Mitochondrial Disorders Flashcards by Josh Klonoski

The mitochondrial genome is _________ bp

16,571 bp

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The mitochondrial genome is 16,571 bp, __________and does/does? not contain introns?

Circular
Does not contain introns

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The mitochondrial genome contains ______ proteins and _______ tRNAs and ______rRNAs

13 proteins
22 tRNAs
2 rRNAs

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The mitochondrion utilizes over _______ gene products to function with more than _______ in the respiratory chain alone

1500 gene products (963 nuclear encoded)
90 (102 nuclear genes) in the respiratory chain

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The main function of mitochondria is ________ ____________?

oxidative phosphorylation
oxidizing O2 to H2O
Substrate level phosphorylation of ADP

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Each glucose molecular can produce ________ ATP (largely respiratory oxidation) and _______ GTP (Krebs cycle).

38 (32 in ETC)
2 GTP

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Mitochondria are involved in metabolism and energy production as well as ___________ modulation/homeostasis, ________ stress, ______ signaling and ________

calcium modulation
oxidative stress
cell signaling (ROS)
apoptosis

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Complex ______ is completely encoded by nuclear DNA

Complex II (SDH)

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Complex ________ contains COX 10, 14, 15, 20 and SURF1

Complex IV

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The mitochondrial genome is one piece and ______________

polycistronic

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Does the mitochondrial genome have recombination?

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Mitochondrial DNA replication is ____________

Continuous
(irregardless of cell cycle)

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The main mitochondrial DNA polymerase is encoded by the __________ (nuclear/mitochondrial) __________ gene

nuclear
POLG1
(POLG2 minor role/accessory subunit)

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The mitochondrial _________ and ________ RNAs are unique and encoded by mtDNA

ribosomal
transfer

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Mitochondrial codon usage is unique or the same?

Unique

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Does mtDNA contain histones?

No histones

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The mutation rate of mtDNA is ______ to _____ times higher than nDNA

6-10x higher

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On average, each mitochondria has an average of _______ copies of mtDNA and each cell has _______ mitochondria

2.6 copies
750 mitochondria/cell (about 1500 copies per cell)

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Mitochondrial ____________ may determine whether the mutation or wildtype phenotype is expressed

heteroplasmy
(vs homoplasmy)

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The key determinants of mitochondrial disease include _______ inheritance, mitotic ______ segregation, ______-_______ replication, ______plasmy and the _______effect

Maternal
passive/independent (segregation)
post-mitotic (replication)
heteroplasmy
threshold (effect)

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Oocytes contain ___________ copies of mtDNA while after fertilization each cell contains ~ ____________ copies of mtDNA at the 8 cell stage

500,000
~50,000

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The typical threshold is generalized as ________ but may be as high as 100% (homoplasmy)

70%

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Maternal mitochondrial inheritance is ensured by ________ ________ _______

paternal mitochondrial elimination (PME)
*delay usually causes embryonic lethality

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____% of mitochondrial disease is sporadic

75%

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Overall prediction of recurrence risk, in the absence of a detected maternal mutation is _______ to _______%

10-15%

The carrier frequency of deleterious mitochondrial mutations is 1 in _______?

1 in 200

The prevalence of deleterious mitochondrial mutations across all ages is 1 in ____________

4300

Mitochondrial biochemical tests are unreliable but include ______, _______ and ________

Lactate GDF15 FGF21 Alanine ----------- methylmalonic acid (SUCLA) -myopathic 3 methylglutaconic acid (non-specific)

Leigh's disease involves which ox phos complexes?

I, II, III and IV

Neuropathy, ataxia, retinitis pigmentosa syndrome (NARP) involves complex _______ of ox phos

V (ATPase 6)

The ________ genes are part of complex ______ and involved in pheochromocytomas and paragangliomas

SDH (A-D) Complex II

The _______ genes and complex ______ are involved in LHON, MELAS, Leigh's syndrome and leukodystrophy

ND (NADH) 1,2,3,4 and 6 NDUFS (NADH:ubiquinone oxidoreductase) 1,2,4,7,8 Complex I

LHON, MERRF, MELAS, Leigh's disease and NARP are all caused by _______ mutations

point

___________ and _________ syndromes are caused by mtDNA deletion/duplication

Pearson Kearns-Sayre

POLG1, DGUOK, MPV17 and TK2 are caused by ______ _______ syndromes

mitochondrial depletion syndromes

Biopsies or samples collected for mitochondrial disease testing (3-4)?

Leukocytes Fibroblasts Muscle/nerve Liver

Currently ______ _____ ______ is the preferred testing to rule out a mitochondrial disease

whole genome sequencing (WGS)

4 vitamin treatments with generally good treatment response in specific mitochondrial diseases?

