Mitochondrial Bioenergetics Flashcards
Acetyl-CoA obtained from:
Carbohydrates: Decarboxylation of Pyruvate
Glucose (6C) —> 2 Pyruvate (3C) —> 2 Acetyl-CoA (2C)
Lipids: beta-oxidation of FA
TAG —> FA —> Acetyl-CoA
Proteins: Breakdown of various AA —> Acetyl-CoA
Free energy of Aceytl-CoA (delta G)
-7.5 kcal/mol
How Pyruvate enters mitochondria?
Enzyme for decarboxylation of Pyruvate to Acetyl-CoA?
Pyruvate Mitochondrial Carrier
Pyruvate Dehydrogenase Complex (PDC) (releases NADH and CO2)
Pyruvate Dehydrogenase Complex (PDC)
Decarboxyates pyruvate into CO2 and forms Acetyl-CoA and NADH.
PDC: 3 Enzymes + 5 Coenzymes
- Coenzymes: Thiamine Pyrophosphate TPP (Vitamin B1), lipoic acid, FAD (Vitamin B2 - Riboflavin), CoA (Vitamin B5 - Pantothenic Acid), NAD+ (Vitamin B3 - Niacin)
Inactive PDC = Pyruvate converting to lactate —> build-up —> Lactic Acidosis
Pyruvate Dehydrogenase Phosphatase (PDP)
Activates PDC by dephosphorylation
PDP activated by: Ca2+ , Mg2+ —> PDC activation
Pyruvate Dehydrogenase Kinase (PDK)
Inactivates PDC by phosphorylation
PDK activated by: Acetyl-CoA , NADH , ATP (feedback inhibition)
PDC inactivated by: Pyruvate, CoA, NAD+, ADP (feed-forward stimulation of PDC via inactivation of PDK)
Citrate Synthase rxn and regulation
Catalyzes TCA reaction:
oxaloacetate + Acetyl-CoA —> Citrate
Stimulated by: Insulin, Acetyl-CoA, Oxaloacetate
Inhibited by: Citrate, NADH, Succinyl-CoA, ATP
Isocitrate Dehydrogenase (reaction and regulation)
Catalyzes TCA reaction:
Isocitrate —> alpha-ketoglutarate
Rate-limiting Enzyme
Produces NADH and CO2
Stimulated by: ADP, Ca2+
Inhibited by: NADH, ATP
Alpha-ketoglutarate Dehydrogenase Complex (reaction and regulation)
Catalyzes TCA reaction:
Alpha-ketoglutarate —> Succinylcholine-CoA
Produces NADH and CO2
Stimulated by: Ca2+
Inhibited by: NADH, Succinylcholine-CoA, ATP, GTP
Anabolic molecules in TCA
Malate: malate—>oxaloacetate—>PEP—>glucose
Citrate: Citrate—>Acetyl-CoA —>FA synthesis
alpha-ketoglutarate: Glutamate—> Glutamine, Proline, Arginine
Oxaloacetate: Aspartate, Aspargine
2-Oxoglutaric Aciduria
Rare disorder with global developmental delay / severe neurological problems
- metabolic acidosis
- severe microcephaly
- mental retardation
Fumarase Deficiency
Severe Neurological impairment, fatal outcome within 2 years of life
- increased urinary excretion of fumarate, succinct, alpha-ketoglutarate and citrate
- encephalomyopathy
- dystonia
Autosomal Recessive disorder
Succinyl-CoA synthetase (SCS) deficiency
Associated with mutation 2/3 subunits making up enzyme
Mutated genes: SUCLA2, SUCLG1
Standard reduction potential relation with free energy change
ΔG’ = -nFΔE’
Standard reduction potential and Standard free energy change are inversely related
OxPhos complexes that create ROS
Respiratory chain complex I and III
They produce superoxide anions and hydrogen peroxide (some of which gets reduced by glutathione)
Overproduction of ROS: Damage to DNA, Protein, lipids
Normal production: Growth, hormone synthesis, inflammation
Proton motive force (PMF)
Constitutes (1) pH gradient. (2) Membrane potential
ATP Synthase
Complex IV of the respiratory chain.
Harnesses energy contained in pmf
7.3 kcal/mol to form ATP
Oligomycin
Drug that disrupts proton transport through the ATP synthase channel
Cytochrome-c
Mobile electron-carrying molecule moving between complex III and IV of the respiratory chain.
Travels in the intermembrane space and the inside of the inner mitochondrial membrane (where the chain complexes are located)
CoQ (ubiquinone)
A lipophilic molecule that is a mobile electron carrier for complexes I and II, bringing electrons to complex III.
Uncoupling in proton gradient
Normally in OxPhos, electron transfer is coupled with the proton gradient.
When gradient is disrupted —> Uncoupling occurs
- ATP synthesis uncoupled from electron transfer
- Protons re-enter matrix from intermembrane space
- ATP synthesis inhibited
- HEAT GENERATED (thermogenesis)
How NADH (reduced) crosses mitochondrial membrane
Electron transfer via
(1) malate-aspartate shuttle: heart, liver, kidneys —> NADH (e-) enters ETC at COMPLEX I
(2) Glycerophosphate shuttle: skeletal muscle, brain —>FADH2 (e-) enters ETC at CoQ (ubiquinone)
Where malate-aspartate shuttle takes place?
Heart
Liver
Kidneys
Where glycerphosphate shuttle takes place?
Skeletal muscle
Brain
