Oxidative phosphorylation - The Warburg Effect

Oxidative phosphorylation - The Warburg Effect

1. Oxidative phosphorylation

   • Mechanism of action
     • It takes place in the electron transport chain in the mitochondrial ridges
       • The electron transport chain is composed of the oxidative phosphorylation complex
         • The oxidative phosphorylation complex is composed of proteins that are generated in the cytosol forming complexes that come to assemble in the mitodondrial ridges.
           • Complexes of the electron transport chain
             • Complex 1
               • Name
                 • NADH dehydrogenase
               • Functions
                 • Receive and oxidize NADH
                 • Transfers the oxidized electrons from NADH to coenzyme Q
                 • Allows proton (H) exit into the intermembrane space of the mitochondria
             • Complex 2
               • Name
                 • Succinate dehydrogenase
               • Functions
                 • Receive and oxidize FADH2
                 • Transfers the oxidized electrons from FADH2 to coenzyme Q
                 • Does not allow protons (H) to exit into the intermembrane space of the mitochondrion
             • Complex 3
               • Name
                 • Ubiquinone cytochrome C oxidoreductase
               • Functions
                 • Receive electrons from coenzyme Q
                 • Transfers the electrons received from complex 1 and 2 to cytochrome C
                 • Allows proton (H) exit into the intermembrane space of the mitochondria
             • Complex 4
               • Name
                 • Cytochrome oxidase
               • Functions
                 • Receive electrons from cytochrome C
                 • Reduce O2 by converting it to H20
                 • Allows proton (H) exit into the intermembrane space of the mitochondria
             • Complex 5
               • Name
                 • ATP synthetase
               • Functions
                 • Collects the protons accumulated in the intermembrane space and the ADP + inorganic phosphorus
                   • And converts them to ATP
       • The reducing power of NADH and FADH will be transported by shuttles
         • Complex 1 receives NADH
           • NADH is oxidized losing its electrons and becoming NAD
             • The NAD will be reused in the different processes of the mitochondria such as
               • The Krebs cycle
             • The electrons obtained pass towards coenzyme Q
               • The electrons that are in coenzyme Q pass to complex 3
                 • Complex 3 will pass the electrons to cytochrome C
                   • Cytochrome C pass electrons to complex 4
                     • In complex 4 there is the reduction of oxygen from the electrons that have been transported by the complex chain
                       • When the transfer of electrons occurs by the oxidation of NADH to NAD, as the electrons pass through the different complexes, it begins to generate
                         • The exit of protons from the mitochondrial matrix towards the intramembrane space, this exit occurs through the complexes
                           • Complex 1
                             • The accumulation of these protons will generate an electric PH potential
                               • That potential will be used by ATP synthetase, which will collect
                                 • Electric potential (accumulated H)
                                   • To form ATP
                                     • This ATP will return to the mitochondrial matrix and will be used for all the physiological processes of the cell.
                                 • ADP
                                 • Inorganic phosphorus
                           • Complex 2
                           • Complex 3
                           • Complex 4
         • Complex 2 receives FADH2
           • The FADH2 will be oxidized, losing its electrons and becoming FAD
             • The NAD will be reused in the different processes of the mitochondria such as
               • The Krebs cycle
         • Types of shuttles
           • Aspartate malate
             • Transfers reducing power from NADH to NADH
           • Glycerophosphate
             • Transfers the reducing power of NADH to FADH2
   • Pathophysiology associated with a failure in oxidative phosphorylation
     • Leber's hereditary optic neuropathy
       • Characterized by acute central vision loss
       • It begins in the third or fourth decade of life
       • Generated by many mutations of mitochondrial DNA
     • Mitochondrial encephalomyopathy
       • Caused by mutations in the mitochondrial tRNAleu gene
       • It is a progressive neurodegenerative disease
       • Characterized by episodes of chemical strokes
     • Myoclonic epilepsy with ragged red fibers
       • It is characterized by
         • Dementia
         • Uncontrolled muscle contractions
         • Ataxia
         • Myopathy
       • Caused by mutations correspond to the mitochondrial tRNAlys gene
     • Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia
       • Caused by a large contiguous deletion in mtDNA that results in gene loss
       • They are characterized by
         • Ophthalmoplegia
         • Retinitis pigmentosa atípica
         • Miopatía de fibras rojas rasgadas
         • Deafness
     • Neuropathy, ataxia, and retinitis pigmentosa
       • It is a progressive condition
       • Characterized by
         • Neuropatía sensitiva
         • Muscular weakness
         • Sight loss
       • Caused by mutations in the ATP6 gene in mtDNA

2. The Warburg Effect

   • Who discovered it?
     • Discovered by the German chemist Aby Moritz Warburg (1866-1929)
   • Mechanism of action
     • Cells go into hypoxia
       • Only anaerobic metabolism can occur
         • Generating a decrease in ATP production
           • Cells create metabolic adaptations to try to obtain greater efficiency in obtaining energy
             • Cells become addicted to glucose for energy
               • The tumor induces angiogenesis to restore oxygen
                 • Angiogenesis
                   • Formation of new blood vessels
                 • In the Warburg effect they will continue to produce lactate
                   • By maintaining the production of more anaplerotic molecules are generated
                     • Anaclerotic molecules
                       • Molecules that will be used for other things than obtaining energy
                       • In anaerobic glycolysis we find
                         • Dihydroxyacetone-phosphate
                           • Goes the pentose phosphate pathway
                             • For the synthesis of Ribose
                         • Glyceraldehyde-3 phosphate
                           • Glycerol can be obtained from this molecule
                         • 1,3 Bisphosphoglycerate
                           • Regulator of the affinity of hemoglobin with O2
                             • Reduces affinity
                               • These anaplerotic molecules cause the proliferation of the tumor, sacrificing ATP production
               • Cells become addicted to
                 • Obtain rapid ATP synthesis
                 • Allows obtaining anaclerotic molecules
                 • Acidifies the tumor environment
                   • Due to the accumulation of lactate outside
                 • Route activation
                   • Tumor survival
                   • Metabolic adaptation
   • The first hit for the metabolic adaptation of the Warburg effect is detected by the hypoxia-induced factor (HIF1)
     • The hypoxia factor is activated under the amount of O2
       • Generate
         • Increase the expression of
           • GLUT 1
           • GLUT3
         • Increases hexokinase activity
         • Increases activity of pyruvate phosphofructokinase
           • Phosphorylated glucose at a higher rate
         • Higher expression of pyruvate kinase M2
           • Increases the rate of transformation of PEP to pyruvate
         • Higher expression of LDHA
           • To convert pyruvate to lactate
         • Increased MCT4 expression
           • It allows to remove the lactate to acidify the environment
         • You get more NADH
           • To protect against free radicals associated with hypoxia
         • Decreases the degradation of tumor cell proteins
           • Decreases proteolysis
         • Induce cell proliferation and survival
           • Route CDK5

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