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Genetics of cell growth and division > Jones 5-8 > Flashcards

Jones 5-8 Flashcards

1
Q

Mitochondrial morphology

A

Size and shape of mitochondria varies between cell types and with cell cycle stage
Double membrane
Folds of cristae – large surface area
Enlarged mitochondria are often associated with disease state

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2
Q

How do mitochondia exist?

A

as constantly-evolving networks within the cell cytoplasm rather than totally separate organelles
Continuous fusion and division

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3
Q

How are mitochondria dynamic organelles?

A

Balance of fusion and fission

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4
Q

Why are mitochondrial dynamics important?

A
  • Mitochondria can’t be made; they have to be inherited in cell divisions
  • Accommodating cell growth
  • ATP generation in oxygen poor regions of the cell e.g. move mitochondria to different areas of the cell
  • Redistribution of mitochondria with cell division
  • Genetic complementation – defects in one mitochondria are compensated for by others
  • Important for cell survival
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5
Q

What are the three central players of mitochondrial dynamics?

A

1) Mitofusins
2) OPA1 (M) /Mgm1 (Y)
3) Drp1 (M) /Dnm1 (Y)
GTP-hydrolyzing proteins (GTPases) that belong to the dynamin superfamily

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6
Q

What is the function of mitofusins?

A

MOM fusion

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7
Q

What is the function of OPA1/Mgm1?

A

MIM fusion

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8
Q

What is the function of Drp1/Dnm1?

A

division of outer and inner mitochondrial membranes

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9
Q

What is used in yeast to study mitochondria?

A

MitoTracker Red: Selectively localises to mitochondria; covalently attaches to membrane proteins
Mito-GFP: Expressed in only one parental strain; under control of Gal1/10 promoter

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10
Q

After cell fusion what happens to the two mitochondrial populations?

A

Almost complete fusion

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11
Q

What happens in Drosophila melanogaster sperm development?

A

Mitochondria undergo dramatic reorganisation – essential for fertility
Failure in mitochondrial fusion - infertility
fzo gene identified: encodes the founding member of the conserved mitofusin GTPase family
fzo required for mitofusion and fertilisation

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12
Q

What was conclded from the ts fzo mutants

A

mitochondrial fusion cannot occur without functional mitofusion
In mutants you get unopposed fission so get individual mitochondria and no networks

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13
Q

What happens if mitochondrial fusion is impaired in mammals?

A

Knockout mice lacking Mfn1 and/or Mfn2 (mammalian mitofusins) die due to placental defects; cells have fragmented mitochondria
Human neurodegenerative disorder Charcot-MarieTooth disease type 2A results from mutations in human mitofusin Mfn2

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14
Q

What does a mutation in mgm1 cause?

A

a decrease in fusion events on the MIM

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15
Q

What are the main steps of mitochondrial fusion?

A

1) Docking/tethering: Mitofusin dimers form
2) GTP hydrolysis: Outer membranes fuse
3) Tethering and fusion: Inner membranes fuse via Mgm1 (yeast), opa1 (mammalian)

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16
Q

What is another potential function of opa1?

A

maintenance of cristae structure

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17
Q

Why is mitochondrial fission important?

A

• Important for the remodelling and rearrangement of mitochondrial networks, as well as for enabling mitochondrial segregation during cell division

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18
Q

What is the phenotype of a dnm1 knockout?

A

large nets of mitochondria due to failed mitochondrial division

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19
Q

How do dnm1/drp1 proteins function?

A

Dnm1 (yeast)/Drp1 (mammals) protein physically associates with other copies of itself in curved structures on outer surface of mitochondria.
Curved Drp1/Dnm1 structures constrict and pinch off mitochondria using the energy from GTP hydrolysis

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20
Q

What are the main steps of mitochondrial fission?

A

1) Drp1 recruitment: Fis1 recruits Drp1 to membrane
2) Oligomerization: Multiple Drp1 molecules join together to form scission machine
3) Fission: GTP hydrolysis fuels membrane scission

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21
Q

How is fusion/fission regulated?

