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Leary Flashcards

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1
Q

What are mitochondria

A

cellular organelle
Double membrane bound
Contain mitochondrial DNA which is maternally inherited

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2
Q

Inner vs outer mitochondrial membrane

A

Inner mitochondrial membrane is protein loaded, contains the ETC, and is impermeable which is needed for the proton gradient

Outer mitochondrial membrane is permeable with many holes, doesn’t have many proteins

These properties are relevant to how the organelle functions as a whole and contributes to cellular homeostasis

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3
Q

Where is the mtDNA, Krebs cycle, and metals

A

matrix of mitochondria

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4
Q

What are cristae? Which enzymes are concentrated there?

A

Inner folds of the mitochondrial membrane
Used to increase surface are to put more proteins and enzyme to produce more ATP

Enzymes of oxidative phosphorylation are concentrated within the cristae

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5
Q

T/F the function of the inner membrane is different depending on where it is

A

true

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6
Q

What are the reducing equivalents used in the ETC

A

NADH feeds into complex I and FADH2 feeds into complex II

These are needed for the ETC to function

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7
Q

Why might one tissue have more cristae than another

A

The inner membrane architecture is optimized for the tissue it functions in

Tissues that need more ATP will have more cristae

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8
Q

T/F mitochondria are static

A

False its a dynamic reticulum that responds to intracellular cues and extracellular stimuli

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9
Q

What are some cues that can cause the mitochondria to hyperfuse to become one organelle

A

Starvation
Translation inhibition
Viral infection
Conditions when differentiation is important

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10
Q

When would the mitochondria hyperfragment?

A

Cancer, bacteria, OXPHOS poisons
Conditions when cell division is important

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11
Q

What enzymes drive Fusion

A

MFN1 and MFN2

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12
Q

L-OPA1 vs S-OPA2

A

L-OPA1 is required for fission
S-OPA1 is required for fusion

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13
Q

Why are mitochondrial dynamics important

A

Adapting organelle function to a broad range of cues
Failure to appropriately balance fission and fusion will impair organelle function and cellular homeostasis

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14
Q

What are some basic challenges of mitochondrial content

A

They have a large proteome and require many proteins to function
They have their own genome which encodes crucial polypeptides
They have to coordinate expression of nuclear and mtDNA-encoded protein products (crucial to maintaining or expanding existing populations of organelles)

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15
Q

Describe the number of organelles and mitochondrial volume across tissues

A

Number varies between 1 and 1000
Fold difference ranges from 2-40%

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16
Q

how is the balance of mitochondria maintained

A

maintained between rates of biogenesis and degradation

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17
Q

What is mitophagy

A

Self-eating process in mitochondria, way to degrade mitochondria

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18
Q

Mitochondria alter their _____ and ____ to fulfill diverse functions

A

shape and number

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19
Q

why are fission and fusion important

A

Allows mitochondria to respond to internal and external cues and adapt to their environments ot fulfill the necessary conditions to survive

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20
Q

What are the 6 essential processes for maintaining homeostasis that the mitochondria plays a role in

A

ATP production
Epigenetics
Peroxisome biogenesis
Fe-S cluster synthesis
Apoptosis & cell cycle control
Regulation of cellular metal ion homeostasis

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21
Q

How does cytochrome C initiate apoptosis

A

Cytochrome C is tethered to the inner membrane under normal circumstances but when the inner membrane is compromised cytochrome C can be released and initiate apoptosis

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22
Q

Which processes do cytochrome c oxidase assembly affect?

A

ATP production and regulation of cellular metal ion homeostasis

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23
Q

How many subunits are encoded in nuclear and mtDNA of the mitochondria

A

4 complexes responsible for making the ETC and fifth for creating ATP

only complex 2 is completely from nuclear DNA and the other complexes are a mix of mtDNA and nuclear

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24
Q

What are some basic characteristics of mtDNA

A

16.6kb double stranded, circular genome
genome was compacted because it is more efficient
Present in multiple copies per organelle
Maternally inherited
In the matrix in order to protect it
Encodes 13 proteins
Lacks introns

