Driving natural systems: Chemical energy production and use Chemical energy and metabolism ATP usage and production Driving natural systems: Chemical Mitochondria and bioenergetic energy production and use control Modelling systems of chemical reactions Driving natural Metabolism systems: Chemical energy production and use I Metabolism: the sum of the physical and chemical processes Chemical energy in an organism by which its and metabolism material substance is produced, maintained, and destroyed ATP usage and production [anabolism], and by which energy is made available Mitochondria and bioenergetic [catabolism] control I Metabolism allows organisms to Modelling systems control biomass and energy of chemical reactions I A set of chemical transformations, often enzyme-catalysed I A complicated network: simplified through tools like flux balance analysis I Metabolism provides the energy for inference and control I Metabolism is itself controlled and regulated: metabolic control analysis, active regulation Driving natural Free energy systems: Chemical energy production I Energy that can be harnessed to perform work and use I At constant temperature and pressure (which we shall assume), the appropriate expression is the Gibbs free energy G(p; T ) Chemical energy and metabolism G(p; T ) = U + pV − TS ATP usage and production I Internal energy U, pressure p, volume V , temperature T , entropy S Mitochondria and bioenergetic I Change in free energy, where αj ; Xj are a feature and associated control potential that influence our system (e.g. N; µ: copy number and Modelling systems chemical potential of chemical species): of chemical reactions X X dG = Vdp − SdT + µi dNi − Xj dαj i j I We’ll consider chemical reactions, which take place at fixed p and T I Particle numbers Ni may be changed by reactions, and we also have to include the pair f∆Ψ; qg for charge across a membrane potential I Our Gibbs free energy change X dG = µi dNi − F∆Ψdq i Driving natural Energy from chemical reactions systems: Chemical energy production I Reversible chemical reaction with Si substrates, Pi products, and and use stoichiometry given by ai , bi : a1S1 + a2S2 + ::: b1P1 + b2P2 + ::: Chemical energy and metabolism I Change in free energy ATP usage and X production dG = µi dNi − F∆Ψdq i Mitochondria and bioenergetic I Chemical potential µ is a measure of the ‘concentration gradient’ in a control system Modelling systems 0 of chemical µi ∼ µi + RT ln ci reactions I For above reaction: µ dN = (µ0 + RT ln[S ]) × (−a ) Si Si Si i i µ dN = (µ0 + RT ln[P ]) × b Pi Pi Pi i i X 0 X bj X aj µi dNi = C(a; b; µ ) + RT ln[Pj ] − RT ln[Sj ] i j j I Broadly, if Z is total charge carried through a potential ∆Ψ (∆Ψmito ' −160 mV): ! Q [P ]bi ∆G = ∆G0 + RT ln i i − ZF∆Ψ Q ai i [Si ] Driving natural Activation energies systems: Chemical energy production and use Q bi ∆ = ∆ 0 + i [Pi ] − ∆Ψ Chemical energy I G G RT ln Q ai ZF i [Si ] and metabolism I Reactions with a negative ∆G net release energy and are sometimes ATP usage and described as ‘happening spontaneously’ production I There is still an activation energy / geometric contraints to overcome Mitochondria and bioenergetic (though this is sometimes possible to do thermally) control I ∆G doesn’t tell us how fast a reaction will progress Modelling systems of chemical reactions Driving natural Rates of chemical reactions systems: Chemical energy production I Chemical reaction and use a1S1 + a2S2 + ::: b1P1 + b2P2 + ::: Chemical energy and metabolism I Law of mass action: reaction rate ν / collision probability / reactant ATP usage and concentration [Xi ] production Y Y ν = ν − ν = k [S ]ai − k [P ]bj Mitochondria and + − + i − j bioenergetic i j control Modelling systems I Equilibrium constant is calculated when ν+ = ν− of chemical reactions Q eq bj k+ [Pj ] keq = = eq k Q ai − [Si ] I At equilibrium, in absence of charge coupling: ! Q [P ]bi 0 = ∆G = ∆G0 + RT ln i i Q ai i [Si ] I So 0 ∆G = −RT ln keq 0 I Negative ∆G ! k+ > k− ! forward reaction Driving natural ATP (adenosine triphosphate) as a cellular fuel source systems: Chemical energy production and use Chemical energy and metabolism ATP usage and production I ATP is used to provide energy for most energy-demanding cellular Mitochondria and processes bioenergetic control I Neurotransmitter synthesis: provides the energy for inference Modelling systems I Gene expression and regulation: provides the energy for control of chemical reactions I Muscle contraction: motion I Active transport across membranes I How do organisms synthesise and obtain energy from ATP? Driving natural ATP (adenosine triphosphate) as a cellular fuel source systems: Chemical energy production and use Chemical energy and metabolism ATP usage and production Mitochondria and bioenergetic