Question

Explain why any functional impairment of PDC, TCA cycle and ETC/oxidative phosphorylation can cause lactic acidosis.

Answer 1

The normal endpoint of anaerobic metabolism of glucose in the tissues is lactic acid. The lactic acid exits the cells and transporte to the liver, and oxidized back to pyruvic acid and finally converte to glucose and it is also known as Cori cycle. Because of continual oxygen debt and buffering abilities of body lactic acidosis ensue.

REASON OF LACTIC ACIDOSIS DUE TO PDC

Pyruvate dehydrogenase complex (PDC) deficiency caused due to low levels of enzymes that are nessessary for an chemical reaction that take place in the cells of the body. These enzyme are the part of three enzymes known as pyruvate dehydrogenase complex. pyruvate dehydrogenase complex convert pyruvate into acetyl-CoA. Acetyl-CoA is helps the body make energy through kreb’s cycle.

But when pyruvate dehydrogenase complex is not functioning properly, pyruvate could not be converted to acetyl-CoA. So pyruvate is build up in cells. And the pyruvate is turn into lactic acid, which is in large amounts toxic to the body and cause lactic acidosis. When pyruvate does not converte into acetyl-CoA, the body could not perform citric acid cycle. so enough energy is not prepared for the body for properly function.

PDC deficiency cause due to genetic changes like mutations and pathogenic variants in any genes which provide instructions for the body for produce enzymes for the pyruvate dehydrogenase complex.

REASON OF LACTIC ACIDOSIS DUE TO TCA CYCLE

Pyruvate carboxylase or PC is a mitochondrial enzyme which contain biotin and catalyze the conversion of pyruvate to oxaloacetateso it involve in gluconeogenesis and production of energy by replacement of the citric acid cycle with oxaloacetate. it is a rare metabolic disorder.

Pyruvate carboxylase is a mitochondrial enzyme containing biotin made by four functional domains i.e. biotin carboxylase domain, carboxyl transferase domain, the tetramerization domain (PT) and biotin carboxyl carrier protein . PC catalyzes the exchange of pyruvate to oxaloacetate, and involve in gluconeogenesis and production of energy by citric acid cycle with oxaloacetate. PC is also link to the urea cycle and it is produce from oxaloacetate by transamination.

REASON OF LACTIC ACIDOSIS DUE TO ETC OR OXIDATIVE PHASPHORILATION

The electron transport chain dysfunction cause decrease production of adenosine triphosphate. decreased adenosine triphosphate level result up-regulation of glycolysis and lead to increased production of pyruvate. This increased pyruvate is may be transaminated to alanineor it reduce and form lactic acid. So because of chondrial dysfunction found lactic acidosis. lactic acidosis is found more commonly in patient who have mitochondrial DNA mutations .

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