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International Journal of Applied Exercise Physiology

ISSN: 2322-3537 2014, 3(1)

Journal homepage: www.ijaep.com

Oxygen Deficit: The Bio-energetic Pathophysiology

Abhay Kumar Pandey

Present address: Tutor, Department of Physiology, All India Institute of Medical Sciences, Bhopal, Madhya
Pradesh, India

Article history: Received 3 may 2014; accepted 23 august 2014

mechanisms affect the amount of oxygen

1. Introduction
delivered to them, and these are under
Scarcity of oxygen in humans arises via
regulatory control of several functional
three modes. The environment may have
and metabolic systems.
low oxygen to breath. There can be disease

in respiratory system causing hindrance to

2. Aerobic energy metabolism and
uptake of oxygen from environment and
the Cytochrome oxidase
the circulatory system may be sluggish to
enzyme/system
supply to body parts that starve for
Oxygen delivered to the cells after
oxygen. Thirdly the chemico-cellular
taken in from the environment, participates
components of blood which carry oxygen
in reactions of aerobic energy production
may be lowered or defective. In reference
through cytochrome oxidase enzyme
to body cells several limiting sites and
catalyzed reactions. These mitochondrial
International Journal of Applied Exercise Physiology Vol. 3(1)

enzymes therefore are the ultimate part of and cell dysfunction. This involves series

respiratory system procurement of oxygen. of successive changes in activity of

These enzymes form energy currency or different enzyme complexes. Hypoxic

microergic molecules ATP and creatine dysfunction at cellular level starts at

phosphate using glucose from food and substrate site involving mitochondrial

oxygen. Deficit in oxygen availability enzyme complex I (MEC I). This initially

decreases this and causes failure of energy increases but finally depresses the activity

supply to run biological processes. Such of NADH-oxidase pathway causing

state is called tissue hypoxia or failure of disorder of electron transfer at the NADH-

bioenergetics. Suppression of function of Coenzyme Q site and process of

the cytochrome oxidase enzyme system by conjugated oxidative phosphorylation.

external toxic molecules was demonstrated Finally, the cytochrome oxidase enzymes

first and later even endogenous factors themselves are affected. This is verified in

infringing upon their functioning are functional changes studied in neurons,

revealed. State of oxygen deprivation also myocardial cells or hepatocytes. The ATP

impairs kinetic properties of these content then starts declining in proportion

enzymes. to fall in oxygen tension (PO2) in the cell

environment. The membrane of

3. Principles underlying biological mitochondria gets disrupted as also of

hypoxia under oxygen other organelles within cells. There is

deprivation release of enzymes in cytoplasm, active

The severity and/or duration of generation of free radical products and half

deprivation of oxygen availability of energy dependant functional events of

determine changes in energy metabolism cells. Degradation of adenine nucleotide to

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International Journal of Applied Exercise Physiology Vol. 3(1)

adenosine, inosine and hypoxanthine pathway and designated as compensatory

increases and finally the cell dies. Total phase of bio-energetic hypoxia. Stage II,

inactivation of cytochrome oxidase system the non-compensated stage, is

however, can occur only in complete characterized by suppression of electron

absence of oxygen or anoxia. transporting function at site of cytochrome

Status of respiratory enzymes under b-c in respiratory chain reactions. The

oxygen deprivation has been examined terminal stage III or bio-energetic hypoxia

(Pelikan PC et al, 1987), and above pattern involves inhibition of cytochrome oxidase

is verified in states if ischeamia (decreased under anoxia. All these stages correlate

blood supply) in various organs (Jennings with phasic changes in ATP content and

RB et.al, 1976; Mela L et.al, 1976; energy dependent cellular processes and

Narabayashi H et.al, 1982; Okayasu T parameters regulating life (Belousova VV

et.al, 1985; Rouslin W et.al, 1980; Vietch et.al, 1992). Only in the terminal phase,

K et.al, 1992). Their experiments there occur increased membrane

demonstrated not only decreased activity permeability, lipid peroxidation and

of the NADH-oxidase oxidation in degradation of adenine nucleotides. The

hypoxia, but also that inhibition of MEC-I activation of NAD-dependent oxidation

occurs before inactivation of other initially in hypoxic state is peculiar urgent

mitochondrial enzymes (Veitch K et.al, compensatory event of energy system,

1992). Three stages of bio-energetic seen also in exercise and stress.

hypoxia can be distinguished. Stage I,

relates to inactivation of the NAD- 4. Effect of toxic agents

dependent oxidation and parallel Specific toxicants of the cytochrome

enhancement of succinate oxidation oxidase enzyme system, e.g. cyanides,

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azide or carbon monoxide inhibit electron Capacity to resist state of oxygen

transfer and compromise the capacity of deficit varies in different individuals.

enzymes to react with oxygen and the Genotype and phenotype of metabolism,

process is called cyto-toxic, histo-toxic or maturity of regulatory mechanisms and

chemical hypoxia. Many chemicals capacity to re-adjust toward sustaining

suppress MEC-I and impair electron viability underlie such differences. Such

transfer at NAD-CoQ site. Such agents variation is important to determine

include barbiturates, rotenone, piericidine development, course and outcome of

and several rotenon-like chemicals that consequent pathological states (Lukjanova

react with hydrophobic site of MEC-I LD, 1996).