A

Balanced by mitofusin levels

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22
Q

How does regulation occur at many levels/ cellular contexts?

A
  • Protein stability
  • Protein cleavage
  • Protein conformation
  • Changes such as phosphorylation
  • Protein localization via association with binding partners
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23
Q

How do mitochondrial fission proteins function?

A

Phosphorylation
Ubiquitination
E.g. Drp1 activity controlled by phosphorylation at different sites
Through action of PKC/Cyclin B/PKA

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24
Q

How do mitochondrial fusion proteins function?

A

Proteolysis
Ubiquitination
E.g. ubiquitin-mediated degradation of Fzo1
E.g. proteolytic cleavage of inner membrane dynamins (Opa1/Mgm1)

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25
Q

What is mitophagy?

A

Mitochondrial autophagy

26
Q

What is the purpose of mitophagy?

A

Important for maintenance of healthy mitochondrial population
Response to changes in mitochondrial membrane potential

27
Q

How does mitophagy remove defective mitochondria?

A

1) damaged/defective mitochondria tagged with a specific kinase and ubiquitin ligase
2) mitochondrial fusion disabled
3) destruction by proteosome

28
Q

How is mtDNA organised?

A

Into nucleoids

nucleoids distributed throughout mitochondrial network

29
Q

What are nucleoids?

A

MtDNA packaged with proteins

1-10 mtDNA copies per nucleoid and 10-1000 nucleoids per cell

30
Q

What happens to nucleoids with decreased fission?

A

nucleoids cluster together and lose even distribution throughout network

31
Q

Where are nucleoids during fission?

A

nucleoids present at 80% of fission sites
63% of the time at both tips
37% of the time at one only

32
Q

Do nucleoids move to the fission sites or does the location of the nucleoids dictate where division occurs?

A

not clear

33
Q

What is the ERMES complex and what does it do?

A

ER-mitochondria encounter structure

complex associates with mitochondria fission sites. Present at 60% of division sites

34
Q

Why is mitochondrial fusion/fission important for mtDNA integrity?

A
  • MtDNA undergoes frequent mutations due to close proximity with the ROS generation site
  • Mitochondrial dynamics plays an important role in compensating for these mutations
  • Mammalian cells with defects in mitochondrial fusion or fission machinery have reduced mtDNA content and an increased rate of mtDNA mutation
35
Q

What is the Evidence for complementation?

A

Studied restoration of OXPHOS function through complementation in cybrids - Cybrids are cytoplasmic hybrids
OXPHOS capacity was measured in mammalian cells
• Mutants had a much lower level
• Cybrids gave an intermediate level
Deletion/repair of mutant mtDNAs?
Segregation of mutated mtDNAs and elimination by mitophagy?

36
Q

How does mitochondrial morphology change at G1/S phase transition?

A
  • needs increase in ATP levels to generate biomolecules

* To increase the efficiency of ATP synthesis, mitochondria fuse and elongate.

37
Q

How does mitochondrial morphology change during mitosis?

A

Mitochondrial fragmentation is needed to ensure distribution of mitochondria to daughter cells.

38
Q

What is essential for mitosis-related mitochondrial fission ?

A

Drp1

39
Q

How is Drp1 phosphorylated?

A

by the cdk1/cyclinB MPF complex at S585A

40
Q

How is mitochondria distributed during asymmetric cell division?

A
  • Mitochondria either move in a retrograde or anterograde fashion – move to either end
  • Proposed that fitter mitochondria are more motile and are moved to the bud cell tip – have to move further – get healthier mitochondria in bud cell
  • Sticking points. Site-specific anchorage retains mitochondria to certain locations.
  • Quality control. Which mitochondria end up in the bud? Mitochondria anchored in bud tip have fewer ROS
41
Q

What are the quality control mechanisms?

