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Mitochondrial trifunctional protein deficiency

Mitochondrial trifunctional protein deficiency

Mitochondrial trifunctional protein (MTP/TFP) deficiency is a rare disorder of fatty acid oxidation which causes neonatal onset of a condition resulting in sudden unexplained infant death (SIDS), infantile onset of a hepatic Reye-like syndrome and late-adolescent onset of skeletal myopathy.

Mitochondrial trifunctional protein (MTP/TFP) deficiency is a rare disorder of fatty acid oxidation which causes neonatal onset of a condition resulting in sudden unexplained infant death (SIDS), infantile onset of a hepatic Reye-like syndrome and late-adolescent onset of skeletal myopathy. Trifunctional protein deficiency is characterized by decreased activity of MTP enzymatic function in 3 steps in mitochondrial beta-oxidation of fatty acids. Genes coding for the alpha and beta subunits of MTP are located at 2p23.3.



Mitochondrial trifunctional protein (MTP/TFP) deficiency is thought to be a result of impaired fatty acid oxidation (FAO) due to mutations in hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase subunit A (HADHA HADHA/LCHAD) or subunit B (HADHB). A major phenotype of newborns that are MTP-deficient is sudden infant death syndrome (SIDS), which manifests after birth once the infant begins nursing on lipid-rich breast-milk. The resulting build-up of unprocessed fatty material can disrupt heart functions. Impaired FAO can promote a pro-arrhythmic cardiac environment. 



A research team led by Hannele Ruohola-Baker at University of Washington generated stem cell-derived cardiomyocytes from HADHA-deficient hiPSCs (human induced pluripotent stem cells). When treated with a mixture of fatty acids, they HADHA mutant cardiomyocytes manifested the disease phenotype of defective calcium dynamics and repolarization kinetics resulting in a pro-arrhythmic state. 



Researchers used a cocktail of engineered microRNAs to transition the cardiomyocytes from the fetal to an adult state that is able to utilize FAO as an energy source. The HADHA mutant cardiomyocytes transitioned to a pathological state with reduced fatty acid beta-oxidation, reduced mitochondrial proton gradient, disrupted cristae structure and defective cardiolipin remodeling. The study concluded that HADHA is required for fatty acid beta-oxidation and cardiolipin remodeling, essential for functional mitochondria in human cardiomyocytes. Elamipretide (SS-31) is a drug the researchers are focusing on that could potentially treat the disease. The drug is used to stimulate hearts and organs that have oxygen deficiency. 



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