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Molecular Cell Biology > Lecture III > Flashcards

Lecture III Flashcards

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1
Q

What are the 2 classes of dynamin GTPases?

A

mitofusins (MFN1 & MFN2) for the fusion of the OMM

OPA1 for the fusion of the IMM

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2
Q

What can be observed in mitochondria if MFN1 is genetically removed?

A

the mitochondrial network becomes highly fragmented

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3
Q

What is the main player between MFN1 & MFN2?

A

MFN1

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4
Q

What are heptad repeats (HR)?

A

found in MFN1 and MFN2, and they are helical structures important in trans interactions between MFN1 proteins localized in nighboring mitochondria

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5
Q

What kind of proteins are MFN1 & MFN2?

A

transmembrane proteins

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6
Q

Describe OPA 1:

!!!

A

GTPase protein that undergoes a finely regulated process of transcriptional regulation and post-translational regulation

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7
Q

How many splicing variants of OPA1 are there for humans? for mice?

A

8

4

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8
Q

What do the OPA1 splicing variants depend on?

A

inclusion or exclusion of specific exons that determine the cleavage site doe post0translational processing

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9
Q

Where are OPA1 proteins imported?

A

into the mitochondria and inserted into the IMM

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10
Q

What do the upper bands of this western blot on HeLa cells lysate represent? lower bands?

A

long forms of OPA1 (L-OPA1)

isoforms generated upon cleavage

**this is a healthy cell

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11
Q

What mediates the fusion of mitochondria?

A

L-OPA1

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12
Q

What are OMA1 and YME1L? What do they do?

A

transmembrane proteins that protrude the intermembrane space

cleave OPA1 and give soluble short forms that accumulate in the IM space

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13
Q

In cases of stress, describe what happens with OMA1:

A

OMA1 is over-activated and it over-processes OPA1 so there are no more L-OPA1

*eventually OMA1 is degraded upon cleavage of OPA1 since its activity would result in a danger for the cell

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14
Q

How can OPA1 mediated the fusion of the IMM?

A

L-OPA1 mediates the fusion of the IMM through heterotypic cell interactions with cardiolipin (only found in IMM) of the neighboring mitochondrion

*through protein lipid interactions

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15
Q

MFN mediates the fusion of…

A

OMM

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16
Q

L-OPA1 mediates the fusion of…

A

IMM

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17
Q

S-OPA1 mediates the fusion of…

A

not defined

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18
Q

What can L-OPA1 do at the base of cristae?

A

oligomerize and generate tight junctions at the base of the cristae when combined with a lot of proteins as MICOS complex and cardiolipin

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19
Q

Why is cristae formation important?

A

necessary for oxidative phosphorylation

confinement of the cytochrome c

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20
Q

What are the 3 models that describe the organization of the respiratory chain?

A

fluid model

solid model

plasticity model

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21
Q

What is the fluid model of the respiratory chain?

A

complexes are randomly distributed and they float around the membrane

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22
Q

What is the solid model of the respiratory chain?

A

all complexes are closely packed

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23
Q

What is the plasticity model of the respiratory chain?

A

combination of the fluid model and the solid model

it is the most accepted and confirmed by the isolation of complexes with a protocol of Blue native PAGE›

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24
Q

Are respiratory chain complexes organized?

A

yes, they are organized in an optimal arrangement in order to maximize electron flux and ATP production

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25
Q

What do mutations on the proteins of that maintain cristae shape result in?

A

widening of the cristae structure, with a consequential loss of ATP synthesis and release of cytochrome c

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26
Q

What mediates mitochondrial fission?

A

Drp1

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27
Q

What do patients with a mutation in Drp1 have?

A

encephalopathies and motor behaviors

*most die before 10 years of age

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28
Q

What is Drp1?

A

cytosolic protein that is recruited to OMM upon fission or physiological stimulus

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29
Q

What receptors does Drp1 bind to?

A

Fis1

Mff

MiD49

MiD51

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30
Q

What happens after Drp1 binds to a receptor?

