L8 Mitochondrial Pharmacology Flashcards
4 main compartments of mitochondria
- outer membrane
- inner membrane space
- inner membrane (folded into cristate, machinery for OXPHOS)
- matrix (location for metabolic reactions)
How many genes does mtDNA encode?
37 (of which 13 are involved in the synthesis of subunits of respiratory chain)
3 main roles of mitochondria
- Energy production by OXPHOS
- Central carbon metabolism
- Biosynthesis of intermediates for cell growth & function
What are primary mitochondrial diseases?
A group of rare genetic metabolic disorders caused by mutations in nuclear or mitochondrial DNA, which result in malfunctioning mitochondria
Mutations in mtDNA only affect…
the integrity of the respiratory chain
Mutations in nuclear DNA disturb…
OXPHOS by impairing mitochondrial protein import, translation & assembly
When do secondary mitochondrial diseases occur?
When other pathological processes negatively impact mitochondrial homeostasis (age-related conditions e.g. neurodegeneration, metabolic disorders, HF)
Main role of mitochondria
energy production
OXPHOS can be divided into 2 basic parts. What are they?
The redox steps (ETC) and the energy-generation events (chemiosmosis)
Main steps of oxidative phosphorylation
- Delivery of electrons by NADH and FADH2
- Electron transport and proton pumping
- Splitting of oxygen to form water
- ATP synthesis
Complex I donates its electron (from NADH) to __
coenzyme A
FADH2 donates its electron to __
Complex II
Coenzyme A donates electrons to __
Complex III (cytochrome C oxidoreductase)
Oxygen collects electrons from __
Complex IV
Mitochondrial membrane potential is vital for…
maintaining the physiological function of the ETC to produce ATP
Significant loss in mitochondrial membrane potential results in…
depletion in cellular energy and subsequent cell death
Mitochondrial dysfunction causes significant changes in __ and __
cellular energy metabolism and ROS generation
Examples of harmful consequences of excessive mitochondrial ROS production
- lipid oxidation
- mtDNA/RNA damage
- protein oxidation
- Ca²⁺-dependent activation of MPTP
- cytochrome C release
Cytochrome C release from mitochondria will induce __
apoptosis (via activation of the intrinsic pathway)
Mitochondrial homeostasis is preserved by the fine coordination between two opposing processes:
- Generation of new mitochondria by mitochondrial biogenesis
- Removal of damaged mitochondria by mitophagy
What are the consequences of mitochondrial biogenesis?
- Increased OXPHOS capacity
- Diminishment of pathological oxidative stress
- Repair of mitochondrial-associated dysfunction
Important stimulant of mitochondrial biogenesis
PGC1α