1. Riboflavin (sensorineural hearing loss - SLC42A2, SLC52A3) 2. Thiamine (biotin-thiamine BG disease- SLC19A3, TPK1, PDHA1) 3. Biotin (BTD, HLCS) 4. Riboflavin (ACAD9, multiple acyl-coA dehydrogenase deficiency (ETFA,ETFB, ETFDH, SLC25A32, FLAD I) 5. Coenzyme Q ( PDSS1, PDSS2, COQ2, COQ4, COQ6, COQ7, ADCK3, ADCK4, COQ9) *cyclic panopterin (molybdenum cofactor deficiency MOCS2, MOCS2, GPHN)

________ is the most common nDNA gene while _______ is the most common mtDNA gene involved in Leigh's syndrome

SURF1 (complex IV) ATP6 (also in NARP) - complex V **also PDH, Complex I genes

Disease characterized by basal ganglia and brainstem lesions with respiratory insufficiency and severe hypotonia with classic onset 3-24 mo

Leigh's disease

Mitochondrial tRNA is ______ by nuclear genes

charged YARS2, DARS2, LARS2, CARS2 etc.

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is caused by _____ mutations

tRNA-Leu A3243G -80% ** also in CPEO and MIDD *also T3217C (7.5%) and A3252G(<5%)

The _______ mutation in tRNA-Leu can cause MELAS, CPEO and MIDD

A3243G (DHU loop of tRNA)

MELAS can be treated with oral/IV _______, citrulline or taurine (NO regeneration)

arginine

Myoclonic epilepsy and ragged-red fibers with cardiac arrhythmias and lipomas is caused (80-90%) by mtDNA _________ mutations

tRNA-Lys G8344A

The _________ mutation in tRNA-Lys can cause MERRF and Madelung lipomatosis (brown fat)

G8344A (80-90%) (TpsiC loop of tRNA)

Leber hereditary optic neuropathy (LHON) causes painless central vision loss at 12-30 years with worse phenotype in males and is caused by a complex _______ deficiency

Complex I (ND4 G1178A) - homoplasmic 50-70%

LHON is caused by complex I deficiency and most commonly the gene _______ G1178A mutation

ND4 NADH-ubiquinone oxidoreductase chain 4 protein

LHON is caused by complex I deficiency and most commonly the ________ mutation in ND4 (NADH-ubiquinone oxidoreductase chain 4 protein)

G1178A

Neurodegeneration, ataxia and retinitis pigmentosa is caused by mutations in the mitochondrial ___________ gene and T8993C>G

ATPase6

NARP is most commonly caused by the T8993C>G mutation in the mitochondrial ATP6 gene and complex _______

Complex V

NARP is most commonly caused by the _________ mutation in the mitochondrial ATP6 gene and complex V

T8993C>G

________ __________ is usually fatal and consists of sideroblastic anemia, pancreatic insufficiency, lactic acidosis and myopathy

Pearson syndrome

_______ ________ consists of retinitis pigmentosis, ptosis (unilateral) and one of the following (cardiac conduction block, CSF protein >100 or cerebellar ataxia)

Kearns-Sayre syndrome

Pearson and Kearns-Sayre syndromes are caused by large _____ to _______ kb deletions of mtDNA

1 to 10 kb deletions

Most common mitochondrial depletion syndrome

POLG1 deficiency syndrome (AR/AD CPEO, AR Alpers Huttenlocher syndrome AHS)

Myopathic mitochondrial depletion syndrome

TK2 - thymidine kinase 2

4 genes of mitochondrial depletion syndromes with hepatocerebral predominant phenotypes

1. POLG1 2. MPV17 (originally Navajo) - mitochondrial inner membrane protein 3. DGUOK (deoxyguanosine kinase) 4. C10orf2 (Twinkle) - helicase

_______ may cause liver dysfunction in AR POLG1 (AHS)

Valproate

__________ and _________ genes are mitochondrial depletion syndromes with early progressive liver disease

DGUOK and MPV17 deoxyguanosine kinase and mitochondrial inner membrane protein

_________ is a mitochondrial depletion syndrome caused by mutations of TYMP

MNGIE

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a mitochondrial depletion syndrome caused by mutations of _______

TYMP thymidine phosphorylase

6 genes of mitochondrial depletion syndromes

1. POLG1 2. MPV17 (originally Navajo) - mitochondrial inner membrane protein 3. DGUOK (deoxyguanosine kinase) 4. C10orf2 (Twinkle) - helicase 5. TYMP 6. RRM2B

Mutations in _______ cause hypotonia, severe encephalopathy, tubulopathy and can be associated with MNGIE

RRM2B ribonucleotide-diphosphate reductase subunit M2 B)

The mitochondrial tRNA for _________ is involved in MERRF while the mitochondrial tRNA for __________ is involved in MELAS

tRNA-Lys MERRF and Madelung tRNA-Leu MELAS, CPEO and MIDD