Mitochondria Flashcards
why are mitochondria referred to as powerhouses of the cell?
as provide most energy for cell function
what 5 parts form the structure of mitochondria?
outer mitochondrial membrane,
intermembrane space,
inner mitochondrial membrane,
cristae
matrix
What is found within the outer mitochondrial membrane? 2
- porins: small permeable molecules
- outer translocases TOMs: selective transport proteins
What is found within the intermembrane space of the mitochondria? 3
small molecules,
peptides
cytochrome C
what is cytochrome C (found in intermembrane space of the mitochondria)
protein essential for funtion of electron transport by transfer e- between complexes 3+4
what part of mitochondria is similar to cytosol in solute composition?
intermemb space
What is found within the inner mitochondrial membrane of the mitochondria?
- small IMpermeable molecules (selective transport)
- inner translocases TIMs: selective transport proteins
is the inner mitochondrial membrane impermeable or permeable to most small molecules?
impermeable
where can we find OXPHOS (electron transport complexes for oxidative phosphorylation)?
cristae
What is found within the matrix of the mitochondria?
- mtDNA
- mtRNA
- proteins
What is the structure of mitochondrial DNA (mtDNA)?
- circular double strand
- no introns
- packed in protein-DNA aggregates
How many copies of mtDNA exist in a mitochondrion?
multiple
what is meant by no introns? mtDNA
most of mtDNA encodes for a protein or a ribosome
most proteins for structure and function are encoded in the nuclear DNA and are imported via?
TOMs and TIMs
mitochondrial DNA has limited repair and is highly prone to damage (oxidative stress) and?
mutations
mtDNA is packed in nucleoids. What are nucleoids?
protein DNA aggregates
How many genes are within the mtDNA and what do they code for?
- 37 genes:
- 13 proteins for proteins of ETC, rRNA + all tRNAs
what is the role of TFAM (mitochondrial transcription factor A) ?
coats and stabilises mtDNA
regulates transcription/ replication
what is the specific replicative machinery of mtDNA known as?
replisome
the replisome of mitochondria is comprised of Twinkle, POLG…
what are these?
Twinkle: DNA helicase
POLG: DNA polymerase gamma
where is mtDNA replication primarily initiated?
D loop region non coding
role of Twinkle?
open the 2 strands of mtDNA
(DNA helicase)
what are the 3 safeguards of mitochondrial health for cell homeostasis?
mitochondrial dynamics, mitochondrial biogenesis and mitophagy
whats mitochondrial dynamics?
fusion and fission
whats mitochondrial biogenesis
de novo synthesis (generation of new) of mitochondria
whats mitophagy?
removal of mitochondria in lysosomes by autophagy
Why are mitochondria said to be very dynamic organelles?
undergo fusion and fission
What molecules are involved in mitochondria dynamics?
Mitofusins, OPA1, Fis1, Drp1….
How are mitochondria dynamics related to bioenergetics status of cell?
- Fusion: more efficient for OXPHOS
- Fission: less efficient for OXPHOS - may be indicative of mitochondrial stress
what process can occur v quickly and can induce to cell stress and death?
mitoc. oxidation
What is the master regulator of mitochondrial biogenesis?
PGC-1a
(a TF that can be activated by diff molecular pathways e.g. AMPK)
How does PGC-1a regulate mitochondrial biogenesis?
- it translocates to cell nucleus to activate TFAM expression
- TFAM essential to coordinate mitochondrial biogenesis through mtDNA transcription/replication
What triggers mitophagy?
mitochondria being dysfunctional or damaged
mitophagy is primarily initiated in dysunctional mitochondria. What stabilizes at the OMM before parkin is activated?
PINK1
mitochondria is primed for degradation through autophagy and occurs in the?
lysosome
–> engulfed form autophagosomes + removes fusion w lysosomes
give one condition where mitophagy may be initiated in non damaged mitochondria via pink1 independant mechanisms?
hypoxia (BNIP3L/NIX pathway)
Why is coordination of biogenesis and mitophagy essential?
- self-repair: replace damaged mitochondria by new healthy units
- adjust mitochondrial mass to cope w cellular demands
to keep an appropriate turnover of healthy mitochon.
mitochondria are essential for cellular homeostasis. Give one thing that is produced and one thing that is regulated?
production of ATP via oxidative phosphorylation (OXPHOS)
regulation of central metabolic pathways
production of ATP via oxidative phosphorylation (OXPHOS) involves transfer of e- from where through where?
NADH + FADH through mitochon. complexes… to make ATP
true or false, mitochondrial mass can be adjusted to satisfy energetic demands?
true
does fusion or fission support oxidative phosphorylation?
fusion
fission more linked w glycolysis
what are the functions of mitochondria?
(all)
- regulation of cellular bioenergetics and metabolism
- Control of cell death
- Generation of Reactive oxygen species (ROS)
- Cell differentiation/reprogramming
- Cellular ageing (senescence)
- Calcium Transport
- Steroid synthesis
- Hormonal signalling
…
Describe the process of cell death control in a mitochondria.
- intrinsic cell death signals activate BAK and BAX in cytosol
- triggers OMM permeabilisation via formation of pore complexes
- cytochrome C released into cytosol
- binds to Apaf-1 (apoptosome)
- caspase(s) activate and apoptosis occurs
mitochondria can generate ROS (reactive oxygen species), how might this occur during OXPHOS?
fraction of e- leaks and reacts with O2 to produce superoxide + H2O2
ROS production is excerabted in damaged mitochondria, true or false?
true
What mitochondria antioxidant systems exist to scavenge ROS?
