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Health Sciences > Mitochondrial Regulation Of Inflammation? oi > Flashcards

Mitochondrial Regulation Of Inflammation? oi Flashcards

1
Q

What is the major goal for any cell that performs cellular respiration?

A

✅ produce ATP ⚡️

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2
Q

Where does glycolysis occur and is this process aerobic or anaerobic?

A
  • cell cytoplasm
  • anaerobic
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3
Q

Where does krebs cycle occur and is this process aerobic or anaerobic?

A
  • mitochondrial matrix
  • aerobic
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4
Q

Where does ETC (Oxidative Phosphorylation) and Chemiosis occur and is this process aerobic or anaerobic?

A
  • inner mt membrane
  • aerobic

Produces lots of ATP from one glucose made

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5
Q

What is the main function of the mitochondria ?

A

To produce ATP for cellular function ⚡️

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6
Q

Briefly discuss the structure of the mitochondria?

A
  1. Outer mt membrane
  2. Inter membrane space
  3. Inner mitochondrial membrane
  4. Inner mitochondrial membrane
  5. Cristae
  6. Matrix
  7. MtDNA (present int he cell cytoplasm)
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7
Q

Describe the characteristics of the outer mitochondria membrane?

A

✅ freely permeable to small moles via transmembrane proteins called porins.

⚡️ transport of proteins across the outer mt membrane requires “outer translocases” called TOMS —> lots of different subtypes of TOMS (ie TOM20), TOM70

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8
Q

Describe the characteristics of the inter membrane space?

A
  • this the space between the outer and inner mt membrane
    It has :
  • ✅ small peptides
  • ✅ peptides
  • ✅ Cytochrome C
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9
Q

What is the function of Cytochrome C?

A
  • it is a protein essential for the function of the ECT (it transfers e-s from from complex 3 - 4 thus facilitating generation of ATP, the cells primary energy source.
  • CytC is also involved in apoptosis — programmed cell death where it’s released from the Mt into cytoplasm leading to a cascade of events leading to death.
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10
Q

Describe the characteristics of the inner mt membrane?

A
  • 🧈 it is impermeable to most small molecules, due to their high content of cardiolipin.
  • ⚡️ It allows for selective (active transport) via inter translocases (ie TIMS)
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11
Q

What is the function of TIMS and TOMs and where are they located?

A

TIMS - inner mt membrane
TOMS - outer mt membrane

Function —-> allow translocation of proteins from the across the membranes (they are too big to freely pass through).

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12
Q

What are the characteristics of the cristae?

A
  • they are the invaginations of the inner mt membrane - they are where ECT is located and oxidative phosophorylation will take place.
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13
Q

What are the characteristics and function for the Matrix?

A
  • this is the space enclosed by the inner mt membrane
  • ✅ 🧳 here we can fond specific protiens needed for mitochondrial function, as well as MtDNA and mtRNA and some ribosomes.
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14
Q

Where is MtDNA located?

A

Inside the matrix of the , packed into protein - DNA aggregates called nucleoids.

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15
Q

Describe the structure of MtDNA?

A
  • circular dsDNA ⭕️
    ❌ NO introns - all of it is coding DNA
  • aggregated to a protein and thus forms a “nucleoid”.
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16
Q

In humans, what does mtDNA encode for?

A

✅ rRNA
✅ TRNA
✅ And 13 proteins that integrate in the ETC

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17
Q

Is MtDNA found free in the mt matrix?

A

NO - it’s in a protein - DNA aggregate called a nucleoids.

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18
Q

What is the limitation of mtDNA compared to nuclear DNA?

A

🙅‍♀️ mtDNA has a very limited repair potential —> it is HIGHLY prone to damage in oxidative stress and mutation.

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19
Q

Nucleoids are protein - mtDNA aggregates. What are the proteins that make up the nucleoids and what is their function?

A
  1. TFAM (mitochondrial transcription factor A) ——> tickcoats and stabilises mtDNA 🧥, and then regulates replication and transcription of mtDNA.
  2. TWINKLE — helical enzyme used to open up the 2 strands of mtDNA for replication
  3. POLG - DNA polymerase gamma
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20
Q

Why is mitochondrial quality control important for the mitochondria?

A
  • because they are highly dynamic organelles and it they are under continuous replacement. MtQC is this important in maintains cell health by regulating different processes.

♾️ they are also used to maintain cellular homeostasis ==> we can optimise mt mass to adapt to cell bioenergetics and also to remove damaged Mt that is becoming toxic for cells.

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21
Q

What are the 3 major processes of mitochondrial QC?

