with cell cycle
- Relative to nDNA, mtDNA has a high mutation rate
- mtDNA exists in a “nucleoid” but has no histones
• Disease-causing mtDNA mutations occur in tissue-specific fashion
- Point mutations (single or few nucleotide basepairs)
- Deletions or duplications (common 5 kilobase deletion)
- Depletion or proliferation (mtDNA genome copy number change)
Threshold effect
• Specific heteroplasmy load for a specific mtDNA mutation that any given tissue
tolerates before it shows signs of pathology
Heteroplasmy vs. homoplasmy
• Homoplasmic wild-type: only (100%) wild-type mtDNA is present
• Homoplasmic mutant: only (100%) mutant mtDNA is present
• Heteroplasmy: 2 different populations of mtDNA are present in a given cell or
tissue (e.g. wild-type and mutant)
RR with maternal inheritance pattern to full siblings
1-4% if no symptoms in
mother;
up to 50% if symptomatic
mother (EMPIRIC RISK)
Manifestations of mito disease
optic neuropathy, rentinopathy and external ophthalmoplegia, deafness, stroke, ataxia, epilepsy, encephalopathy and migraines, cardiomyopathy and conduction defects, diabetes, renal failure, anemia, liver failure, intestinal pseudoobstruction and diarrhea, peripheral neuropathy, muscle weakness, exercise intolerance, cramps, atrophy, and hypotonia
NARP
Neurogenic Ataxia and Retinitis Pigmentosa
LHON
Leber Hereditary Optic Neuropathy
MERFF
Myoclonic epilepsy with Ragged Red Fibers
MELAS
Mitochondrial Encephalomyopathy, lactic acidosis, and strokes
Low percentage heteroplasmy of MELAS (<30%)
Diabetes Mellitus
Pancytopenia, symptoms improved with blood transfusion, follow up labs revealed persistent pancytopenia. Bone marrow aspiration revealed sideroblastic anemia
Pearson Syndrome
Acute encephalopathy, SNHL, bilateral ptosis, regular classes with 1:1 and modified assignments, autism
Kearn Sayre Syndrome (KSS)
Anemia, exocrine pancreas dysfunction, fatal in infancy, deletion detecte din blood
Pearson syndrome
Retinitis pigmentosa, PEO, cardiac conduction block , increased CSF protein, cerebellar ataxia, short stature, HL, demetia, diabetes, limb weakness, hypoparathyroidism, growth hormone difficiency. Deletion detected in CNS and muscle. Childhood - young adulthood onset.
Kearns-Sayre Syndrome (KSS)
Ptosis, opthalmoplegia (lose ability to move eyes laterally). Deletion detected in muscle. Young adulthood to late adulthood onset.
Progressive External Ophthalmoplegia (PEO)
MtDNA deletion disorders
large mtDNA genome deletions (1.1 to 10 kb).
Usually de novo.
POLG disorders
- Alpers-Huttenlocher syndrome (AHS)
- Childhood myocerebrohepatopathy spectrum (MCHS)
- Myoclonic epilepsy myopathy sensory ataxia (MEMSA)
- Ataxia neuropathy spectrum (ANS)
• Progressive external ophthalmoplegia (autosomal recessive or autosomal
dominant)
Childhood-onset progressive and severe
encephalopathy with intractable epilepsy and liver failure
Alpers-Huttenlocher syndrome (AHS)
Infantile or childhood
onset developmental delay or dementia, lactic acidosis, myopathy, failure to thrive,
liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss
Childhood myocerebrohepatopathy spectrum (MCHS)
Epilepsy, myopathy,
and ataxia without ophthalmoplegia
Myoclonic epilepsy myopathy sensory ataxia (MEMSA)
Ataxia, sensory ataxia neuropathy
dysarthria, seizures and ophthalmoplegia
Ataxia neuropathy spectrum (ANS)
Progressive weakness of the extraocular eye muscles resulting in
ptosis and ophthalmoplegia , with or without generalized myopathy, variable
degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression,
Parkinsonism, hypogonadism, and cataracts
Progressive external ophthalmoplegia (autosomal recessive or autosomal
dominant)
The ONLY polymerase for the mtDNA genome
Polymerase-γ (gamma) - POLG
• 3 functional regions of POLG:
- Exonuclease: proofreading
- PEO and mtDNA deletions/point mutations
- Linker: linker between polymerase and exonuclease region
- Ataxia and mtDNA deletions
- Polymerase: replication
- Alpers syndrome and mtDNA depletion
- Seizure, dementia, regression, cortical blindness, liver disease
Diseases with immediate onset after birth (congenital lactic acidosis) are most
likely caused by
autosomal recessive nDNA mutations
Diseases with later (adult) onset are more often due to
mtDNA mutations
A majority of mitochondrial disease is caused by
autosomal recessive inheritance
The only proven therapy for mito disease
Exercise
Four principles of maternal inheritance
1) Asexual, inherited from mothers only
2) Heteroplasy, co-existence of 2+ types of mtDNA in cell, tissue, or organism (mutation and tissue dependent)
3) Bottleneck: heteroplasmy can vary drastically among siblings and is unstable
4) Threshold, heteroplasmy can be tolerated to a certain limit in cells; lower threshold in tissues with high energy demands
