Inflammation regulation Flashcards
what is the main structure and molecules used in the mitochondria?
what is mtDNA?
mitochondrial DNA; circular double strand
37 genes
limited repair potential and highly prone to damage (oxidation stress) and mutation
how does the mitochondria undergo quality control?
- mitochondrial dynamics (fusion and fission)
- mitochondrial biogenesis
- mitophagy (destroyed)
what is fission/fusion mechanism of mitochondria?
fission: mitochondria division
fusion: mitochondria seperation
different molecules involved-
fission: DRP1
fusion: MFN1, MFN2, OPA1
what is the fission/fusion mechanism in relation to OXPHOS?
fission - less efficient for OXPHOS (mitochondria stress)
fusion - more efficient for OXPHOS
what does mitochondrial oxidation lead to?
cell stress and death
what is mitochondrial biogenesis?
generation of mitochondria
what is mitophagy?
removal of mitochondria by lysosomes
what is the mechanism of mitochondria biogenesis?
- PCG-1a regulates mitochondria biogenesis
- regulates the nuclear expression of TFAM
- signals mtDNA transcription/replication
- allowing mitochondria replication
what is the mechanism of mitophagy?
- primarily initated by dsyfunctioned mitochondria
- stabilisation of pink1 at the OMM and activation of Parkin
- mitochondria primed for degradation through autophagy
- mitochondria degradation in the lysosomes
why is biogenesis and mitophagy essential?
essential for…
1.mitochondria self repair to replace unhealthy mitochondria
2. mitochondrial mass to cope with increase/decrease cellular demands (cellular homesostasis)
how is the regulation of cellular biogenergics and metabolism maintained?
- production of ATP via OXPHOS
- regulation of central metabolic pathways
- mitochondrial mass adjusted to satisfy energy demands
- influenced by mitochondrial dynamics (fusion/fission)
fusion: supports OXPHOS
fission: linked with glycolysis
what is produced during OXPOS?
reactive oxygen species (ROS)
superoxide (o2-)
when is ROS produced?
superoxide (o2-) released in damaged mitochondria
what are mitochondria antioxidants?
used to scavenge ROS to stop cell signalling
Manganese Superoxide dismutase (MnSOD ) Thioredoxin 2 (Trx2)
why are Balanced mitochondrial Redox key for cell signalling?
Posttranslational modifications of proteins
Action on signal transduction
what is senescence?
cellular ageing - end to cell proliferation
what causes senescence?
stress
oncogene activation
telomere shortening (ageing)
what is the function of the mitochondria?
- Regulation of cellular bioenergetics and metabolism
- Control of cell death
- Generation of Reactive oxygen species (ROS)
- Cell differentiation/reprogramming
- Cellular ageing (senescence)
Other key functions:
6. Calcium Transport
7. Steroid synthesis
8. Hormonal signalling
what is the main role of mitochondria in inflammation?
A. Polarization/reprogramming of immune cells
B. Antiviral responses
C. Immune responses to DAMPs
what cells are involved in mitochondria inflammation?
- macrophages
- damage-associated molecular patterns (DAMPs)
what type of cytokines do macrophages produce?
- pro-inflammatory M1
-iNOS
-IL-1b
-TNF-a - tissue repair/angiogenesis M2
-IL10
-TGF-b
-ECM deposition
how are pro-inflammatory cytokines expressed?
Characterized by mitochondrial fission - M1 macrophages
- Glucose utilized for aerobic glycolysis
- Broken Krebs cycle
- High levels of succinate and mtROS
- Stabilization of HIF-1α
= Expression of pro-inflammatory cytokines
how are tissue repair/angiogenesis cytokines expressed?
Characterized by mitochondrial fusion - M2 macrophages
- OXPHOS (more efficient in E production)
- Intact Krebs cycle
how is Mitochondria key for macrophage polarization?
Blocking mitophagy during M1 polarization = inc Mitochondria mass = reduced expression of pro inflammatory cytokines
what is Mitochondrial antiviral signalling protein (MAVS)?
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
what do Mitochondrial antiviral signalling protein (MAVS) do?
- Inhibition of RNA translation
- Degradation of RNAs
- Inhibition of viral assembly
what can induce Mitochondrial fission? what does this cause?
Hepatitis (HBV and HCB)
human parainfluenza virus 3 (HPIV3)
Coxsackie B virus (CVB)
causes mitophagy
what disrupts MAVS signals?
SARS-Cov1
Dengue
how does SARS-Cov1 affect the mitochondria?
Target the mitochondria = disrupt MAVS using Orf9b = trigger degradation
= promote mitochondrial fusin
what do mitoDAMPs do?
Recognise signalling molecules inside the cell that indicate range
= trigger innate immune response
- macrophages
- neutrophils
how do mitoDAMPs lead to distal organ inflammation?
activates TLR9 receptors which is an extracellular signal for neutrophil activation =adhesion of mtDNA leading to distal organ inflammation
what did COVID-19 pts experience with mitoDAMPs?
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
what are risks of aggregated mtDNA?
- traumatic brain injury
- acute ischemic stroke
- acute liver failure
- cancer
- diabes
- ageing
how do mitoDAMPs signal?
extracellular - neutrophil activation by TLR9
intracellular - release of pro-inflammatory IL-1B and IL-18
what does the release of pro-inflammatory IL-1B and IL-18 cause?
- diabetes
- ageing
- neurodegenerative processes