A

forms a contractile ring around the OMM after the oligomerization

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31
Q

Upon GTP hydrolysis, Drp1 mediates _______.

A

the separation of the OMM

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32
Q

Where are the Drp1 receptors located?

A

all over the OMM

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33
Q

What is mitokinesis?

A

division of the mitochondria

mitochondria uses the cytoskeleton and actin myosin fibers to contract to divide into 2 mitochondria

once the mitochondria meets with the ER, a preconstriction site is generated and there is nucleation of the actin cytoskeleton

myosin 2 is recruited to fission site

myosin 2 activity results in the constriction of the mitochondria and the generation of 2 daughter mitochondria

dyamin (Dyn2) may be impacted

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34
Q

What could happen if the mitochondria cannot control fusion and fission events?

A

hyper-fragmentation of the mitochondrial network

formation of giant mitochondria

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35
Q

What causes hyper-fragmentation of the mitochondrial network?

A

OPA1 or mitofusion mutations

36
Q

What causes the formation of the giant mitochondria?

A

Drp1, which prevents the fission process

*results in a huge mitochondria that accumulates ROS

**very dangerous for all cells but especially neurons

37
Q

What have the mitochondria shown in terms to adaptation?

A

they are able to adapt in response to the cell’s nutrients

38
Q

What happens if the cell is in a condition of ss deprivation?

A

mitochondrial network has the tendency to hyperfuse

39
Q

What happens if the cell is in a condition with high levels of nutrients?

A

mitochondrial network has the tendency to be fragmented

40
Q

What ahppens if the mitochondria are completely depolarized?

A

they are targeted to mitophagy

41
Q

How are cells targeted for autophagy/mitophagy?

A

the cargo (in this case: mitochondria), is ubiquitinated which allows for the interaction with specific receptors

42
Q

What triggers mitophagy?

A

hypoxia and ROS, which can alter and dissipate the mitochondrial membrane potential

43
Q

Where is PINK1 integrated?

A

inner membrane

44
Q

Hw is PINK1 delivered to the inner membrane?

A

through a pre-sequence, which is recognized by TOM/TIM pathway

pre-sequence is then cleaved and the PINK1 is imported and localized in the inner membrane where it can phosphorylate its substrate

45
Q

What is PINK1 involved in?

A

mitophagy

46
Q

What are the 2 proteins involved in mitophagy?

A

PINK1 and Parkin

47
Q

What 2 proteins are mutated in the genetic form of Parkinson’s disease?

A

PINK1 and Parkin

48
Q

What happens in a mitochondrial damage condition that depolarizes the membrane?

A

PINK1 is no longer imported → accumulation of OM → dimerization and auto-phosphorylation of PINK1 → OM proteins are ubiquitinated → proteins are retrotranslocated to the cytosol for degradation

*PINK1 and the proteins of the OM phosphorylate themselves in this process

**this combined post-transcriptional modification recruits Parkin, an E3ubiquitin-ligase, to the OMM

49
Q

What does the combined post-transcriptional modification process result in?

A

further ubiquitination of the OM proteins

the high ubiquitination and phosphorylation of the OM act as a recruitment signal for p62, which is the receptor for the autophagosome

50
Q

What is the receptor of the autophagosome?

A

p62

51
Q

Why is fission important?

A

leads to the biogenesis of mitochondria

pre-requisite for the degradation of mitochondria

52
Q

What was discovered last year about a fission event needed for mitochondrial biogenesis?

A

a mid-zone fission is needed, which is mediated by the interaction of the mitochondria and ER

53
Q

How does a cell know when fission leads to mitophagy?

A

fission is located at the periphery where there is lots of rubbish like damaged and oxidized proteins

54
Q

What is the mechanism where fission occurs at the periphery to signal for mitophagy through the interaction of the mitochondria and lysosomes mediated by?

A

Mitochondrial fission 1 protein (FIS1)

55
Q

What does FIS1 bind to?

A

Drp1

56
Q

Where is calcium abundant?

