Hypoxic Mitochondria PDF

Hypoxic Mitochondria Jules Devaux | [email protected]  Introduction UBO L1-M2 ORPHY - M1 2014-Hypoxie et altitude: 2009-2014 Physiology 2013-Effet de l’entraineme...

Hypoxic Mitochondria Jules Devaux | [email protected]  Introduction UBO L1-M2 ORPHY - M1 2014-Hypoxie et altitude: 2009-2014 Physiology 2013-Effet de l’entrainement UoA -M2 PPARalpha et nitrate sur f° mito 2014-Mitochondrial function in hypoxia-tolerant fish species 2015 - Mitochondrial PostDoc 2021-24 Research Technician adaptations in reef Effect of TºC on Centre for Brain research sharks Mt function PhD 2015-2019 Mitochondrial adaptations in Hypoxia tolerance BIOSCI758 ASML Applied Surgery and Metabolism Lab Tony Hickey Anthony Phillips Mitochondria Eco-physiology Sepsis Climate change Wound Healing Hypoxia Fatty liver Temperature Lymphatic fluid Exercise physiology CSF Pre-eclampsia Antioxidant Photosynthesis Pathology … … [email protected] [email protected]  Introduction Nicolas Pichaud Uni. Moncton Tony Farrell Holly Shiels UBC Uni. Manchester Steve Hands Graham Scott Mike Murphy LSDU McMaster Uni. Cambridge Uni. Why studying hypoxia? Why studying hypoxia?  Why studying hypoxia? Global warming and “oxygen Minimum Zones”  Introduction Oxygen Hypoxia? Mitochondrial (dys)function Hypoxia tolerance  O2 Fundamentals O2 Normoxia @ 0 atm: 0.21atm = 21.27 kPa =160 mmHg = 0.299 g.L-1 = 100%air sat PO2 Partial pressure Pa / bar / atm / torr / mmHg / % O2 Fundamentals  O2 Fundamentals Organisms changed throughout evolution as a result of oxygen fluctuations 4% 10-20% 35% 15% 27% 21%  O2 Fundamentals Oxidases Collagen Per day: ~550L (25 mol) 1mol O2 = ~3.5 mol ATP ~75kg O2 Fundamentals ~$9,500,000 !!!!! (NZD)  Mt function 101 Introduction Oxygen Hypoxia? Mitochondrial function Hypoxia tolerance  Mt function 101 Apoptosis DNA Cyt c release Protein synthesis ROS production Antioxidant response Metabolism Reductive stress Glutamate Lactate ß-oxidation Neuromediator clearance Glutamine->ate Hormone synthesis ATP Estrogen Redox balance NAD(H) Q10 Ca2+ regulation O2 Heat production Hibernation pH balance  Mt function 101 Glycolysis ATP LDH pyruvate lactate + H+ anaerobic aerobic e- oxphos ATP TCA O2  Mt function 101 Traditional view - “Chain” | Linear system - IMM - impermeable?!? - Individualised complexes … OUTDATED  Mt function 101 Supercomplexes - CI - CIII - CCO - Electron transfer - Localised Q-pool - Contained CytC pool  Mt function 101 - Cardiolipin - "Lubricant" for mt complexes  O2 Fundamentals - Cardiolipin - "Lubricant" for mt complexes  Mt function 101 - Cardiolipin - "Lubricant" for mt complexes Barth syndrom - Cardiomyopathy - Skeletal myopathy - ~exclusive in male - TAZ gene => taffazin  Mt function 101 - Proteins: - OPA - MICOS (mitochondrial contact site) - F0-F1 ATPase  Mt function 101 H+ ∆Ψm +++ ++ O2 c=n/V ATP  Mt function 101 - Functionality: - Proton tunnelling - "Efficient" ATP synthesis ∆Ψm +++ ++ ++ O2 c=n/V ATP H+ n=C.V Mt function 101  Mt function 101 ++ ∆Ψ +++ ∆Ψm + O O ATP AT H H Temperature  Mt function 101 Electron transport chain system 3D network  Mt function 101 Electron transport chain system  Introduction Oxygen Hypoxia? Mitochondrial function Hypoxia tolerance Hypoxic zones  How to define hypoxia? “Simply put, hypoxia is a shortage of O2“ So any level under 0.21 (atm) = 21.27 (kPa) =160 (mmHg) = 8.9 (mg.L-1) = 100% ? “…This is clearly an oversimplification“ Farrell & Richards; 2009 How long? To which level ? For who ? What scale are we talking about? O2 from air to mitochondria Environmental hypoxia  Acute hypoxia Richards, J. G. (2011). "Physiological, behavioral and biochemical adaptations of intertidal fishes to hypoxia." J Exp Biol 214(Pt 2): 191-199. Species exposed to acute hypoxia Triplefin fishes  Introduction Oxygen Hypoxia? Mitochondrial function Hypoxia tolerance Hypoxic zones Measuring hypoxia  How to determine hypoxia tolerance? Loss of equilibrium  How to determine hypoxia tolerance? Pcrit  How to determine hypoxia tolerance? Pcrit Nilsson, G. E. and S. Ostlund-Nilsson (2004). "Hypoxia in paradise: widespread hypoxia tolerance in coral reef fishes." Proc Biol Sci 271 Suppl 3: S30-33. How to determine hypoxia tolerance? How to determine hypoxia tolerance? Pcrit  Hypoxia tolerance Hypoxic zones Measuring hypoxia Animal scale Tissular / cellular Sub cellular  How to survive under hypoxia? How to supply enough ATP with limited O2?  