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25
Where is the mtDNA bottleneck during oogenesis
QC step
26
Can mitochondrial diseases be heterogenic
no, will only be a carrier
27
T/F mitochondrial diseases are extraordinarily homeogeneic
false heterogeneic
28
Is OXPHOS complex biogenesis different from the nucleus
fundamentally yes
29
What is cytochrome c oxidase
protein in complex 4 of ETC used as a model protein
30
Cytochrome C oxidase structure
14 structural subunits 3 mtDNA-encoded 11 nuclear-encoded
31
Why use a cytochrome C oxidase as a model protein
Consists of nuclear and mtDNA encoded subunits Rate-limiting to ATP production under a range of physiological conditions Commonly observed metabolic lesion Most thoroughly characterized from a genetic, biochemical and molecular biological perspective
32
Why are nuclear subunits important?
They are important for stability, affect rates of activity, and alter the structure of the enzyme
33
What are 2 important prosthetic group for cytochrome c oxidase
COX1 and COX2
34
Describe the assembly of cytochrome c oxidase
Assembly is highly ordered and modulated in nature 4 stages
35
How do mutations in mtDNA occur
spontaneously or inherited
36
What is the threshold effect
tissues accumulate mutant mtDNA and once they reach a threshold it starts to have an effect Explains later onset of disease manifestation
37
What were the barriers or challenges with respect to diagnosing the genetic basis of these diseases?
Lack of adequately diverse and sensitive diagnostic tools incomplete or absent sequence coverage of relevant regions of the human genome lack of an adequate model system to study human disease Heterogeneity
38
What is the genetic explanation for early onset disease?
The assembly of the cytochrome C oxidases uses a toolbox of many different factors which are essential to the assembly Mutations to these factors could explain the early onset of the disease
39
mtDNA vs nuclear DNA
40
SCO1 vs COX
SCO1 is the yeast version of COX10 COX10 could rescue yeast SCO1 null cells but the yeast SCO1 could not rescue COX10
41
What might be some reasons for not being able to use yeast to study a humane mitochondrial disease gene?
Can't interact with the correct proteins and proteins usually work in tandem
42
What was the visualization technique that revolutionized mitochondrial disease work
blue-native PAGE
43
How were SCO1 and SCO2 first identified
Was identified through the yeast PET mutant collection. Mutations in functional yeasts were related to a single enzyme or biosynthetic pathways which helped characterize different defects They were identified as high copy suppressors of a yeast COX 17 mutant
44
What do mutations in human SCO result in
severe early onset disease with a fatal outcome
45
What are the simples ways to rescue disease caused by mutations in a given gene like SCO1 or SCO2? Problems?
Genome editing: Ethical dilemmas Re-introduce the wild-type protein into the system: Not feasible for short-lived protein, costly, systemic delivery Treating with copper: Was able to rescue COX deficiency in SCO2 patient cells, can rescue heart but not brain function
46
Why can copper treatment rescue SCO2 null cells but not SCO1 null cells
Coppers need to insert into the protein and it was shown that SCO1 acted as the insertase
47
How can ubiquitously expressed mutations be heterogeneic
Tissue specific: Difference in half-life Abundance of a given COX assembly factor abundance of metals Unique effects on protein
48
What were historic challenges in mitochondrial disease diagnosis
Clinical heterogeneity Limited diagnostic toolbox (old tools) Lack of reference genome sequence (reliance on large pedigrees) Reliance on a single model organism (inadequate models)
49
What are on-going challenges with mitochondrial disease diagnosis
clinical heterogeneity Multiple model organisms available We have the human genome sequence now, however if the mutation is in the intron that may affect splicing and we do not have intron sequences
50
What is a mitochondrial disease treatment that is currently in phase 2 trials and could be a viable strategy? how does it function? Barrier?
Mitochondrially targeted nucleases Promotes degradation of mutant mtDNA The nuclease recognizes the mutation and cuts the DNA Need to be put in via a viral delivery system which may not work for isolated organs, nuclease is very large
51
Could supplementation be used to treat mitochondrial disease
Protein supplement is difficult due to half-life issues and SCO2 lives in a membrane Vitamin supplementation has minimum benefit Thin air does not work because it results in hypoxia
52
What is the effect of thin air supplementation
Rescues the mitochondrial DNA, but hypoxia results in cancer and death
53
Can copper supplementation be used to overcome genetic defects that impede copper site biogenesis
When copper is unbound it can produce many free radicals and cause damage Can rescue heart defects but not brain The copper needs something protein to cross the BBB
54
What are some tissue-specific challenges associated with COX deficiency
Differences in half-life of the holoenzyme Differences in abundance of a given COX assembly factor Differences in abundance of metals essential for assembly
55
How can unique allelic variants in a single COX assembly factor give rise to distinct, tissue-specific forms of disease?
Unique effect on the residual function of a protein Unique effects on the residual functions of a protein
56
What is cardiolipin
Cardiolipin is a unique protein to the inner mitochondrial membrane Cardiolipin curves the membrane to promote cristae formation Allows for mitophagy among other functions
57
What is the rate-limiting enzyme for cardiolipin biosynthesis
Tafazzin It is essential in the final step of cardiolipin biosynthesis
58
What is Barth syndrome
Results from mutations in TAZ, the gene encoding Tafazzin
59
When does the mitochondria fragment or fuse
Fragment to go into a resting state and remove damaged organelles Fuse for the complementation of gene products and requires the cooperation of the entire compartment, in response to stress and starvation
60
What happens when the quality control machinery cannot maintain proteostasis?
Protein folding will be impaired, when there is membrane potential damage, proteases cannot help resulting in no proton motor force and autophagy
61
What is the quality control mechanism for mito
Contains many proteases in every subcompartment Processing peptidases and ATP-dependent proteases sense folding stated and ensure quality control
62
Why is autophagy important
Important for garbage disposal It is important for adaptive responses as it provides nutrients and adapts to stress conditions
63
Where is quality control machinery concentrated? What 2 things does it fuse together)
Concentrated around the phagophore Fuses autophagosome and lysosome
64
Micro & macroautophagy share a common set of essential ____ proteins
ATG (autophagy) proteins which are critical for induction of the process and autophagosome formation
65
# 5 things What are the broad stages of autophagy
Phagophore biogenesis Autophagosome formation Autophagosome maturation (fusion with lysosome) Breakdown of cargo Recycling Specific types of autophagy requires unique elements
66
Functions of PINK1 and PARKIN? What do mutations in these cause?
PINK1 recruits PARKIN to the damaged mitochondria PARKIN poly ubiquitinates VDAC1 P62 then binds poly Ub-VDAC1 This facilitates the interaction of the organelle with core autophagic machinery Results in parkinsons disease
67
Inability to clear defective mitochondria from neuronal cells contributes to the clinical progression of _________ __________
Parkinsons disease Damages neurons

BMIS 435 (17 decks)

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