8/13/2019 Lactate Acidosis

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Most cells in the body normally metabolizeglucoseto form water andcarbon dioxidein a two-step process.

First, glucose is broken down topyruvatethroughglycolysis.Then,mitochondriaoxidize the pyruvate into

water and carbon dioxideby means of theKrebs cycleandoxidative phosphorylation.This second step

requiresoxygen.The net result isATP,the energy carrier used by the cell to drive useful work, such as muscle

contraction. When the energy in ATP is used during cell work viaATP hydrolysis,protons(positively

chargedhydrogen ions,or cations) are released. The mitochondria normally incorporate these freehydrogennucleiback into ATP, thus preventing buildup of unbound hydrogen cations, maintaining neutral pH.

If oxygen supplyis inadequate (hypoxia), the mitochondria are unable to continue ATP synthesis at a rate

sufficient to supply the cell with the required ATP. In this situation, glycolysis is increased to provide additional

ATP, and the excess pyruvate produced is converted intolactateand released from the cell into the

bloodstream, where it accumulates over time. While increased glycolysis helps compensate for less ATP

fromoxidative phosphorylation,it cannot bind the hydrogen cations resulting from ATP hydrolysis. Therefore,

hydrogen cation concentration rises and causes acidosis.[5]

The excess hydrogen cations in lactic acidosis are widely believed to actually derive from production of lactic

acid. This is incorrect, as cells do not produce lactic acid; pyruvate is converted directly into lactate, the anionic

form of lactic acid. When excess intracellular lactate is released into the blood, maintenance of electroneutralityrequires a cation to be released, as well. This can reduce blood pH. Glycolysis coupled with lactate production

is neutral in the sense that it does not produce excess hydrogen cations, However, pyruvate production does

produce them. Lactate production is buffered intracellularly, e.g. the lactate-producing enzymelactate

dehydrogenasebinds one hydrogen cation per pyruvate molecule converted. When such buffer systems

become saturated, cells will transport lactate into the bloodstream. Hypoxia certainly causes both buildup of

lactate and acidification, and lactate is therefore a good "marker" of hypoxia, but lactate itself is not the cause

of low pH.[6]

There is a view that in exercise and critical illness, lactate production is not generated by lack of

oxygen but bycatecholamine-driven glycolysis, and that the lactate serves as anenergy source for other

tissues.[7]

Lactic acidosis sometimes occurs without hypoxia, for example, in rareinborn errors of metabolismwhere

mitochondria do not function at full capacity. In such cases, when the body needs more energy than usual, for

example during exercise or disease, mitochondria cannot match the cells' demand for ATP, and lactic acidosis

results. Also, muscle types that have few mitochondria and preferentially use glycolysis for ATP production

(fast-twitch or type II fibers) are naturally prone to lactic acidosis.

Lactic acidosis is an underlying process ofrigor mortis.Tissue in themusclesof the deceased carry out

anaerobic metabolism in the absence of oxygen, using muscle glycogen as the energy source, and significant

amounts of lactic acidare released into the muscle tissue. With depletion of muscle glycogen, the loss

ofATPcauses the muscles to grow stiff, as the actin-myosin bonds cannot be released. (Rigor is later resolved

by enzymatic breakdown of the myofibers.)

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