Abali - Mitochondria

Question 1

Mitochondrial Transcription

Answer 1

polycistronic transcription (broken to mRNA, rRNA, tRNA)
-Requires RNApol, TFAM (transcription factor) and mtTF B1/B2

Question 2

Mitochondrial Translation

Answer 2

Differences: no 5’ untranslated, cap, polyA tail, only use 22 tRNAs. Relaxes codon-anticodon pairing, so third letter (UG”A”) is less relevant, allowing one tRNA to pair with 4 codons, need less tRNA.

• Initiation: IF1, IF3.
• Elongation: EFTu, G1
• Termination: mitochondrial release factor RF1A

Question 3

Mitochondrially-Produced Proteins

Answer 3

all involved in oxidative phosphorylation

• ND1-6
• Cyt b
• COX I-III
• A6 & A8

Question 4

Distinctive Features of mitochondrial genetics(6)

Answer 4

1) High mtDNA mutation rate (due to oxidative species proximity)
2) Maternal inheritance of mtDNA
3) Bottleneck effect
4) Random replicative segregation of mitochondria
5) Threshold effect
6) Changes with age

Question 5

Characteristics of Mitochondrial Disease Inheritance

Answer 5

• all offspring of mom are at risk, male = female
• affected male children won’t pass on defect, affected kids can be disease state or carrier depending how mitochondria are randomly segregated
• Threshold effect can cause reduced penetrance/expressivity, changes (for worse) over time

Question 6

Hallmark symptoms of mitochondrial diseases (2)

Answer 6

lactic acidosis, “ragged red fibers” (massive mitochondrial proliferation in muscle)

Question 7

Leigh Syndrome (LS)

Answer 7

NO RRFs

• progressive childhood mitochondrial encephalopathy (brain dysfunction). Death ~5 yrs.
• caused by mutations in EITHER mtDNA/normal DNA encoding energy metabolism. so mostly AR, some x-linked/maternal inheritance

Question 8

LHON - Leber Hereditary Optic Neuropathy

Answer 8

NO RFFs

• Causes painless progressive vision loss
• maternal inheritance, male prevalence. Caused by mtDNA mutations coding ETC complex I.
• Findings: loss of retinal ganglion cells in macula densa, degeneration of papillomacular bundle

Question 9

CPEO & Kss - Chronic Progressive External Opthalmoplegia and Kearns-sayre syndrome

Answer 9

YES RFFs (and spongy myelinopathy)
-Symptoms: opthalmoplegia (paralysis of eye muscles), weakness, ataxia, pigmentary retinopathy (degenerative loss of sight), loss of hearing, dementia, seizures.  Cardiac issues, GI impairment, diabetes, endocrine issues, SHORT STATURE, renal dysfunction

Question 10

MELAS - Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes

Answer 10

RFFs + cortical lesions, pseudolaminar necrosis, basal ganglia mineralization
-Symptoms: ENCEPHALOPATHY (seizures, dementia), recurrent stroke-like episodes in youth, myopathy, LACTIC ACIDOSIS. Ataxia, deafness, pigmentary retinopathy & short stature sometimes.

Question 11

MERRF - Myoclonic Epilepsy with Ragged Red Fibers

Answer 11

RFFs + system degeneration of cerebellar, brainstem and spinal cord tracts/nuclei
-Symptoms: myoclonus (involuntary twitching), epilepsy, ataxia, dementia

Question 12

Mitochondrial Replication

Answer 12

D-Loop: site of replication initiation, heavy strand transcription promoters
Nuclear-source 3 part replisome: DNApolgamma, p55, p40. Does DNApol and exonuclease/proofreading activity, lyase.
MtSSB: mitochondrial SSB stabilizes open strand during replication
Twinkle: mtDNA helicase + primase
Finished product is packaged in nucleoids (1-2 mtDNA molecules)
Mitochondrial DNA repair