Mitochondrial toxicity and autophagy - Pertubation by xenobiotics
13 important questions on Mitochondrial toxicity and autophagy - Pertubation by xenobiotics
Why does an electron leak result in ROS?
For what field mitochondria toxicity is important?
What is the result of blocking the TCA cycle?
Less electrons for the ETC.
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What does the compound fluoroacetate?
Fluoracetate is converted into flourocitrate.
This is similar to citrate. Citrate normally goes into the cycle. When Fluorocitrate get the spot, it inhibits the enzyme aconitase.
- Accumulation of citrate
- Blocking of glycolysis.
What causes fluoroacetate in human? And why?
- Lethal at 10 mg/kg
- Convulsions; CNS toxicity
- Cardiac arrhythmias
- Fibrillations
- Organ toxicity
Symptoms due to energy deficiency. Organ selectivity of the effects mirrors the high sensitivity of the brain and heart to be among the first organs that succumb to energy deprivation. Citrate accumulation is an indicator of poisoning.
How does it work chemically with fluoroacetate?
What succinate dehydrogenases are there and what do they influence?
- Malonate
- 3-Nitropropionic acid
They target the citric cycle and complex III of the ETC.
In the citric cycle:
Succinate is converted to fumarate by the enzyme succinate dehydrogenase. And fumarate can produce FADH2.
What is a toxicological (neurotoxin) difference between malonate and 3-nitropropionic acid?
- Malonate toxicity dependent on dose
- 3-NP = acute poising
- So, what causes binding to cardiolipin?
- Name a drug that does this.
- Drugs will concentrate in the inner membrane => leading to oxidation of cardiolipin => leading to displacement of cytochrome c in the inner membrane => initiate apoptosis
- Doxorubicin
What is doxorubicin for drug?
- Anti cancer
- Risk of cardiomyopathy
- Risk of accumulation
- Dose dependent
- Organ selective toxicity
What is the molecular mechanism of doxorubicin cardiotoxicity?
- Redox cycling
Doxorubicine bevat een quinon-structuur.
Neemt een electron op (van NADH)
Forms a semiquinone => give electron to O2 => superoxide.
What is the role of carnitine?
What are the two consequences of fatty acid beta oxidation inhibition?
- (1) Severe energy crisis. Mitochondrial -oxidation of fatty acids is the primary source of energy in some organs (e.g. liver, heart). In patients with preexisting mitochondrial diseases, the risk for VPA-induced liver injury is increased.
- (2) Accumulation of fatty acids. Microvesicular steatosis is phenotypically characterized by the accumulation of many small to mid-size lipid droplets in hepatocytes, distending the cells. Accumulation of these lipids also causes increased rates of lipid peroxidation and oxidative stress
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