A
  • ✅ mitochondrial dynamics (fusion and fission)
  • ✅ Mitochondrial biogenesis (de - novo synthesis of mitochondria)
  • ✅ Mitophagy (removal of mt in lysosomes via autophagy).
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22
Q

MQCQ, Dynamics of mitochondria : how can mt change their morphology?

A

The process of fusion and fission.

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23
Q

Why is the morphology of the mt network important to know?

A

It can provide us with clues about the bioeneergetic status of the cell.

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24
Q

MQCQ, Dynamics of mitochondria : Which mitochondrial functions does mt fusion and fission play a crucial role in?

A
  • OXPHOS —> involved in cellular respiration to produce a lot of ATP.
25
Q

MQCQ, Dynamics of mitochondria :
What is mt fusion and what does it allow for?

A
  • ✅fusion → the joining of 2 mitochondria together.
    • By doing so → allows for an exchange in contents and repair of damaged components, and more tubular networks which are more energetically efficient → thus promoting more efficient for Oxidative Phosphorylation.
26
Q

MQCQ, Dynamics of mitochondria : what controls mt fusion?

A
  • mitofusins 1 and 2 (MFS1/MFS2) and OPA1.
27
Q

MQCQ, Dynamics of mitochondria : What is mt fission and what does it normally indicate?

A
  • fission → the separation of one Mt → two.
    • Involves segregating damaged portions of the mitochondria for degradation and thus ensures the overall integrity for OxPhos machiner
    • It is less efficient for Oxidative Phosphorylation → and so may be indicative of ** mitochondrial stress.**
  • 🤔 Mitochondrial fission may be indicative that the cell is relying on other metabolic pathways, eg glycolysis.
28
Q

What controls mt fission?

A

DRP1 and FIs1

29
Q

How does Mt dynamics play a role in responding to mitochondrial oxidation

A

MTOx —> occurs during oxphos and leads to hyper-fragmentation of the mt network ==> it occurs very very fast and can lead to cell stress and death in the worst case scenario.

MtOX —> generates ROS as byproducts —> damage to cellular components, leading to oxidative stress. Excessive ROS production will trigger the ACTIVATION of DRP1* —-> this PROMOTES MT FRAGMNTATION WHICH LEADS TO FORMATION OF SMALLER MT.

Furthermore, MtOx can induce damage which to mt components leading to the need for MTQc in which mt fission is involved ——> mt fission segregates damaged portions of the Mt for removal by Mitophagy.

🌟by promoting mitochondrial fission, oxidative stress can facilitate the removal of dysfunctional mitochondria thus maintains mt health and function.

30
Q

MtQC : biogenesis and mitophagy : what is mt biogenesis and what is it regulated by?

A

Mitochondrial biogenesis → generation of mitochondria DE NOVO (ie NEW mitochondria).

  • Mt biogenesis is primarily regulated by PGC1 alpha - this is a transcription factor that can be activated by different molecular pathways (eg AMPK).
31
Q

Mt QC : biogenesis and mitophagy : how does PCG1 alpha lead to the de novo synthesis of mitochondria?

A

PCG1 is a transcription factor
It will translocate to the cell nucleus and activate expression of TFAM
TFAM is internalised into the mt and will coordinate mt biogenesis by regulating the transcription and replication of mtDNA.

32
Q

MTQC. : biogenesis and mitophagy —> What is mitophagy?

A

Mitophagy → removal of mitochondria in lysosomes by autophagy.

33
Q

Where is mitophagy primarily initiated?

A

✅ dysfunctional or damaged mitochondria
✅ hypoxic mitochondria (ie PINK1 independent mitophagy)

34
Q

What is the removal of damaged mt controlled?

A

PINK1 and Parkin pathway
- basically - Ie the mt is damaged, it triggers the stabilisation of Pink1 at the outer mitochondrial membrane → which will be phosphorylated to Parkin, which will prime the mitochondria for degradation via autophagy.
- The Mt are then engulfed into autophagosomes and are then finally removed via fusion with lysosomes.

35
Q

Describe how mitophagy can also be initiated in non - damaged mitochondria? (Ie a PINK1 independent mechanism)

A

This occurs during hypoxia.
✅ controlled by the BNIP and NIX pathway

Here the mitochondria are removed to help cells adapt to the low oxygen environment, conserve energy and mitigate oxidative stress which ultimately will promote cell survival in challenging conditions.

36
Q

What are the two key processes that mt biogenesis (de novo synthesis) and mitophagy are essential for?

