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Samenvatting - BMS42 Targeting Cellular Processes (MED-BMS42)
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Targeting Metabolism with Small MoleculesSSA1 - iRAT1 – 02/10
1. NADH is a carrier of electrons and is produced, among others, during glycolysis. In which cell
does the energy captured in NADH lead to the largest amount of ATP?
Muscle cell > because red blood cells do not have mitochondria
2. Fatty acid synthesis and breakdown occur in different locations inside the cell. As such, the
activity of these processes can be regulated according to demand. In which intracellular
location does the catabolism of fatty acids (i.e. beta-oxidation) take place?
Mitochondria > synthesis happens in cytosol but catabolism in mitochondria.
3. Regulation of the activity of the TCA cycle is an important means to regulate the bioenergetic
status of a cell. What is the effect of a decrease in the cellular concentration of NADH on the
speed of the TCA cycle? The speed of the TCA cycle…
When there is a lot of NADH, then a lot of glycolysis took place. Cell has been breaking down food
components and is producing energy. The cell will be able to make enough ATP. The speed of the
TCA cycle will decrease.
4. The pyruvate dehydrogenase complex serves as a bridge between carbohydrates and the TCA
cycle. Which of the following compounds acts as negative allosteric effector of the pyruvate
dehydrogenase reaction?
ATP, NADH, Acetyl-CoA > when the cell has enough of these, the cell knows there is enough energy
5. During the TCA cycle an energy-rich nucleotide is formed, i.e. GTP. In which form is most of the
energy captured?
NADH > also FADH2, which both donate energy
6. “We observed a 17-month-old girl with profound and initially isolated episodes of
hypothermia. Thereafter, she developed growth delay, repetitive corneal and bone lesions.
Moreover, persistent hyperlactataemia in plasma and in CSF were reported. A deficit in
respiratory chain complexes III and IV was demonstrated in isolated skeletal muscle
mitochondria, circulating lymphocytes and fibroblasts by spectrophotometric and
polarographic studies. Describe the relevance of the production of lactate in this patient.
Lactate is produced to:
To form NAD+ > needed for anaerobic glycolysis to produce ATP due to negative feedback to form
Acetyl-CoA from Pyruvate. Pyruvate builds up, NAD+ converts pyruvate in lactate
7. The case study mentioned in the former question also reported a decrease in the expression of
UCP3 (uncoupling protein) mRNA. Which of the symptoms could be explained by this
observation?
Hypothermia > protein involved in brown fat. UCP: embedded in inner membrane of
mitochondria. Mitochondria build up proton gradient, normally ATP synthase produces ATP. If UPC
is present, this gradient will not exist anymore.
8. A 34-year-old farmer was brought to the ER with serious breathing problems. His breathing
was increased, his body temperature was 39,3oC and he displayed profuse sweating. He
appeared to have used the insecticide o-dinitrocresol during the past few days. Shortly after
entering the ER he went into a coma and died. Autopsy showed that he hardly had any fat, he
suffered from a slight oedema and his bone marrow was strikingly red. How can the symptoms
described above be explained? O-dinitrocresol is a compound that:
, Inhibits the built up of the electrochemical gradient in the mitochondria >
Red bone marrow because they need more blood cells because they need and use more oxygen.
Oedema: lots of fluid into the tissue. Normally to prevent oedema and keep fluid in the blood
albumin is used. Albumin will be used up and digested because you need ATP. This will result in
oedema.
9. Reduced QH2 is not formed by which of the following?
Complex III and cytochrome c > complex I transfers electrons from NADH to ubiquinone, reducing
it to ubiquinol (QH2). Complex II oxidizes succinate to fumarate and transfers the electrons to
ubiquinone, reducing it to QH2. NADH donates electrons to complex I, forming QH2. Succinate
donates electrons to complex II, forming QH2
10. The graph below shows an experiment in which isolated mitochondria are supplied of malate
and Pi. Only upon addition of ADP does O2 consumption start. Which complex is inhibited by
compound X in this experiment?
Complex I > when succinate is added oxygen consumption was started again, succinate is used by
complex II. So this means that complex I is inhibited
11. The graph below shows an experiment in which isolated mitochondria are supplied of malate
and Pi.
Complex IV (cytochrome c oxidase): The lack of response to ADP, succinate, ascorbate, and DNP
suggests that complex IV is inhibited. Since complex IV is responsible for transferring electrons to
oxygen, its inhibition would prevent the final step in the electron transport chain, resulting in
reduced oxygen consumption regardless of upstream activity.
, LE – Mitochondrial diseases: pre-clinical drug discovery – 03/10
Mitochondrial function and disease
• Lots of diseases are caused by or linked to malfunctioning of mitochondria
Glucose is converted into pyruvate by glycolysis and pyruvate is converted into Acetyl-CoA before it
goes into the citric acid cycle (with oxygen present). Without oxygen pyruvate is converted into
lactate. This cycle is to generate ATP. During TCA cycle, NAD+ is reduced to NADH by capturing
electrons from metabolic intermediated. NADH donates these electrons to complex I into the ETC:
, The mitochondrial electron transport chain (ETC)
• Several big protein complexes (compex I to IV)
• Complex I: NADH-Q reductase)
• Complex II: succinate dehydrogenase
• Complex III: cytochrome c reductase
• Complex IV: cytochrome c oxidase
• Complex V: ATP synthase
• Complex I converts NADH into NAD+ and therefore receives electrons > has a proton pump
but also donates electrons to Q
• Complex II receives electrons from conversion of FADH2 into FAD > no proton pump so
donates electrons to Q
• Q= ubiquinol
• Q gives electrons to complex III
• Complex III gives electrons to cytochrome C
• Cytochrome C gives electrons to complex IV
• Complex IV converts oxygen into water
• Happens in mitochondrial membrane
• pH and electron gradient occurs
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