Summary: 1: Mol. Reg. Of Energy And Nutrient Metabolism | Jaap Keijer

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• 1 Energy Metabolism

• 1.1 Introduction

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• What is the difference between a tumour cell and a cancer cell? What is metastasis?

  A cancer cell is invasive: it intrudes upon and destroys adjacent tissue, and sometimes metastasis, spreading to other locations in the body via lymph or blood.

• 1.2 Energy Metabolism

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• What is the aerobic ATP production chain?

  glucose -> glycolysis (produces 2 ATP) -> pyruvate -> acetyl coA -> TCA cycle (produces CO2) -> NADH and FADH2 -> Oxidative phosphorylation (requires O2) -> 32 ATP

• What is the Warburg Effect? Why is it found in cancer cells?

  Cancer cells display 'aerobic glycolysis': they produce ATP in the anaerobic chain in the presence of O2. Aerobic glycolyis is used to produce the nutrients needed for cell growth.

• What are the 2 drivers of altered cancer cell metabolism?

  1: tumor microenvironment: spatially and temporally heterogeneous, regions of low pH and low O2 and regions of normal pH and high O2 (near blood vessels)
  2: oncogenic signalling: cancer-associated signalling pathways induce metabolic reprogramming. 

• Oncogenic signalling: what do HIF, Ras/Myc/Akt and p53 do?

  HIF (hypoxia inducing factor) decreaeses O2 dependence.
  Ras, Myc and Akt upregulate glucose consumption and glycolysis.
  Loss of p53 facilitates the Warburg effect, the uncoupling of glycolysis from O2 levels.

• What are the advantages of the metabolic reprogramming?

  1: Increased biosynthesis of macromolecules
  2: avoid apoptosis (by blocking ROS)
  3: engage in local metabolite-based paracrine (close by) and autocrine (self) signalling

• What are the liabilities of metabolic reprogramming?

  1: build up of toxic metabolites
  2: high energetic demand, rely on increased ATP production via glucose or alternatives ie glutamine or FAs
  3: normal feedback is impaired, which may impose a selective disadvantage under treatment conditions

• 1.3 Mitochondria

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• What are the 10 functions of mitochondria?

  1: produces ATP
  2: responds dynamically to cellular energy demand
  3: regulates use of energy substrates (lipids, sugar, AmAcs)
  4: regulates urea cycle
  5: regulates calcium homeostasis
  6: regulatec AmAcs metabolism
  7: iron metabolism: heme and iron-sulphur (FeS) synthesis
  8: mediates apoptosis
  9: mediates innate immune defence
  10: regulates oxidative signalling, regulated by ROS

• Which are the 5 compartments of a mitochondrium?

  1: outer mitochondrial membrane (MOM)
  2: intermembrane space
  3:inner mitochondrial membrane (MIM)
  4: cristae, infoldings of MIM
  5: matrix

• 1.4 Mitochondrial Energy Metabolism

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• What are the 4 stages of mitochondrial energy metabolism?

  1: substrates are transported into mitochondria
  2: substrate oxidation
  3: electron transport chain (ETC) = respiratory chain
  4: ATP synthesis