A
  • mitochondrial self repair → replacing damaged mitochondria by new heathy units. (Ie keeping an appropriate turnover of healthy mitochondria).
  • ✅adjusting mitochondrial mass to cope with cellular demands (ie lack of oxygen)
37
Q

How can we change the mitochondrial mass?

A

Biogenesis (+) and autophagy (-)

38
Q

How do we change the mt morphology?

A

Fusion and fission

39
Q

If a cell has mt undergoing mt fission, what alternative pathways could be undergoing to generate ATP (bioenergetic regulation)?

A

Alternative to generating APT via OXPHOS —> glycolysis

40
Q

In what ways are mitochondria essential for cellular homeostasis?

A
  1. Regulation of cellular bioenergetics and metabolism — production of ATP energy via OXPHOS and the regulation of of central metabolic pathways, as well as QC in regards to adjusting mitochondrial mass (mito/biogen) and adjusting mt morphology.
  2. Involved in cell death via different intrinsic signals. (Ie ER stress or DNA damage can activate BAX/BAK in the cytosol —> apoptosis)
  3. Mt is also involved in the generation of ROS and the redox state of the cell (in oxphos,some electrons will will react with O2 —> ROS. ROS production is also >er in damaged mt —- ROS can also be benefitcal however, as it allows for post translational modification and + signal transduction.
  4. Mt is used in cell differentiation and reprogramming
  5. Mt also has been seen to control the processes of cell ageing (ie cell senescence). (A hallmark of senescent is that a cell will have lots of mt mass).
41
Q

What is the SASP phenotype and why its it important?

A

Senescence associated secretory phenotype —> allows for characteristic secretion of inflammatory and fibrotic factors.
Mt have this phenotype and thus +++ senescence

If we remove mt from a cell before the induction for senescence, it will prevent the developement of the SASP phenotype and the releae of inflammatory and fibrotic features associated with SASP

42
Q

What are 3 other lesser spoken about functions of the mitochondria?

A
  • ✅ calcium transport
  • ✅steroid synthesis
  • ✅Hormonal signalling - calcium transport
43
Q

What are 3 immune processes that mitochondria have role in?

A
  • ✅polarisation and reprogramming of immune cells
  • ✅antiviral responses
  • ✅immune responses to DAMPs (ie the role of Mt as a DAMP).
44
Q

Describe the role of the mitochondria on the immune system?

A

Mt fusion - indicative and better for mt that produce energy via oxphos - such as T memory and T naive cells.

Mt fission —> indicative of mt stress — indicates cells are useign glycolysis to meet metabolic demand - like T effector cells.

45
Q

How can we reprogram the adaptive immune system so that we can match our desired needs in terms of which type of immune cell response we want during the immune response?

A

We can use mt fission or fusion promotors to control mt dynamics, depending on what type of immune response we want.

We can use mt to reprogramme cells in the immune system to match our desired needs ie if we want >er tmem actin, MDIVI fusion promoter will promote >er oxphos, increased mt fusion, increased cell half life.

This concept was verified using pharmacological compounds that promote mitochondrial fusion → eg “mitochondrial fusion promoter M1 And Mdivi 1”. When the T effector cells were treated with these compounds → mitochondrial fusion was increased. Furthermore, changes that were more in line with the T memory cells were also imposed → reprogrammed it to be more like T memory cells. :

  • ✅increased OxPhos.
  • ✅Increased cell half life.
46
Q

Mt also have a role in the innate immune system, where they can play a role in the polarisation of cells in the innate system. What does this mean?

A

Mt can play a role in whether macrophages can either be M1 or M2 phenotype which each have their own distinct function and gene expression profiles.

47
Q

Are M1 macrophages pro or anti inflammatory?

A

PRO inflammatory

48
Q

Are M2 macrophages pro or anti inflammatory?

A

ANTI inflammatory

49
Q

What sorts of things activate M1 macrophages and which cytokines are invovled?

A

Activated by microbial products and pro - inflammatory cytokines.

PRO INFLAMMATORY cytokines that +++++ M1 macrophages
- iNOS, IL -1 beta and TNF - alpha

50
Q

How have mt play a role in the polarisation of innate immune cells?

A

Mt fission associated with +++ of M1 macrophages in order to —> ROS and produce pro inflammatory cytokines —> 💥 ** enhances M1 phenotype and promotes the inflammatory response**. Furthermore, M1 macrophages use glucose for aerobic glycolysis —-> (rmb how mt fission is associated with cells using alt method of energy production) —-> pro inflammatory response

M2 macrophages - function supported by Oxphos to produce ATP which is more efficient than glycolysis. Such cells are characterised by mt fusion. M2 macrophages are activated by anti - inflammtory cytokines that are invovled in tissue repair —-> restore homeostasis in affected tissue and help to dampen inflammation , promote tissue repair and angiogensis etc.

