CC: Oxidative Phosphorylation Flashcards
What are the 4 specific ways to disrupt mitochondrial function that we discussed in class?
1) Blocking TCA Cycle or Fatty Acyl ß-Oxidation
2) Ionophoretic/Protonophoretic Uncoupling and Disruption of the MPTP (Membrane Permeability Transition Pore)
3) Direct Inhibition of ETC (poisons)
4) Increased permeability of INNER membrane & loss of electrochemical gradient
What blocks the TCA Cycle?
Step 2) Sodium Fluoroacetate
What causes uncoupling of oxidative phosphorylation?
Ionophores: Pentachlorphenol FCCP DNP (dinitrophenol) Valinomycin
What directly inhibits the ETC?
Poisons, of which there are several, each acting at a different Complex in the chain.
What directly inhibits Complex 1 of the ETC?
Rotenone (derived from Derris root; used as fish poison and insecticide)
Amytal (barbituate)
Piericidin A (antibiotic)
Doxorubicin (Adriamycin®) (chemotherapy but cardiotoxic, binds to cardiolipin)
What directly inhibits Complex 2 of the ETC?
Nothing that we discussed. Complex 2 does not traverse the IMM. Instead, it only comes in contact with the matrix and deals specifically with FADH2.
What directly inhibits Complex 3 of the ETC?
ANTIFUNGALS! and a couple others…
Cadmium (Cd++) Antimycin A (antifungal) Stigmatellin (antifungal) Myxothiazol (antifungal; also Complex I) Azoxystrobin (strobilurin antifungal) Atovaquone (napthoquinone; toxoplasmosis, babesiosis, pneumocystis pneumonia, malaria in the combo drug Malarone)
What directly inhibits Complex 4 of the ETC?
Inorganics:
CO (carbon monoxide)
N3- (azide molecule)
Cyanide (cherry trees, targets respiratory center in CNS)
H2S (swine [poo] lagoons)
Phosphine (from zinc phosphide, a fumigant on farms)
What directly inhibits Complex 5 (aka ATP Synthetase) of the ETC?
Oligomycin
What does Cyanide do to the body?
Bright RED Blood due to the inability of ETC to utilize Oxygen in the blood. Body thinks you need more O2 so tachypnea ensues. DEATH occurs very quickly, VERY toxic.
What are sources of Cyanide?
Cherry Trees (trimmings), Spring Sorghum
How do you Dx Cyanide toxicosis?
> 200 ppm cyanide in forage
1-2ppm in blood or muscle
History of access to sources (cherry trees most common)
How do you treat cyanide toxicosis?
Cyanide binds to iron in Complex 4 so competitively binding it to another iron source, Methemoglobin, will work. SODIUM NITRITE will oxidize hemoglobin to methemoglobin.
SODIUM THIOSULFATE will react as a cofactor with Rhodanese (liver enzyme) to make thiocyanate which is removed in the Urine.
What does sodium fluoroacetate do in the body?
It will dissociate and FluoroAcetate binds OAA becoming FluoroCitrate which then binds irreversibly to ACONITASE enzyme (Step 2). Inhibiting ACONITASE inhibits the entire TCA Cycle.
What tissue is most susceptible to sodium fluoroacetate toxicity in the Dog and Cat?
Dog CNS Cat HEART
What are the tissues most susceptible to mitochondrial problems?
CNS and PNS, Cardiac Muscle (Heart), Skeletal Muscle, Kidney Proximal Tubules, Pancreatic ß-cells