A
  • Mitochondrial fusion repairs low-functioning mitochondria by intra-organellar complementation
  • Molecular chaperones bind to and stabilize unfolded proteins
  • Proteases both within and outside the organelle degrade damaged mitochondrial proteins
  • Mitophagy and mitochondrial fusion and fission eliminate mitochondria that are beyond repair
42
Q

What are the mitophagy proteins?

A

PINK1

PARKIN

43
Q

What is PINK1?

A

PTEN-induced putative kinase protein 1 (serine threonine kinase)

44
Q

What is PARKIN?

A

E3 ubiquitin ligase

45
Q

How do PINK and PARKIN function in healthy mitochondria?

A

Functional membrane potential

PINK1 is imported and degraded

46
Q

How do PINK and PARKIN function in defective mitochondria?

A
  • Lack of membrane potential
  • PINK remains on surface and recruits PARKIN
  • Mitochondrial proteins ubiquitinated
  • Destruction by mitophagy
47
Q

What degenerates in Parkinson’s disease?

A

degeneration of the dopaminergic neurons in substantia niagra
leads to reduced Complex 1 activity in the substantia niagra

48
Q

What mutations have been linked to familial PD?

A

Pink1, Parkin and mtDNA (amongst others)

49
Q

Why do you seen mitochondrial dysfunction in PD?

A

result of defective mitophagy

50
Q

Yang et al., 2008

Parkinsons disease

A

Organism: drosophila and human cell lines
PINK1 plays a role in regulating dopaminergic physiology
PINK1 -> fis1 -> Drp
Pink1 in a positive regulator of mitochondrial fission

51
Q

How is Autosomal Dominant Optic Atrophy caused?

A

Affects mitochondrial encoded complex 1 subunits
Mutation in Opa1 (optic atrophy 1)
Associated with mtDNA depletion

52
Q

What are the symptoms of DOA?

A

o Opthalmoplegia
o Ataxia
o Deafness
o Resulting from decreased OXPHOS

53
Q

Ban et al., 2010

DOA

A

Organism: Mice and cell lines
OPA1 is essential for MIM fusion
OPA1 interaction with membrane:
stimulates higher order assembly
enhance GTP hydrolysis
cause membrane deformation into tubules
mutant OPA1 -> fragmented mitochondria -> fusion is prevented

54
Q

How is Charcot Marie tooth type 2A (CMT2A) caused?

A
  • Most common hereditary peripheral neuropathy
  • Most of the CMT2A cases involve Mfn2 mutations, mainly in the GTPase domain. Can be gain of function or loss of function
  • Defects in mitochondrial motility have also been linked to CMT2A
  • CMT2A patients have reduced OXPHOS which has been linked with increase in mtDNA deletion
55
Q

Chapman et al., 2013

CMT2A

A

Organism: zebrafish
MFN mutation causes fusion failure
leads to motor dysfunction phenotype
adult onset and progressive motor defects
altered motility associated with NMJ defects

56
Q

Huntingtons diease

Shirendeb et al., 2011

A 
Brain tissue samples
abnormal dynamics in HD
high levels of fission proteins
low levels of fusion proteins
CypD upregulated and increases with HD progression
increased expression of mtDNA encoded complexes in ETC
lower mitochondria function 
more oxidative damage
57
Q

Mutations in Htt cause?

A 
Mitochondrial imbalance
impairred axonal transport
decreased mitochondria function
damages neurons
colocalises with drp at MOM
58
Q

Neurodegenerative disease

seo et al., 2010

A

Neurons have a high metabolic demand
Alzhiemers - AB accumulation causes mitochondria dysfunction and aberant structures
AB induces fission

59
Q

Ageing

Seo et al., 2010

A 
direct link between mtDNA mutations and ageing
decline in Mt turnover
reduced mitochondrial bigenesis
inefficient mitochondrial degradation 
protective mechanisms are impaired
organelle plasticity decreases
lysosomal autophagy decreases
60
Q

How is degradation of a single mitochodria different to that of a mitochodrial network?

A

individual defective mitochondrial proteins are degraded by the proteasome
sections of mitochondria are removed by mitophagy

Genetics of cell growth and division (4 decks)

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