MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

nemoci-sympt/METABOLISMUS/downuv-syndrom/10-energie

Amino acid catabolism

  • Source of energy especially in times of starvation or high-protein content diet
  • Generation of intermediates of the citric acid cycle, including:
    • Pyruvate,
    • Acetyl CoA,
    • Oxaloacetate,
    • Alpha-ketoglutarate
  • In human blood, glutamine is the most abundant free amino acid
  • Glutamine catabolism, as an energy source, plays an important role in
    • Cancer cell survival (Jiang et al. 2019)
    • Survival of mutant cells that harbor oxidative phosphorylation defects (Chen et al. 2018)
  • Amino acid catabolism results in
    • Ammonia - a toxic byproduct

Beta oxidation of lipids

  • Fats provide an efficient means for storing energy for later use
  • Fatty acids are broken down into acetyl-CoA molecules
    • Through beta oxidation inside the mitochondria
  • Each cycle of beta-oxidation, fatty acid is reduced by two carbon lengths producing
    • One molecule of acetyl-CoA
    • One molecule each of NADH
    • One FADH2
  • Acetyl-CoA molecule
  • Reduced electron carriers
    • Transfer their high energy electron to the mitochondrial electron transport chain
  • Acetyl-CoA can be converted to ketone bodies
    • Acetoacetate
    • Beta-hydroxybutyrate
    • Acetone
  • Produced by the liver during periods of glucose depletion
  • Ketone bodies are transported into organs
    • Requiring energy and converted back into acetyl-CoA
  • molmed.biomedcentral.com/articles/10.1186/s10020-020-00225-8

Defects of mitochondrial function

  • Contribute to a general loss of cellular functions
  • Most of which strictly depend on ATP availability (Coskun and Busciglio, 2012; Butterfield et al., 2014b; Valenti et al., 2018).
  • Mitochondria are the key organelles responsible for energy production
    • ATP through oxidative phosphorylation (OXPHOS) (Rolfe and Brown, 1997).
    • Oxidation, by beta-oxidation and Krebs cycle, of major macromolecules into key intermediates including:
      • Pyruvate,
      • Fatty acids,
      • Amino acids
    • Sources of reducing equivalents:
      • NADH, and/or FADH2
  • Loss of mitochondrial structure and function
    • Associated with increased ROS production,
    • Contributes to DS pathological phenotypes (Valenti et al., 2018).
    • Also other neurodevelopmental disorders such as:
      • Rett’s syndrome
      • Autism (Valenti et al., 2014),
      • Alzheimer’s disease
      • Parkinson’s disease (Johri and Beal, 2012)
      • ALS

Fuel molecules to high energy compounds

  • Adenosine-5'-triphosphate (ATP),
  • Guanosine-5'-triphosphate (GTP),
  • Reduced nicotinamide adenine dinucleotide (NADH)
  • Reduced flavin adenine dinucleotide (FADH2)
  • Reduced nicotinamide adenine dinucleotide phosphate (NADPH) (Dashty 2013)
  • Glucose is the most important source of energy
  • Other monosaccharides,
  • Fatty acids,
  • Ketone bodies,
  • Amino acids,
  • Nucleosides
    • Can also be used as an energetic source in a cell-specific manner (Berg et al. 2008).

Reduced rate of energy metabolism

  • Due to mitochondrial dysfunction
  • Significantly impairs neuronal functions and development and survival (Mattson et al., 2008).
  • ATP production and redox homeostasis in brain
    • Mitochondria are essential to sustain neural developmental processes including:
    • Cellular proliferation
    • Differentiation,
    • Axonal and dendritic growth
    • Generation of synaptic spine and pre-synaptic compartments (Mattson et al., 2008)
  • Mitochondrial deficits in DS is mainly the result of reduced efficiency to produce ATP through OXPHOS
    • Together with decreased
      • Respiratory capacity
      • Disruption of membrane potential
      • X mitochondrial dynamics.

Generalized metabolic and bioenergetic dysfunction

  • Present in DS
  • Contribute to organ developmental problems, neurological dysfunction
    • Neurons being highly ATP-dependent cells
  • Neurodegeneration as well
    • Bioenergetic deficit can cause problems with protein processing
  • Fundamental role of metabolic and bioenergetic alterations in DS
    • Suspected for over 70 years
    • Periodically re-emerged as a working hypothesis (Simon et al. 1954; Anon 1954; Breg 1977; Shapiro 1983; Blass et al. 1988; Lejeune 1990; Chango et al. 2002; Coppede 2009; Izzo et al. 2018; Vacca et al. 2019; Antonaros et al. 2020)

Krebs cycle

  • Acetyl-CoA molecule inside the mitochondria is fully oxidized to carbon-dioxide.
  • The total yield of one cycle is
    • One molecule of GTP
      • Readily converted to ATP by a nucleoside-diphosphate kinase enzyme (Haddad and Mohiuddin 2019).
    • Three molecules of NADH,
    • One molecule of FADH2
      • NADH and FADH2 are reduced electron carriers
  • molmed.biomedcentral.com/articles/10.1186/s10020-020-00225-8

Oxidative phosphorylation

  • NADH and FADH2 donated-electrons reach the mitochondrial electron transport chain
  • Generate an electron flow through the mitochondrial Complexes (I, II, III and IV)
    • Thus pumping protons into the inner membrane space from the mitochondrial matrix
      • Resulting proton gradient is then used by the ATP synthase (also known as Complex V) to generate ATP molecules
        • From ADP and inorganic phosphate
  • Oxidative phosphorylation produces 24–28 ATP molecules per glucose equivalent
    • More ATP than any other part of the cellular respiration (Haddad and Mohiuddin 2019)


Oxidační fosforylace

Pseudo-hypoxic state

  • Pathophysiological alterations that resemble the cellular responses associated with hypoxia
    • Even though the supply of the cells with oxygen is not disrupted
  • May be, at least in part, responsible for a variety of functional deficits associated with DS, including
    • Reduced exercise difference
    • Impaired neurocognitive status
    • Neurodegeneration
  • molmed.biomedcentral.com/articles/10.1186/s10020-020-00225-8

Pseudohypoxia

  • Hypoxia-like change in the metabolic phenotype of cells in diabetes
  • State in which cells or tissues express hypoxia-related genes and proteins
  • Use re-wired metabolic pathways even when there is enough oxygen present
  • Pseudohypoxic phenotypes have been observed in a number of pathophysiological conditions, including
    • Sepsis (Tannahill et al. 2013)
    • Alzheimer’s disease (Salminen et al. 2017)
    • Component of physiological aging (Verdin 2015)
  • Warburg (Warburg et al. 1927) observed similar phenomenon in various tumor cells;
    • Even when the cells are aerobic, they tend to mobilize glycolysis
    • Often not as an alternative, but as a supplementary process to the normal oxidative phosphorylation
      • To maximize ATP generation that the cancer cells require for their fast division and multiplication
  • molmed.biomedcentral.com/articles/10.1186/s10020-020-00225-8

Anaerobic state

  • Pyruvate remains within the cytoplasm and converts to lactate
  • Two molecules of NADH that are produced in glycolysis are oxidized to NAD+
    • By the reduction of pyruvate to lactate
  • Anaerobic glycolysis produces only two molecules of ATP
  • Unused glucose molecules are packed and stored in the form of glycogen
    • Serving as a fast energy resource in the liver and in the muscle (Melkonian and Schury 2019).
O úroveň výše

Poslední aktualizace: 30. 9. 2024 22:16:52