5: epigenetics in mitochondrial diseases

Question 1

What are some metabolic disorders associated with differential mtDNA methylation?

Answer 1

insulin resistance, obesity, non alcoholic steatohepatitis (NASH)

Question 2

what changes to the mtDNA is found in obese and insulin resistant patients?

Answer 2

hypermethylation of D-loop region -> reduction in mtDNA copy number -> reduced mt gene expression, components of oxphos complexes -> mitochondrial dysfunction

Question 3

what changes to the mtDNA is found in nonalcoholic steatohepatitis (NASH) patients?

Answer 3

mitochondrial NADH dehydrogenase 6 (MT-ND6) is highly methylated in the liver of nonalcoholic steatohepatitis patients

• MT-ND6 is an essential component of complex I, critical for its proper assembly
  decrease in MT-ND6 -> mt physiology and key mt functions affected -> can lead to NASH

Question 4

what are some neurodegenerative diseases associated with differential mtDNA methylation?

Answer 4

down syndrome
alzheimer’s disease
parkinson’s disease

Question 5

what are the changes in a down syndrome patient?

Answer 5

a decreased S-adenosylmethionine (SAM) availability -> hypomethylation -> decreased glutathione (antioxidant) -> DNA damage increases

Question 6

what happens in a patient with alzheimer’s disease?

Answer 6

accumulation of tau neurofibrillary tangles and amyloid beta plaques -> mitochondria unable to debride plaques -> neuronal cell death -> brain shrinks

Question 7

what changes to the mtDNA is found in alzheimer’s disease?

Answer 7

• increased DNA methylation in D-loop
• reduced MT-ND1 gene
  (early-stage AD-related pathology)
  level of mt 5hmC unchanged in D-loop, MT-ND1 and MT-ND6
• hypermethylation of mt tRNA -> decrease in tRNA production -> not enough mtDNA encoded (eg subunits) -> dysfunctional -> retrograde signalling to nuclear encoded genes -> alter nuclear gene expression -> neuronal degeneration (also in supranuclear palsy)

Question 8

what changes to the mtDNA is found in parkinson’s disease?

Answer 8

• reduced DNA methylation in D-loop
• MT-ND6 remains unchanged
  (in the substantia nigra)
• level of 5hmC unchanged in D-loop, MT-ND1 and MT-ND6

Question 9

what are some cancers associated with differential mtDNA methylation?

Answer 9

colorectal tumour

Question 10

what changes to the mtDNA are found in colorectal cancer?

Answer 10

decreased methylation (demethylation) in D-loop -> increase mtDNA copy number -> increased expression of ND2 (a subunit of complex I)
percentage of D-loop methylation decreases from stage I until 0% in stage IV

Question 11

what can an increase in mtDNA copy number lead to?

Answer 11

increased cell proliferation, prevents apoptosis

Question 12

what are some CVDs associated with differential mtDNA methylation?

Answer 12

pulmonary hypertension

Question 13

what changes to the mtDNA are found in cardiovascular diseases?

Answer 13

platelet mtDNA methylation
increased methylation of complex IV subunits (MT-CO1-3, tRNA leucine 1 gene (MT-TL1))

Question 14

what are some changes to the mtDNA in pulmonary hypertension?

Answer 14

overexpression of DNMT1 and DNMT3B -> SOD2 (superoxide dismutase 2) promoter hypermethylated -> SOD2 expression downregulated -> impaired H2O2-mediated redox signalling (cannot protect mt proteins and DNA from oxidative stress) -> activates (HIF)-1a -> proliferative, apoptosis-resistant state

Question 15

what are some changes to the mtDNA in aging?

Answer 15

• increased DNA methylation (at promoter and COX7A1 gene) -> downregulation of COX7A1 -> decrease in oxidative capacity, decrease in mt function
  (COX7A1 is a respiratory chain component
• increased methylation of MT-RNR1 -> decreased rRNA -> decreased translation of mt proteins -> decreased complex subunits -> defects in ETC activity, ATP production
• high (>10%) methylation levels in ppl older than 85, only in women -> mortality risk

Question 16

what does mt stress induce?

Answer 16

ATFS-1 (TF of UPRmt) is induced, accumulates in nucleus -> UPRmt upregulated -> nucleus becomes small and compacted, lifespan extends
in normal condition, ATFS-1 translocates into the mt and is degraded
both conditions have normal H3K9me2 levels