The Brain Hypometabolism Hypothesis Part 77: Linking Oxidative Phosphorylation to Hypoxic Ischaemic Brain Injury

Model Brain

Having covered a number of key metabolic processes it is now possible to detail the link between Oxidative Phosphorylation and Hypoxic Ischaemic Brain Injury with reference to the previously discussed material. The terms and hypotheses involved are further elaborated below.

Hypoxic Ischaemic Brain Injury occurs when there is an interruption of cerebral blood flow leading to a reduction or cessation of delivery of Oxygen to the cells in the Brain. The term denotes the combination of hypoxia and ischaemia both of which can contribute to pathology.

However one clear pathological mechanism is the cessation or reduction in Oxygen supply. In the energy metabolic pathways various nutrients are involved in the production of Acetyl CoA which is incorporated into the Citric Acid Cycle in which NADH is produced. This is utilised in Oxidative Phosphorylation where Oxygen acts as an electron acceptor.

Since Oxidative Phosphorylation generates a relatively large amount of ATP, the reduction or cessation of the Oxygen supply interrupts this important supply of energy. This in turn interrupts the supply of energy to the ATP dependent ion channels resulting in membrane depolarisation and an influx of Calcium ions.

What is Oxidative Phosphorylation?

Oxidative phosphorylation is a series of chemical reactions in which electrons are transferred, nutrients are metabolised and ATP is formed. Nutrients are oxidised and the donated electrons are processed in the electron transport chain. ATP formation via ATP Synthase utilises the electron/proton gradient across the mitochondrial membrane according to the Chemiosmotic Theory.

What is the Chemiosmotic Theory?

The Chemiosmotic Theory is central to the understanding of Oxidative Phosphorylation. Proposed by Dr Peter Mitchell in 1961, the theory states that the energy for ATP generation derives from electrical and chemical gradients resulting from the transfer of electrons and protons across the mitochondrial membrane in the electron transport chain.


Ball and Stick Model of ADP by Jynto (Public Domain)

What is ADP?

Adenosine Diphosphate (ADP) is a precursor of ATP. ATP is synthesised from ADP and inorganic Phosphate by the enzyme ATP Synthase. ADP contains Adenine and Ribose both of which are also found in RNA.

What is ATP Synthase?


ATP Synthase by ALoopingIcon using QuteMol (CC BY 2.5)

ATP Synthase is an enzyme that combines inorganic phosphate and Adenosine Diphosphate to form Adenosine Triphosphate (ATP). This in turn is used as a source of energy.

What is Complex I?


Complex I by Tim Vickers (Public Domain)

The first step in Oxidative Phosphorylation in humans is the transfer of electrons from NAD via Complex I. The structure of Complex I is shown above. Complex I is also known as NADH-coenzyme Q Oxidoreductase. NADH donates electrons to Complex I in a reaction requiring Coenzyme Q10. The electrons are further transferred via Flavin Mononucleotide and Iron-Sulfur Complexes before the transfer of proteins into the intermembrane space.

What is NAD+?


NAD+ by Ben Miller (Public Domain)

Nicotinamide Adenine Dinucleotide (NAD) has a number of properties

  1. NAD exists in a reduced (NADH) and oxidised (NAD+) form
  2. NAD is a key molecule in oxidative phosphorylation
  3. NAD is formed by two nucleotides

What is Complex II?


Complex II by FVasconcellos and TimVickers (Public Domain)

Complex II is involved in Oxidative Phosphorylation and is also known as Succinate Dehydrogenase. Succinate is oxidised (donating electrons) to form Fumarate. The donated electrons enter the electron transport chain.


Complex III by FVasconcellos and TimVickers (Public Domain)

What is Complex III?

Complex III is also known as Q-cytochrome C Oxidoreductase. Complex III contains Cytochromes. Ubiquinol (a reduced form of Coenzyme Q10) donates electrons to Cytochrome C. Electrons are transferred between molecules in a circuit which causes four protons to be transferred across the Mitochondrial membrane for every 2 electrons. This forms part of the electron transport chain.

ATP Synthase is an enzyme that combines inorganic phosphate and Adenosine Diphosphate to form Adenosine Triphosphate (ATP). This in turn is used as a source of energy.


Complex IV by FVasconcellos and TimVickers (Public Domain)

What is Complex IV?

Complex IV is also known as Cytochrome C Oxidase. Complex IV contains Heme groups, Copper, Magnesium and Zinc. Complex IV facilitates the transfer of electrons to Oxygen in a reaction which results in the formation of water.

The Context of Hypoxic Ischaemic Brain Injury

Sekhon, Ainslie and Griesdale have written an open access article on hypoxic ischaemic brain injury titled “Clinical Pathophysiology of Hypoxic Ischemic Brain Injury after Cardiac Arrest:A “two-hit” Model“. This paper can be used as a starting point for discussion of the events that lead to brain injury following hypoxia. This in turn is relevant to the question of energy usage in the Brain Hypometabolism Hypothesis.

Sekhon, Ainslie and Griesdale posit a simple two stage model of brain injury following cardiac arrest in which injury results from

  1. Primary cerebral hypoxia
  2. Secondary mechanisms after return of cerebral perfusion

In Sekhon, Ainslie and Griesdale’s model they discuss primary and secondary brain injury following a cardiac arrest.

Primary Brain Injury after Hypoxia

Looking more closely at the primary brain injury they state that with a reduction in cerebral oxygen ATP production decreases and there is a switch to anaerobic respiration. This in turn leads to a reduction in ATP dependent ion channel action. There are three main effects

  1. Accumulation of Na+ ions
  2. Accumulation of lactate with acidosis
  3. An influx of Calcium ions into the cells

Secondary Brain Injury after Hypoxia

Sekhon, Ainslie and Griesdale identify 7 factors associated with secondary brain injury after hypoxia in their two stage model. These 7 factors are

  1. Microvascular Dysfunction
  2. Cerebral Oedema
  3. Anaemia
  4. Impaired Cerebral Autoregulation
  5. Carbon Dioxide
  6. Hyperoxia
  7. Hyperthermia

Mypinder S. Sekhon, Philip N. Ainslie and Donald E. Griesdale. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a “two-hit” model. Critical Care. 2017. 21:90. DOI: 10.1186/s13054-017-1670-9Index: There are indices for the TAWOP site here and here

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Disclaimer: The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.

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