|Kim HK, Park WS, Choi SW, Ha SH, Kim N, Han J (2010) BH4 deficiency involved in cardiac mitochondria metabolic pathway remodelling. MiP2010.|
Tetrahydrobiopterin (BH4) is an endogenous essential cofactor for NO synthesis and metabolisms of phenylalanine, tyrosine and tryptophan. To gain a better understanding of how BH4 orchestrate the biological processes in mitochondria and control phenotypic characteristics of an organism, we investigated the BH4 deficiency effect on cardiac mitochondria function and proteomic alteration in sepiapterin reductase gene knock out mouse (Spr-/-) which has severe BH4 deficiency. Spr-/- mouse was shown typical growth retardation induced by BH4 deficiency compared to wild type control mouse. The cardiac mitochondrial morphology alterations in both size and number were observed under electron microscopy. As a systemic approach to evaluate global proteomic modifications in cardiac mitochondria from BH4 deficiency model, we performed 2DE and LC-MS/MS proteomic analysis. We then performed data integrative analysis to systematically validate and organize them into significantly altered biological pathways. Our results suggested that altered proteins in BH4 deficiency induced mitochondrial dysfunction by affecting two major key factors in mitochondria metabolism, the TCA cycle and electron transport system. The systemic prediction was evaluated with various functional validations. The decrease of mitochondrial nitric oxide (mtNO) and increase of ROS production in Spr-/- mouse which induced oxidative damage on mitochondrial function accompanied with mitochondrial membrane potential (ΔΨmt) depolarization, mitochondria respiration rate inhibition and mitochondrial DNA fragmentation. These findings suggest new insights into BH4 as a novel regulator of mitochondrial function.
• O2k-Network Lab: KR Busan Han J
Labels: MiParea: Respiration, mtDNA;mt-genetics, Genetic knockout;overexpression
Stress:Oxidative stress;RONS Organism: Mouse Tissue;cell: Heart
Enzyme: TCA cycle and matrix dehydrogenases
Coupling state: OXPHOS