51
Q

What is polarisation towards the M1 phenotype dependant on?

A

Activation of mitophagy.
A study found that using pharmacological blockers of mitophagy such as cyclosporine A or 3 methyl adenine increased mitochondrial mass (biogen) during M1 polarisation.

Results also shows that blocking mitophagy was also associated with a decreased expression of glycolic genes and the expression of pro - inflammatory factors.

52
Q

Describe the role of mitochondria in the antiviral response (ie immune system)

A
  1. Viral genetic material is sensed by cytoplasmic protein called RIG1
  2. This will lead to assembly fo MAVS (mitochondrial antiviral signalling protein) outside the outer Mt membrane alongside other proteins ie TOM70, and other translocases.
  3. Assembly of MAVS at outer mt membrane activates the host antiviral response leading to release of IFN -1 an innate immune cytokine with antiviral function. IFN will then bind to membrane receptors of non infected adjacent cells to interfere and prevent viral replication by **degrading viral RNA, inhibiting viral assembly, inhibition of viral RNA translation).
53
Q

How can viruses evade the mt MAVS mediated immmune antiviral response?

(Ie so they can still elicit their effects)

A
  1. Via induction of mt fission which leads to mitophagy —> this will reduce mt content and thus reduce action of MAVS and thus minimise antiviral response.
    A) can be achieved via damage to mt function, or trigger mitphagy via PIK1 - Parkin pathway
    B) other viruses can also express factors to direly induce mitophagy
  2. Viruses can disrupt MAVS signalling so that the host antiviral response is NOT activated. This is what we have done for SARS - COv1 virus vaccine. SARS COV 1 encodes for protein Orf9B which interacts with MAVS to trigger its** degradation and thus minimise INF -1 response mediating an antiviral response**
    - SARS COV 1 also promotes mt fusion instead of fission by degrading DRP1 - thus the cells remain intact and functioning for proper viral replication.
54
Q

What is a DAMP and how do they trigger the immune system?

A

A damage associated molecular pattern - a molecule with a physiological function inside a pathogen ** damaged**that alerts danger when released both intracelular and extracellularly.

When they are released from the cell they trigger the innate immune system by activating macrophages, neutrophils and dendritic cells.

55
Q

How do mitochondria activate the innate immune system via damps?

A

Mt cells are major sources of ⭐️ mitoDAMPS. These rlease certain molecules when damaged or stressed such as :

  • ✅mtDNA → we will mostly focus on this as a DAMP as it is one of the major mitochondrial components which will activate innate immunity when released intra and extra cellularly.
  • ✅ATP
  • ✅TFAM
  • ✅Cardiolipin
56
Q

Give 4 examples of mitoDAMPS that mt cells can release?

A
  • ✅mtDNA → we will mostly focus on this as a DAMP as it is one of the major mitochondrial components which will activate innate immunity when released intra and extra cellularly.
  • ✅ATP
  • ✅TFAM
  • ✅Cardiolipin
57
Q

How are mtDNA recognised as DAMPS at extracellular level?

A
  • mtDNA may be released from dying cells and then sensed by TLR9
  • this can lead to the activation of immune system ie neutrophils which then adhere and migrate to distal tissues leading to organ inflammation.
  • we can thus exploit mtDNA as biomarker for disease progression and severity.

In Covid 19 - px with a >er level of mtDNA had >er risk of mortality, ICU , fatal organ dysfunction etc

58
Q

How are mtDNA recognised as DAMPS at extracellular level?

A

MtDNA can act as a damp at intracellar level by triggering inflammasomes NLRP3 and AIM2 when released into the cytosol.
- when activated will lead to the release of pro inflammatory cytokines including IL - 1Beta and IL - 18.

🚨 it’s important to note that the release of mtDNA can occur primarily from DAMAGED mt in cells, thus we need competent QC methods in place to remove dysfunctional mt. This can accululate in tissues and prevent the mtDNA release that can lead to inflammatory rx.

59
Q

Give some examples of conditiosn n which mt function declines, due to mt insult?

A
  • diabetes
  • Agening
  • Neurodegeneritive disease.

Lack of mt function - reduced role in inflammation (relate back to immune cells u woud want for adaptive)

💊 However , improving mt function may offer new thereaptic options for decreasing inflammation and thus improving the clinical outcomes for a wide range of conditions.

Health Sciences (4 decks)

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