control I Two phosphate bonds which may be hydrolysed, releasing energy (ATP $ ADP $ AMP) Modelling systems of chemical I Cells maintain ATP/ADP ratio out of equilibrium reactions 0 −1 I ATP + H2O ! ADP + Pi ; ∆G = −30:5 kJ mol I Under physiological conditions and typical cellular ATP/ADP ratio, ∆G ' −(40 − 60) kJ mol−1 I ‘Energy charge’ sometimes used for energetic status 1 [ATP] + 2 [ADP] [ATP] + [ADP] + [AMP] I The human body contains 0.2 mol ATP. We require the hydrolysis of 100-150 mol ATP per day (50-75 kg). Each ATP molecule is recycled 500-750 times per day. Driving natural ATP production systems: Chemical energy production and use 0 −1 I ATP + H2O ! ADP + Pi ; ∆G = −30:5 kJ mol Chemical energy I Under physiological conditions and typical cellular ATP/ADP ratio, and metabolism ∆G ' −(40 − 60) kJ mol−1 ATP usage and I But this is net energy release – ATP rarely breaks down on its own (it production would be a poor energy currency if it did) Mitochondria and I Proteins that harness ATP are usually ATPases – i.e. enzymes that bioenergetic control catalyse the hydrolysis of ATP (hence overcoming the activation energy) Modelling systems of chemical reactions Driving natural Some other players in bioenergetics systems: Chemical energy production and use Chemical energy I NADH: an electron donor used to transfer high-energy e− and metabolism + 1 + 0 −1 (NADH + H + 2 O2 NAD + H2O : ∆G = −220 kJ mol – one ATP usage and NADH used to synthesis several ATP) production Mitochondria and I Means of producing ATP (and NADH): bioenergetic I Glycolysis: energy production without oxygen (glucose ! 2 control + pyruvate + 2 ATP + NADH + H ) Modelling systems I Krebs cycle / citric acid cycle / TCA cycle: a circular set of of chemical reactions that takes in ‘fuel’ once per cycle and feeds oxidative reactions respiration (we’ll look at this in the practical) − I Oxidative phosphorylation: energetic e power proton pumps, setting up a harnessable electrochemical gradient I Fermentation (glucose ! lactic acid) I Photosynthesis (photons, proton pumps) I Replenishment with nucleoside diphosphate kinases (GTP ! GDP) Driving natural Oxidative phosphorylation systems: Chemical energy production and use Chemical energy and metabolism ATP usage and production Mitochondria and bioenergetic control Modelling systems of chemical reactions Driving natural Oxidative phosphorylation systems: Chemical energy production and use Chemical energy and metabolism (Biochemical detail is not examinable) I ATP usage and I Krebs cycle produces NADH and succinate production I A series of complexes pump protons through the inner mitochondrial Mitochondria and bioenergetic membrane control + + I Complex I: NADH + H ! NAD , pumps 4 protons, reduces coenzyme Modelling systems Q of chemical reactions I Complex II: succinate ! fumarate, reduces coenzyme Q I Complex III: Oxidises coenzyme Q, reduces cytochrome C, pumps 4 protons I Complex IV: Reduces cytochrome C, pumps 2 protons I Electrochemical potential (charge separation + chemical gradient) set up across membrane Driving natural Oxidative phosphorylation systems: Chemical energy production and use Chemical energy and metabolism ATP usage and production Complex V: energetic protons flow back Mitochondria and I bioenergetic into matrix control I F1 subunit in membrane; Fo subunit in Modelling systems the matrix of chemical reactions I (Amazing structure best understood by viewing animation) I Structure and function: John E. Walker, 1997 Nobel Prize in Chemistry Driving natural Oxidative phosphorylation systems: Chemical energy production and use Chemical energy and metabolism ATP usage and production Mitochondria and bioenergetic control Modelling systems of chemical reactions Driving natural Energy and life systems: Chemical energy production and use I Nick Lane: energy per gene expressed is key factor in evolution of complex life Chemical energy I Local mitochondrial genomes: local control of mitochondria and metabolism I Alternative 1: non-local genome, power sources not individually ATP usage and addressable production I Alternative 2: many full genomes localised to power generation: huge Mitochondria and amount of nucleic acid bioenergetic control I Mitochondria: small, individually addressable genomes localised to Modelling systems power generation of chemical reactions I ‘... being large and having masses of DNA is not enough to attain complexity: cells need to control energy coupling across a wide area of membranes using small, high copy, bioenergetically specialized genomes like mtDNA’ I Express 2 × 105 more genes with no energy penalty Driving natural Mitochondrial bioenergetic control systems: Chemical energy production I How can mitochondria be individually addressed by control? and use I