A

outside the cells

57
Q

Why is the fine control of calcium important?

A

calcium is a second messenger and involved in lots of controlled pathways

*loss of its control can destabilize homeostasis

58
Q

What can anti-porters do?

A

extrude calcium outside the cell

59
Q

What can ATPases (aka SERCA) do?

A

internalize large amounts of calcium inside the ER

60
Q

How can mitochondria internalize calcum?

A

they can internalize calcium through a uniporter called Mitochondrial Calcium Uniporter (MCU) located in the IMMM

61
Q

How does MCU work?

A

ligand binds to G-coupled protein receptor at the plasma membrane that leads to the release of inositol-3-phosphate (IP3), which acts as a ligand for IP3 receptor located on the ER membrane

*this interaction leads to the release of calcium from the ER lumen, where it will generate a flux that moves from the ER to the mitochondria

62
Q

How can calcium enter the mitochondria?

A

using VDAC proteins, which are large β-barrel proteins that are porins that are poorly selective for ions

63
Q

How can calcium be exported outside of the mitochondria?

A

using antiporters like Na+/Ca2+ or proton/Ca2+

64
Q

Why is the Ca2+ entrance inside the mitochondria peculiar?

A

MCU has a low affinity for calcium

*this means high conc. of calcium is needed to open the MCU

65
Q

How can we measure calcium inside the mitochondria?

A

we need a sensor protein and a pre-sequence

66
Q

What are 2 sensor proteins developed to measure the calcium inside the mitochondria?

A

photoproteins: emits light upon calcium binding and isolated from jellyfish

GFP-based calcium sensors: composed of 2 fluorescent proteins (CFP and YFP) that are connected thanks to a bridge composed of calmodulin and M13 peptide

67
Q

What is the MCU complex?

A

small protein of the IMM, which is aable to oligomerize

68
Q

What is the MCU composed of?

A

many subunits (structural or gatekeepers)

69
Q

What are the structural components of the MCU?

A

MCUb and EMRE

70
Q

What are the gatekeepers of MCU?

A

MICU1
MicU2
MICU3

*act as regulators

71
Q

What does the structural component of the MCU complex, MCUb act as?

A

dominant-negative subunit

*this means it abolishes the overall activity of the complex

72
Q

What is the distribution pattern of MCI and MCUb?

A

tightly regulated and tissue specific

73
Q

The stoichiometry of MCU + MCUb establishes ____.

A

the magnitude of the uniporter permeability, which is tissue-specific.

74
Q

Describe how the gatekeepers would work if the concentration of calcium is low:

A

MICU2 will interact with MICU1 to keep the channel closed

75
Q

Describe how the gatekeepers would work if the concentration of calcium is high:

A

MICU1 will remove MICU2, which leads to the opening of the channell

76
Q

What is MICU3 in regards to the type of activator?

A

MICU 3 is a positive regulator like MICU1

77
Q

Why is calcium needed in the mitochondria?

A

calcium flux is needed to maximize ATP production

78
Q

What is mitochondrial calcium overload?

A

it occurs when calcium conc. exceeds a certain threshold, which triggers the permeability transition

79
Q

What does mitochondrial calcium overload lead to?

A

apoptosis because the excess of calcium opens the permeability transition pores located in the IMM

80
Q

What to modes can the IMM pores act in?

A

both high and low conductance mode

81
Q

What is a low conductance mode?

A

in physiological condition

82
Q

at is a high conductance mode?

A

condition of cell damage

83
Q

What happens in low conductance mode (physiological condition)?

A

pores open and close very fast and release small calcium waves outside the organelle

*called flickering beacuse it gives the idea of periodic release from inside the cell to the outside

84
Q

What happens in high conductance mode (cell damage)?

A

there is an alteration of the IM permeability that leads to apoptosis

85
Q

What has been recently proposed i terms of mitochondrial permeability transition pores?

A

they could be composed of the aggregation of ATP synthase subunits

Molecular Cell Biology (10 decks)

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