Inflammation regulation Flashcards

1
Q

what is the main structure and molecules used in the mitochondria?

A
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2
Q

what is mtDNA?

A

mitochondrial DNA; circular double strand
37 genes

limited repair potential and highly prone to damage (oxidation stress) and mutation

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3
Q

how does the mitochondria undergo quality control?

A
  1. mitochondrial dynamics (fusion and fission)
  2. mitochondrial biogenesis
  3. mitophagy (destroyed)
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4
Q

what is fission/fusion mechanism of mitochondria?

A

fission: mitochondria division
fusion: mitochondria seperation

different molecules involved-
fission: DRP1
fusion: MFN1, MFN2, OPA1

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5
Q

what is the fission/fusion mechanism in relation to OXPHOS?

A

fission - less efficient for OXPHOS (mitochondria stress)
fusion - more efficient for OXPHOS

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6
Q

what does mitochondrial oxidation lead to?

A

cell stress and death

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7
Q

what is mitochondrial biogenesis?

A

generation of mitochondria

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8
Q

what is mitophagy?

A

removal of mitochondria by lysosomes

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9
Q

what is the mechanism of mitochondria biogenesis?

A
  1. PCG-1a regulates mitochondria biogenesis
  2. regulates the nuclear expression of TFAM
  3. signals mtDNA transcription/replication
  4. allowing mitochondria replication
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10
Q

what is the mechanism of mitophagy?

A
  1. primarily initated by dsyfunctioned mitochondria
  2. stabilisation of pink1 at the OMM and activation of Parkin
  3. mitochondria primed for degradation through autophagy
  4. mitochondria degradation in the lysosomes
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11
Q

why is biogenesis and mitophagy essential?

A

essential for…
1.mitochondria self repair to replace unhealthy mitochondria
2. mitochondrial mass to cope with increase/decrease cellular demands (cellular homesostasis)

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12
Q

how is the regulation of cellular biogenergics and metabolism maintained?

A
  1. production of ATP via OXPHOS
  2. regulation of central metabolic pathways
  3. mitochondrial mass adjusted to satisfy energy demands
  4. influenced by mitochondrial dynamics (fusion/fission)

fusion: supports OXPHOS
fission: linked with glycolysis

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13
Q

what is produced during OXPOS?

A

reactive oxygen species (ROS)
superoxide (o2-)

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14
Q

when is ROS produced?

A

superoxide (o2-) released in damaged mitochondria

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15
Q

what are mitochondria antioxidants?

A

used to scavenge ROS to stop cell signalling
Manganese Superoxide dismutase (MnSOD ) Thioredoxin 2 (Trx2)

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16
Q

why are Balanced mitochondrial Redox key for cell signalling?

A

Posttranslational modifications of proteins
Action on signal transduction

17
Q

what is senescence?

A

cellular ageing - end to cell proliferation

18
Q

what causes senescence?

A

stress
oncogene activation
telomere shortening (ageing)

19
Q

what is the function of the mitochondria?

A
  1. Regulation of cellular bioenergetics and metabolism
  2. Control of cell death
  3. Generation of Reactive oxygen species (ROS)
  4. Cell differentiation/reprogramming
  5. Cellular ageing (senescence)

Other key functions:
6. Calcium Transport
7. Steroid synthesis
8. Hormonal signalling

20
Q

what is the main role of mitochondria in inflammation?

A

A. Polarization/reprogramming of immune cells
B. Antiviral responses
C. Immune responses to DAMPs

21
Q

what cells are involved in mitochondria inflammation?

A
  1. macrophages
  2. damage-associated molecular patterns (DAMPs)
22
Q

what type of cytokines do macrophages produce?

A
  1. pro-inflammatory M1
    -iNOS
    -IL-1b
    -TNF-a
  2. tissue repair/angiogenesis M2
    -IL10
    -TGF-b
    -ECM deposition
23
Q

how are pro-inflammatory cytokines expressed?

A

Characterized by mitochondrial fission - M1 macrophages

  1. Glucose utilized for aerobic glycolysis
  2. Broken Krebs cycle
  3. High levels of succinate and mtROS
  4. Stabilization of HIF-1α
    = Expression of pro-inflammatory cytokines
24
Q

how are tissue repair/angiogenesis cytokines expressed?

A

Characterized by mitochondrial fusion - M2 macrophages

  1. OXPHOS (more efficient in E production)
  2. Intact Krebs cycle
25
Q

how is Mitochondria key for macrophage polarization?

A

Blocking mitophagy during M1 polarization = inc Mitochondria mass = reduced expression of pro inflammatory cytokines

26
Q

what is Mitochondrial antiviral signalling protein (MAVS)?

A

Viral dsRNA is recognized by RIG-I =
Assembly of MAVS at the outer mitochondrial membrane =
Antiviral Interferon-I responses =
“Interferes” with viral replication in non-infected neighbour cells:
1. Inhibition of RNA translation
2. Degradation of RNAs
3. Inhibition of viral assembly

27
Q

what do Mitochondrial antiviral signalling protein (MAVS) do?

A
  1. Inhibition of RNA translation
  2. Degradation of RNAs
  3. Inhibition of viral assembly
28
Q

what can induce Mitochondrial fission? what does this cause?

A

Hepatitis (HBV and HCB)
human parainfluenza virus 3 (HPIV3)
Coxsackie B virus (CVB)

causes mitophagy

29
Q

what disrupts MAVS signals?

A

SARS-Cov1
Dengue

30
Q

how does SARS-Cov1 affect the mitochondria?

A

Target the mitochondria = disrupt MAVS using Orf9b = trigger degradation
= promote mitochondrial fusin

31
Q

what do mitoDAMPs do?

A

Recognise signalling molecules inside the cell that indicate range
= trigger innate immune response
- macrophages
- neutrophils

32
Q

how do mitoDAMPs lead to distal organ inflammation?

A

activates TLR9 receptors which is an extracellular signal for neutrophil activation =adhesion of mtDNA leading to distal organ inflammation

33
Q

what did COVID-19 pts experience with mitoDAMPs?

A

high circulatory levels of mtDNA = distal organ inflammation

predicted risks:
1. mortality
2. intensive care (ICU)
3. intubation
4. fatal organ dysfunction
5. traumatic brain injury
6. acute ischemic stroke
7. cancer
8. diabes
9. ageing
10. acute liver failure

34
Q

what are risks of aggregated mtDNA?

A
  1. traumatic brain injury
  2. acute ischemic stroke
  3. acute liver failure
  4. cancer
  5. diabes
  6. ageing
35
Q

how do mitoDAMPs signal?

A

extracellular - neutrophil activation by TLR9
intracellular - release of pro-inflammatory IL-1B and IL-18

36
Q

what does the release of pro-inflammatory IL-1B and IL-18 cause?

A
  1. diabetes
  2. ageing
  3. neurodegenerative processes