Not enough O2, what can I do? Behavioural response: Escape Hypoxia Air breathing tolerance Aquatic surface ? respiration Fanning behaviour Abdallah, S.J., B.S. Thomas, and M.G. Jonz, Aquatic surface respiration and swimming behaviour in adult and developing zebrafish exposed to hypoxia. J Exp Biol, 2015. 218(Pt 11): p. 1777-86.  Increase supply to meet demand O2 Ventilatory system Circulatory system - VO2 - Heart Rate - Fish gill - Perfusion - Blood pressure - Hb  Increase supply to meet demand MATEY, V., RICHARDS, J. G., WANG, Y., WOOD, C. M., ROGERS, J., DAVIES, R., MURRAY, B. W., CHEN, X. Q., DU, J. & BRAUNER, C. J. 2008. The effect of hypoxia on gill morpholog and ionoregulatory status in the Lake Qinghai scaleless carp, Gymnocypris przewalskii. J Exp Biol, 211, 1063-74.  Increase supply to meet demand apport de + oxygène, nutriments et fats  Decrease demand to meet supply Bradycardia: Decreases heart demand Diminution fq cardiaque - moins de sang Increases perfusion - diminue perfusion ATP/mins ex : poisson volant : changement de densité entre eau et air (pas forcément le fait de rentrer dans l'eau) Seal heart rate RAMIREZ, J. M., FOLKOW, L. P. & BLIX, A. S. 2007. Hypoxia tolerance in mammals and birds: from the wilderness to the clinic. Annu Rev Physiol, 69, 113-43.  Decrease demand to meet supply 8°C Cunner 1°C Cod + soumis événement hypoxique, + tendance diminuer événements métaboliques CORKUM, C. P. & GAMPERL, A. K. 2009. Does the ability to T°C NILSSON, G. E. & RENSHAW, G. M. 2004. Hypoxic survival metabolically downregulate alter the hypoxia tolerance of fishes? A comparative study using cunner (T. adspersus) and Decrease O2 delivery strategies in two fishes: extreme anoxia tolerance in the Greenland cod (G. ogac). J Exp Zool A Ecol Genet Physiol, North European crucian carp and natural hypoxic 311, 231-9. Metabolic depression preconditioning in a coral-reef shark. J Exp Biol, 207, 3131-9.  Decrease demand to meet supply Down-regulation: Metabolic suppression ionic pumps protein synthesis mitochondrial respiration Maintain integrity? coma, T°C diminue  Decrease demand to meet supply What about NO?: Vasodilator apport en O2 + important au niveau des capillaires CCO inhibitor Effect of exercise and altitude. en prenant la place du complexe 4 NO increases O2 supply, yet depresses demand Decrease demand to meet supply  Hypoxia tolerance Hypoxic zones Measuring hypoxia Animal scale Tissular / cellular Intermittent hypoxia is good for you Intermittent hypoxia is good for you niveau de triglycérides qui diminuent dans le temps (bad fats) Moderate hypoxia promotes skeletal muscle cell growth and hypertrophy Surface area ! The hypoxic “cascade” Time of exposure Mitochondrial function  Mitochondrial function glycolysis Mitochondrial function - ∆Ψm  Mitochondrial function moins d'O2 --> moins de protage mbnaire --> perte potentiel mbnaire --> moins ATP - ∆Ψm - ATP  Mitochondrial function crampe : dégrader + ATP qu'on en produit - ∆Ψm --> + de protons - ATP crampe : muscles contractés --> pas assez d'ATP pour être décontracté + acidosis Mitochondrial function - ∆Ψm - ATP + acidosis Mitochondrial function - ∆Ψm - ATP + ADP + acidosis ~ metabolites = accumulation Mitochondrial function  Hypoxia tolerance Hypoxic zones Measuring hypoxia Animal scale Tissular / cellular Genetic scale  Mt function 101 Apoptosis DNA Cyt c release Protein synthesis ROS production Antioxidant response Metabolism Reductive stress Glutamate Lactate ß-oxidation Neuromediator clearance Glutamine->ate Hormone