Mitochondrial dysfunction and ageing Flashcards
mitochondrial function
- Energy production in the form of ATP
- Modulation of nutrient signalling pathways
- ROS production and defence
- Regulation of apoptosis
- Maintenance of cellular proteostasis
- Calcium signalling
- Thermogenesis
structure
- double membrane:
• The outer membrane encloses the entire organelle and has many porins
• Intermembrane space
Because the outer membrane is freely permeable to small molecules, the concentrations of small molecules, such as ions and sugars, in the intermembrane space is the same as in the cytosol.
However, large proteins must have a specific signalling sequence to be transported across the outer membrane, so the protein composition of this space is different from the protein composition of the cytosol.
One protein that is localized to the intermembrane space in this way is cytochrome c.
• Inner membrane has 3 times more proteins than other membranes, high regulation of ion and molecule transport across this membrane
Among these proteins are the ones responsible for the electron transport chain
ATP synthase
Specific transport proteins for metabolites that pass in and out of the matrix
- Cristae= the numerous folds of the inner membrane, which expand the surface area of the inner mitochondrial membrane, enhancing its ability to produce ATP.
- Matrix= the enclosed space within the inner membrane
The matrix contains a highly concentrated mixture of hundreds of enzymes, special mitochondrial ribosomes, tRNA, and several copies of the mitochondrial DNA genome.
Of the enzymes, the major functions include oxidation of pyruvate and fatty acids, and the citric acid cycle.
special features
- They have their own DNA (maternal mtDNA)
• Circular
• No introns
• No histones
• DNA polymerase-y which is less accurate than the nuclear form (beta)
• Codes for 13 proteins - Has its own ribosomes
- Has its own life cycle
- Uses 1500 cellular proteins that are actively transported in to the mitochondrion via TOM/TIM complexes
• In order to go into the mitochondria they need to be unfolded
• Once inside the mitochondrial targeting sequence is cleaved off (protease) and chaperones fold the protein: quality control (if not good –> UPS)
mtROS
- In the electron transport chain ROS can be created by 1-elctron oxidation (complex 1 and 3 mainly) superoxide anion is produced
• Superoxide can be converted into hydrogen peroxide by super oxide dismutase
• H2O2 is also a ROS and can leave the mitochondria via aquaporins and damage cellular components directly or can be turned into harmful hydroxide radicals via the Fenton reaction and Haber Weiss reaction
mtDNA and mtROS
- mtDNA is very sensitive to damage and base mutations due to:
• A lack of nuclear membrane and histone proteins
• Lack of introns
• Directly exposed to ROS in the matrix
• Mitochondria have BER and NER but no DNA double strand break repair
• And besides ROS damage polymerase-y is less accurate and causes more errors
free radical theory of ageing
- ROS produced in the electron transport chain
- ROS damages mtDNA –> mutations
- Faulty proteins are used in the electron transport chain
- More ROS is produced
- ROS leaves mitochondria and damages the whole cell
- Ageing due to systemic tissue damage (and inflammation)
On the other hand, free-radical scavenger systems, DNA repair systems and mitochondrial turnover for removal of the oxidative damages by ROS and free radicals become less efficient in the aging process
mitochondria/ROS and inflammation
Mitochondrial dysfunction and subsequent ROS production leads to NFkB activation (TNFalfa, IL1, IL6) , and release of DAMPs which can activate TLRs on neutrophils (TNFalfa, IL1, IL6) and stimulate the inflammasome (IL1beta) –> chronic systemic inflammation (and thus more ROS) due to age related mitochondrial ROS production (inflammaging)
scavenger system
The scavenger system uses antioxidant in the mitochondria to eliminate ROS before it can damage mtDNA or other cellular components
- super oxide dismutase turns super oxide into H2O2
- H2O2 can be turned into water by catalase or glutathione peroxidases (these also reduce lipid peroxides)
Gpxs use GSH (glutathione) to reduce H2O2, in the proces GSH is oxidised to GSSG whihc can be reduced back to GSH by glutathione reductase
mtDNA repair
BER, NER and MMR which can be initated via H2O2 (ATM/ATR sensors)
no ds break repair (NHEJ/HEJ)
BER
uses glycosylases that remove single bases while leaving the sugar-phosphate intact
NER
use either DDB protein (or XPC) to initiate removal of a short DNA stretch or the bulky lesion causes RNA polymerase to stall which serves as a damage signal
after initiation DNA polymerase and ligase fill in the bases and backbone
MMR
- MutS recognises the mutation (insertion/deletion) and binds to the DNA
- MutL binds to MutS-DNA complex
- MutH recognises a GATC-site –> MutH is a weak endonuclease and creates an incision in the backbone of the DNA (G/A)
(MutH differentiates between the new and old strand because of the lack of methylation of the new strand) - The DNA curves in order to bind MutH to MutL to activate them to create the incision creating an open 3’ end
- Exonuclease can now start from this point and removes the nucleotides including the mutation
- DNA polymerase 1/3 now fills in the gap and ligase fills in the backbone nick
protein repair in mitochndria
- misfolded proteins –> mitochndrial proteases
- non-imported damaged proteins–> UPS
- oxidised lipids/proteins –> exported via vesicles to fuse with lysosome
- mitophagy to remove large damaged portions
life cycle
- biogenesis: can occur due to exercise which induces AMPK which causes transcription of PGC-1alfa –> this causes transcription of NRF1/2 –> TFAM –> transported into mitochondria and initiate mitochondrial biogenesis
- Mitochondrial fusion and fission: occurs constantly in response to damage of ROS or poisons.
They are wrenched apart and stripped from their damaged pieces (mitophagy) and then reassembled into functional mitochondria
• Fusion: MFN1 and 2 and OPA1
• Fission: DRP1 and FIS1 (adaptor)
• Mitophagy: PINK and parkin and
caloric restriction
CR activates systems involved in a more efficient metabolism, a higher protection against cellular damage and the activation of remodelling mechanisms, whereas less efficient metabolism and synthetic pathways are blocked
• Regulators of a more efficient respiratory metabolism such as the AMPK pathway will be preferred over growth inducing pathways such as IGF-1 and Tor pathways
- CR lowers mitochondrial membrane potential and consequently the production of ROS
- CR increases fission, fusion and remodelling of mitochondrial network reducing the amount of damaged mitochondria in the network (mitophagy) via SIRT and FoxO (FoxO is normally inactivated via IGF signalling which is inhibited under CR conditions)
- CR activates SIRT which inhibits the NFkB pathway, reducing inflammation, and increases mitochondrial turnover and induces antioxidant production (via NRF2)