complex. They inflict changes similar to The animals with different sensitivity to

stage I hypoxia. Respiratory chain may be acute hypoxia under normal oxygen

involved at other site by different set of availability and different organization of

chemicals like malonate suppresses energy metabolism exhibit differences in

succinate-dependent oxidation through higher nervous activity (Livanova LM

competitive inhibition of succinate et.al, 1992). There is higher activation

dehydrogenase. under hypoxic state in high resistance

Zinc ion, Antimycin and other animals of NAD-dependent oxidation

compounds block the respiratory chain process in brain (Lukjanova LD, 1996),

near the b-c cytochrome or the MEC-III which correlates to brain resistance against

complex. Potassium cyanide, azide and hypoxia. The NADH-oxidase pathway in

carbon monoxide inhibit cytochrome brain of low resistance animals is

oxidases. expressed more but gets limited earlier in

contrast to high resistance animals. Neither

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International Journal of Applied Exercise Physiology Vol. 3(1)

the mitochondria content nor kinetics of inactivation of respiratory enzymes.

cytochrome oxidases differs in two Recent findings however rule-out effect of

categories of animals. However, succinate pH on energy metabolism under hypoxia

oxidase participates more in cellular (Chambers DE et.al, 1985). Free radicals

respiration reactions in low resistance may be another factor contributing to

animals, and this further increases under ischaemic hypoxic damage of

hypoxic state. Tissue specific features of a mitochondria and consequent dysfunction

aerobic energy formation determine of cellular respiration. In presence of

individual resistance to oxygen deficit. The NADH, the MEC-I and MEC-III

cytochrome oxidase enzyme in low complexes generate superoxide (O2- and

resistance animals exhibits greater affinity H2O2). This is increased due to initial

for cytochrome-C and continues to increase in NAD-oxidase activity under

function longer in hypoxic state, when the hypoxia. In turn the oxygen free radicals

mitochondria start losing cytochrome-C cause loss of activity of the MEC

due to disruption of membrane complexes (Dawson TL et.al, 1993;

(Dudchenko AM et.al, 1996). Narabayashi H et.al, 1982; Okayasu T

et.al, 1985; Veitch K et.al, 1992). Thus,

5. Mechanisms of hypoxic electron transport between NADH-

dysfunction of respiratory chain dehydrogenase and ubiquinone is

enzymes markedly, and between ubiquinone and

cytochrome is partially inactivated. H2O2

Hypoxia associated change in intra- is prominently involved and can be

cellular pH can be considered one of the produced also be non-respiratory enzymes

triggers for metabolic disorder leading to bound to mitochondrial membrane. In

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chemical or toxic hypoxia the free radical transport (Toleikis A et.al, 1980)). This

mechanisms are very prominent. Energy further aggravates free radical damage.

deficient states promote formation of Calcium is key regulator of cell

xanthin oxidase by proteolytic conversion metabolism and deregulation of calcium

from xanthine dehydrogenase, in recovery biology has major significance in hypoxic

from exercise. This process also increases damage. Hypoxia released calcium from

free oxygen radical formation. Various intracellular store which activates

oxidation reactions of monoamine neuro- production of highly active eicosanoid

chemicals also cause oxygen free radical products from arachidonic acid, in addition

generation. Such radicals accumulate in to free radical generation. There is

hypoxic state and alter physic-chemical alteration of mitochondrial enzyme

properties of membrane lipids leading to activities also. Respiration and energy

disturbance in function of membrane production is disturbed.

proteins, transport proteins, enzymes,

receptor for normal signals including ion

channels and the electrical charge. As a 6. Correction of hypoxic disorder of

result there is adverse impact on water and bioenergetics

ionic balance in cells, swelling of

mitochondria, impaired membrane Aerobic energy metabolism is essential

phospholipid metabolism, increased for running and regulation of cellular

fluidity and permeability of membranes processes, threatened in hypoxia. Many

that leaks out in late stages cytochrome C other disease states share this risk. Drugs

and CoQ with failure of MEC-III electron with donor-acceptor activity like quinones,

Vit K get incorporated into respiratory

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International Journal of Applied Exercise Physiology Vol. 3(1)

chain. Then electron flow at NADH-CoQ metabolism with change in activity of

site is shunted and hypoxic disruption of MEC and restoration of NAD-dependent

electron flow from NADH to cytochrome oxidation (Lukjanova LD, 1996). Studies

oxidases is repaired. This is basis for use of energy metabolism under oxygen deficit

of Vit K in treating myopathies with are of paramount significance in

congenital MEC-I deficiency. Many contemporary medical research to open

quinones share similar activity but are too prospects for preventing and treating bio-

toxic for clinical use. Agents promoting energetic failure. This is easily

compensatory ATP production like comprehended by realizing that ischaemic

succinic acid should be useful but succinic cardiac states are chief killers today.

acid poorly enters through biological

membrane. Organic succinate containing Corresponding Author: (Present

Address)
compounds like hydroxy-pyridine
Abhay Kumar Pandey
derivatives do not suffer such barrier and
Tutor
prove protective in hypoxic state. Department of Physiology,
All India Institute of Medical Sciences,
Additionally, agents like mexitol are able
Bhopal, (M.P) India
to permeate succinate to serve energy
E-mail: abhay.physiology@gmail.com
substrate, rendering protection under Phone: +91-7607980255

hypoxia. Supplement of cytochrome C and

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