Mitochondrial transport and metabolism of the vitamin B‐derived cofactors thiamine pyrophosphate, coenzyme A,FADandNAD⁺, and related diseases: A review

Abstract

Multiple mitochondrial matrix enzymes playing key roles in metabolism require cofactors for their action. Due to the high impermeability of the mitochondrial inner membrane, these cofactors need to be synthesized within the mitochondria or be imported, themselves or one of their precursors, into the organelles. Transporters belonging to the protein family of mitochondrial carriers have been identified to transport the coenzymes: thiamine pyrophosphate, coenzyme A, FAD and NAD + , which are all structurally similar to nucleotides and derived from different B-vitamins. These mitochondrial cofactors bind more or less tightly to their enzymes and, after having been involved in a specific reaction step, are regenerated, spontaneously or by other enzymes, to return to their active form, ready for the next catalysis round. Disease-causing mutations in the mitochondrial cofactor carrier genes compromise not only the transport reaction but also the activity of all mitochondrial enzymes using that particular cofactor and the metabolic pathways in which the cofactordependent enzymes are involved. The mitochondrial transport, metabolism

Enhanced Branched-Chain Amino Acid Metabolism Improves Age-Related Reproduction inC. elegans

“…Animals cannot synthesize thiamine and rely on its absorption from their diet. After being imported into animal cells, thiamine is transformed into ThPP by thiamine pyrophosphokinase 31,32 . When thiamine levels are insufficient, BCAA catabolism is impaired, increasing the levels of unprocessed branched-chain keto acids 33 .…”

“…BCKDH is composed of three subunits, E1, E2, and E3. The E1 subunit binds thiamine pyrophosphate (ThPP), which is an essential cofactor and a derivative of thiamine, also known as Vitamin B1 46 . Animals cannot synthesize thiamine and rely on its absorption from their diet.…”

Thiamine deficiency in pregnancy and lactation: implications and present perspectives

“…In mitochondria, TPP is a crucial cofactor for three different 2-oxoacid dehydrogenase complexes, viz, pyruvate dehydrogenase, (PDH) α-ketoglutarate dehydrogenase (αKDGDH), and branched-chain α-ketoacid dehydrogenase (BCKDH) that despite utilizing diverse metabolic pathways, have similar macromolecular assembly structures and catalyze similar decarboxylation processes ( 55 ).…”

Synthesis of Mixed Dinucleotides by Mechanochemistry

“…Specific transporters on the cell surface recognize and import the non-charged water-soluble vitamins that are then rapidly phosphorylated in the cytosol or exported back in the extracellular space by equilibrative transporters [ 8 , 9 , 10 , 11 ]. While transporters of extracellular phosphorylated cofactor precursors remain under intense scrutiny, specific mitochondrial membrane carriers, SLC25A19, SLC25A32, and SLC25A51, have been shown to import across the mitochondrial membrane from the cytosol ThDP, NAD and FAD, respectively, and support the sub-cellular distribution of each cofactors [ 12 , 13 , 14 ] in this organelle. Overcoming vitamin B1, B2 and B3 cofactor depletion in the mitochondrion has been the focus of much basic and clinical research in the past few years [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”

“…We reported that mechanochemistry was particularly effective at generating pyrophosphate bonds from adenosine phosphomorpholidate and nucleotides and sugar phosphomonoesters in moderate to good, isolated yields [ 26 ]. When we explored more comprehensively the scope of mechanochemistry for vitamin B1, B2 and B3 derived cofactor synthesis, we, and others, observed that not all hydroxyl and phosphate precursors shared the same reactivity and thus were not all amenable to the same synthetic sequences [ 12 , 27 , 28 ]. Further, under some instances, phosphoimidazolates proved to be more versatile and amenable to unsymmetrical P-O-P bond formation than phosphomorpholidates.…”