Pyruvate Dehydrogenase, Pyruvate Carboxylase, Krebs Cycle and Mitochondrial Transport Disorders

Despite an almost universal requirement for ATP synthesis by most forms of life, the number of disorders of energy metabolism compatible with human survival continues to expand, while their manifestations reach unsuspected variety. With the exception of mitochondrial respiratory chain diseases and energy metabolism disorders described elsewhere, the most important defects that impact neural integrity are reviewed here. The mitochondrial pyruvate dehydrogenase complex constitutes one of the central pillars of cell metabolism, linking two major catabolic pathways: glycolysis and the citric acid cycle (CAC). Pyruvate carboxylase is another mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate, a critical transition for the replenishment of CAC intermediates and for numerous biosynthetic reactions. Additional disorders are caused by mutations in three CAC enzymes: aconitase, succinate dihydrogenase and fumarase. Finally, impairment of the transport systems present in the inner and outer mitochondrial membranes can also affect energy production, mitochondrial integrity and cellular viability. With rare exceptions, treatment for these disorders is unsatisfactory and remains limited to alternative metabolic substrate administration or residual enzymatic augmentation via manipulation of regulatory sites.