Lecture 17: Delivery of Fuel to the Mitochondria Flashcards
What are the 4 allosteric inhibitors of the TCA?
- NADH
- Succinyl-CoA
- Citrate
- ATP
What are the 4 allosteric activators of the TCA?
- AMP/ADP
- CoA
- NAD+
- Ca2+
Why does calcium stimulate the TCA?
Because internal concentration have been used by muscle contraction, so extracellular calcium is needed = starved state
What are the 3 exergonic steps of the TCA = the steps that are regulated?
1, 3, and 4
Why does NADH produced by glycolysis need to be transported to mitosol?
To be used by ETC
What are the 2 shuttles to transport NADH to mitosol?
- Malate-aspartate shuttle
2. Glycerol-3-phosphate shuttle
Describe the 6 steps of the malate-aspartate shuttle of NADH inside the mitosol.
- IMS: malate dehydrogenase reduces oxaloacetate to malate using NADH
- Malate crosses mito inner membrane via the malate-alpha-ketoglutarate transporter (antiporter)
- malate dehydrogenase oxidizes malate to oxaloacetate using NAD+ and making NADH
- Matrix: aspartate amino transferase converts oxaloacetate to aspartate (using amino group from glutamate to make alpha-ketoglutarate)
- Aspartate crosses mito inner membrane via the glutamate-aspartate transporter (antiporter)
- IMS: aspartate amino transferase converts aspartate to oxaloacetate (giving amino group back to alpha ketoglutarate to form glumatame)
ΔG°’ of oxaloacetate to malate?
Large negative (opposite of the other way around)
How does the concentration of oxaloacetate in the matrix compare to that in the IMS
Low in mitosol
High in IMS
In what 3 tissues is the malate-aspartate shuttle used?
- Liver
- Kidney
- Heart
What is a downside of the malate-aspartate shuttle?
Too slow
Describe the steps of the glycerol-3-phosphate shuttle.
- IMS: glycerol-3-phosphate dehydrogenase coverts DHAP to glycerol-3-phosphate using NADH
- H2 is transferred from glycerol-3-phosphate to FAD forming FADH2 and DHAP (complex II of ETC)
- H2 is transferred from FADH2 to Q
Why does 1 NADH either produce 1.5 or 2.5 ATPs?
1.5 if using glycerol-3-phosphate shuttle because bypassing Complex I so lack of 4 H+ being pumped out of matrix
What is a downside of the glycerol-3-phosphate shuttle?
Only produces 1.5 ATP per NADH instead of 2.5
How many ATP per glucose if the malate-aspartate shuttle for glycolysis NADH is used?
32
How many ATP per glucose if the glycerol-3-phosphate shuttle for glycolysis NADH is used?
30
How are fats (triacylglycerides) transported from the small intestine to target cells? 6 steps
- Bile salts emulsify FAs so that they can access the more aqueous environment
- Pancreas secretes lipases to degrade TAGs into FAs and glycerol
- Mucosa takes up FAs + glycerol, re-esterifies them into TAGs, and packages them into chylomicrons
- Chylomicrons travel through blood and lymph and bind to target tissues
- Lipoprotein lipase activated by apoC-II to hydrolyze TAGs into FAs and glycerol for absorption
- TAGs are reformed
Can TAGs cross cellular or mucosal membranes?
NOPE
What are chylomycrons? What 4 types of molecules in them? Which one responsible for triggering TAG/cholesterol uptake?
Giant oil droplets containing TAGs, cholesterol, phospholipids, and apolipoproteins (triggers)
What happens to the chylomicrons once they deliver TAGs to target cells? 3 steps
- Liver collects them and repackages FAs and cholesterol in them into VLDLs (very low density lipoproteins)
- VLDLs release their FAs to other tissues to become LDLs (with more cholesterol than FAs)
- Liver collects LDLs
Which are responsible for heart disease: VLDLs or LDLs?
LDLs
What happens to the FAs when they are taken up by adipocytes?
They are stored as tryacylglycerides in lipid droplets encased in perilipin which shields them from surrounding water
How do we break down the fat stored in adipocytes? 5 steps
- Adrenaline is released in blood and triggers the release of cAMP
- cAMP activates PKA
- PKA phosphorylates perilipin which changes its conformation
- PKA phosphorylates hormone sensitive lipase
- HSP has access to TAGs and degrades them into FAs + glycerol
How are FAs transported in the blood from adipocytes to target tissues?
Albumin
What are the 2 possible fates of DHAP produced by glycolysis? When does each happen?
- Conversion to glyceraldehyde 3-phosphate (GAP) to continue down glycolysis: need energy
- Conversion to glycerol 3-phosphate to be used in TAG synthesis or in the glycerol-3-phosphate shuttle: well-fed
What are the 2 ways to synthesize glycerol-3-phosphate for TAG synthesis? When is each used?
- Glycerol kinase phosphorylates glycerol using ATP: when glucose is low
- Glycerol 3-phosphate dehydrogenase converts DHAP to glycerol-3-phosphate: when glucose is high
Which ONLY 2 tissues can synthesize tryacylglycerols when glucose is low? Why?
- Liver
- Kidney
They have the glycerol kinase enzyme meaning that glycerol-3-phosphate can be made by glycerol phosphorylation (without DHAP)
How are FAs attached to glycerol-3-phosphate to produce TAGs? 6 steps
- Acyl-CoA synthetase attaches CoA-SH to FA to activate it using ATP (actually 2 steps)
- Acyl transferase removes CoA-SH and attaches the FA to glycerol-3-phosphate
- Steps 1 and 2 repeated to obtain phosphatidic acid
- Phosphatidic acid phosphatase takes off phosphate group on glycerol
- Steps 1 and 2 repeated to add the last FA
How are FAs delivered to the mitosol for beta oxidation? 3 steps. For which FAs does this happen?
- Carnitine-acyltransferase I attaches FA-CoAs to carnitine in cytosol
- Transport to mitosol
- Carnitine-acyltransferase II cleaves off carnitine
FAs that have 14 Cs or more
What is the role of malonyl-CoA?
It’s the product of the first committed step of FA beta oxidation and inhibits CAT I from transporting more FAs in mitosol
What % of FAs are made into TAGs during starvation?
75%
How does the Atkins diet work?
Low of glucose = low glycerol-3-phosphate synthesis = low TAG synthesis in adipocytes
What are the 2 uses for exporting aspartate out of the mitosol?
- Exporting oxaloacetate (for use in the malate/asparte shuttle)
- Exporting Nitrogen
How does the esterification of FAs affect their hydrophobicity? Why?
Increase hydrophobicity because no more negative charge on carboxylic end of FA
What are the 2 ways of synthesizing DHAP? Which one is fastest?
- Glycolysis (fastest)
2. AA degradation
What does the rate of TAG synthesis in adipose tissue (aka fat storage) depend on?
The availability of DHAP
What happens to FAs before they are sent to the mitosol via the carnitine shuttle? What 2 things drives this whole rxn forward?
Fatty-acyl CoA synthetase adds S-CoA to them:
- Adds adenylate (adenosine + P) from ATP
- Adds CoA-SH releasing AMP
Driving RXN forward:
- PPi is degraded by pyrophosphatase
- AMP converted to ATP