(detox. superoxide-> less damaging forms)
- Manganese Superoxide dismutase (MnSOD )
- Thioredoxin 2 (Trx2)
What can ROS damage?
cell components:proteins, DNA and lipids
What exists to maintain balanced mitochondrial redox key for cell signalling?
- Posttranslational modifications of proteins
- Action on signal transduction
How do mitochondria cause cell differentiation/reprogramming?
mitophagy facilitates the process by switching from OXPHOS to glycolysis
What are examples of cell differentiation/reprogramming that the mitochondria play a role in?
Differentiation of:
- neuroblasts into Retinal Ganglion cells
- Stem cells into various lineages (erythrocytes, myotubes…)
Macrophage polarization
What is cellular ageing (senescence)?
permanent arrest of cell proliferation
What are the causes of senescence?
- stress
- oncogene activation
- telomere shortening (ageing)
What unique phenotype accompanies cell senescence and what does it do?
- senescence-associated secretory phenotype SASP
- causes secretion of inflammatory cytokines
How do we know mitochondria play a role in cell senescence?
- senescent cells show high mitochondrial mass
- removing mitochondria prevents senescence
What aspects of inflammation do mitochondria play a role in?
- Polarization/ reprogramming of immune cells
- Antiviral responses
- Immune responses to DAMPs
What T-cells do mitochondria reprogramme?
- naïve
- T-effector
- T-memory
How do mitochondria affect naïve T cells?
mature and exit the thymus primarily relying on OXPHOS
How do mitochondria affect T-effector cells?
Glycolytic metabolism
How do mitochondria affect T-memory Tm cells?
OXPHOS
once naive T cells mature + exit thymus, they can be primed by what to become T-effector Te cells?
antigen presenting cells
why can we taregted mitochondria dynamics ?
as novel approach to reprogram T cells
What does reinforcing mitochondria fusion in T-effector cells cause?
- it imposes T-memory cell features (remember mitochondrial fusion favours OXPHOS)
- increased OXPHOS
- increased cell half-life
What are the two types of macrophages?
M1 and M2
What types of cytokines do M1 macrophages secrete? Name examples.
pro-inflammatory:
- iNOS
- IL-1β
- TNF-α, etc
What mitochondrial dynamic characterises the release of pro-inflammatory cytokines from M1 macrophages?
Mitochondrial fission:
- glucose used for aerobic glycolysis, broken in krebs cycle
-> high levels of succinate and mtROS - stabilisation of HIF-1a
- expression of pro-inflammatory cytokines
What types of cytokines do M2 macrophages secrete? Name examples.
tissue repair/angiogenesis:
- IL10
- TGF-β
- ECM deposition, etc
What mitochondrial dynamic characterises the release of tissue repair/angiogenesis cytokines from M2 macrophages?
mitochondrial fusion:
- OXPHOS
- intact Krebs cycle
Apart from helping to release cytokines, how else do mitochondria affect macrophages?
key for macrophage polarisation by blocking mitophagy during M1 polarisation
results/ effects of macrophages: blocking mitophagy during M1 polarisation
inc mitochon mass
dec glycolytic gene expression
reduced expression of pro-inflamm factors
how can antiviral responses be intiated at the mitochondria?
viral dsRNA recognised by RIGI,
assembly of MAVS at outer mitochondrial membrane,
antiviral interferon 1 responses–>
- inhibition of rna translation,
- degradation of RNAs
- inhibition of viral assembly
what does antiviral interferon-I bind to, to interfere with viral replication?
memb receptors of the non-infected adjacent cells
how does the induction of mitochondrial fission of mitochondrial viral evasion help protect against viruses?
get collapse of mitochondrial function to facilitate their removal and viral factors directly induce mitophagy
whata are the 2 mechanisms of mitochon viral evasion?
induction of mito fission -> mitophagy (Hep B,C, HPV3, CVB..)
disruption of MAVS signalling (SARS-Cov1)
how does the disruption of MAVS signalling such as in the case of SARS cov 2 lead to mitochondiral viral evasion?
targets mitochondria,
disrupts MAVs and triggers its degradation, reduced IFNI responses
promotes mitochondrial fusion through DRP1 degredation,
keeps host cells happy (almost all lung cells rely on OXPHOS)
what is the term given to molecules with physiological function inside the cell that alert about danger when released, intra or extra cellular?
DAMPs
damage associated molecular patterns
damps trigger innate immune responses via recruitment of what 3 cell types?
macrophages, neutrophils and dcs
mitochondria are major sources for damps, what are these damps known as?
mitodamps
what cells involved in immune cell activation + underlying mechanism from studies of bacterial DNA: that activates TLR9 by recognising unmethylated CpGsequences (immunostimulant)
mitodamps
what is the endosymbiant theory?
mitochondria thought to evolve from saprophytic bacteria
I
mtDNA also rich in CpG sequences
I
activates TLR9 receptors
mitoDAMPs: once immune activation as extracellular signal, -> neutrophil activation (TLR9), adhesion and transmigration leading to what?
distal organ inflammation
in COVID19 px, are circulation levels of mtDNA high/low?
high.
associated w circulating levels of inflamm factors
therefore, what can levels of mtDNA/ inflamm factors in COVID19 px predict?
risk of
- mortality
- ICU
- intubation
- fatal organ dysfunction
what can high circulation level of mtDNA also be used as a prognosis factor for?
traumatic brain injury
AIA
acute liver failure
cancer
diabetes
aging
immune activation as intracellular signal can ‘ignit’ inflammasome activation (NLRP3, AIM2) when released in cytosol. what will this release?
pro-inflamm IL-1b and IL-18
normally occur due to mitochondrial damage, highlights need of competent mitophagy to remove dysfunctional mitochondria