synthesis ATP Estrogen Redox balance NAD(H) Q10 Ca2+ regulation O2 Heat production Hibernation pH balance Genetic scale qd il y a O2 --> HIF-1a : tjs produit et consommé  Genetic scale Hypoxia Inductible Factor 1 Degradation regulated by hydroxypyrolase When O2: HIF-1𝛼 degraded HIF-1𝛼 + HIF-1ß: actif Up-regulation: Glycolytic Enz Antioxidants Genetic scale  Mt function 101 cellules cancéreuses : Apoptosis promoteur HIF1-a bcp + stable DNA Cyt c release = supporte mieux hypoxie Protein synthesis ROS production Antioxidant response Metabolism Reductive stress Glutamate Lactate ß-oxidation Neuromediator clearance Glutamine->ate Hormone synthesis ATP Estrogen Redox balance NAD(H) Q10 Ca2+ regulation O2 Heat production Hibernation pH balance  Anaerobic metabolism Glycolysis ATP LDH pyruvate lactate + H+ anaerobic aerobic e- oxphos ATP TCA O2  Anaerobic metabolism Problem… pH = -log10[H ] +  Anaerobic metabolism Problem…  Dealing with acidosis solution… transfrom lactate Mandic, M., et al., Metabolic recovery in goldfish: A comparison of recovery from severe hypoxia exposure and exhaustive exercise. Comp Biochem Physiol C Toxicol Pharmacol, 2008. 148(4): p. 332-8.  Dealing with acidosis solution… transfrom lactate Mandic, M., et al., Metabolic recovery in goldfish: A comparison of recovery from severe hypoxia exposure and exhaustive exercise. Comp Biochem Physiol C Toxicol Pharmacol, 2008. 148(4): p. 332-8.  Dealing with acidosis solution… buffer lactate  Dealing with acidosis solution… buffer lactate Calcium and pH buffering: Turtle shell liaison 2 mols : note: Ca-Lactate Shell, such as blood is a relatively good buffer Jackson, D.C., Surviving extreme lactic acidosis: the role of calcium lactate formation in the anoxic turtle. Respir Physiol Neurobiol, 2004. 144(2-3): p. 173-8. Dealing with acidosis Measuring the mt function  Measuring the mt function mt ADP KCN PO2 JO2 Time Measuring the mt function Measuring the mt function Measuring the mt function Acidosis in NZ fish Acidosis in NZ fish  Acidosis in NZ fish O2 consumption ATP production PO ratio  Mt function 101 Apoptosis DNA Cyt c release Protein synthesis ROS production Antioxidant response Metabolism Reductive stress Glutamate Lactate ß-oxidation Neuromediator clearance Glutamine->ate Hormone synthesis ATP Estrogen Redox balance NAD(H) Q10 Ca2+ regulation O2 Heat production Hibernation pH balance Calcium overload Calcium overload  Calcium overload - Endoplasmic Reticulum - Ca2+ - [Ca2+]intra¢ ~ 150 nm - >500 nm - Linked to apoptosis  Calcium overload Thomas Dupet  Calcium overload Thomas Dupet Redox state Redox state  Redox state Corentin Le Gallic  Redox state Rice, M.E., et al., Brain antioxidant regulation in mammals and anoxia-tolerant reptiles: balanced for neuroprotection and neuromodulation. Comp Biochem Physiol C Toxicol Pharmacol, 2002. 133(4): p. 515-25. Redox state Mitochondrial ROS origin : - Complex I - Q pool Hyper-reduced state within the ETS -> High ∆Ψm - High electron input - Low electron output métabolite qui s'accumule dans presque tous les organes (coeur, foie...) RET : reverse electron transport : electron revienne vers C1 --> anion supexoyde --> moins de ROS produite moins d'oxygène --> moins de ROS rouge : épaulette bleu : red carpet chair : champion de l'hypoxie M101 - Properties 36. MDa 156 O2 !! P50 7.05 => release below 10mmHg relâche oxygène en hypoxie (normal pressure = 26mmHg) 4ºC - 37ºC stable capacité anti-radicalaire - anti oxydante (peut être même + bénéfique que apport en O2)  Summary Problems HTS solutions: ATP supply / demand Metabolic depression Anaerobic capacities Lactate clearance pH / Ca2+ buffering Shell / Blood / other? ionic balance NMDA / Adenosine / Mito Oxidative stress (reox) Antioxidant / Mito cpmlx Summary  Summary Atm Trachea Alveoli Blood Brain Cell Mito 160 150 110 100 34 15 10 mmHg 100 94 69 62 22 9 6 %atm hypoxie pas que interne --> niveau Mitochondrial respiration Under Hypoxia Jules Devaux | [email protected]