Acyl-CoA dehydrogenase 9 (ACAD9) is an assembly factor for mitochondrial respiratory chain Complex I (CI), and ACAD9 mutations are recognized as a frequent cause of CI deficiency. ACAD9 also retains enzyme ACAD activity for long-chain fatty acids in vitro, but the biological relevance of this function remains controversial partly because of the tissue specificity of ACAD9 expression: high in liver and neurons and minimal in skin fibroblasts. In this study, we hypothesized that this enzymatic ACAD activity is required for full fatty acid oxidation capacity in cells expressing high levels of ACAD9 and that loss of this function is important in determining phenotype in ACAD9-deficient patients. First, we confirmed that HEK293 cells express ACAD9 abundantly. Then, we showed that ACAD9 knockout in HEK293 cells affected long-chain fatty acid oxidation along with Cl, both of which were rescued by wild type ACAD9. Further, we evaluated whether the loss of ACAD9 enzymatic fatty acid oxidation affects clinical severity in patients with ACAD9 mutations. The effects on ACAD activity of 16 ACAD9 mutations identified in 24 patients were evaluated using a prokaryotic expression system. We showed that there was a significant inverse correlation between residual enzyme ACAD activity and phenotypic severity of ACAD9-deficient patients. These results provide evidence that in cells where it is strongly expressed, ACAD9 plays a physiological role in fatty acid oxidation, which contributes to the severity of the phenotype in ACAD9-deficient patients. Accordingly, treatment of ACAD9 patients should aim at counteracting both CI and fatty acid oxidation dysfunctions.
Edited by Ruma Banerjee Three mitochondrial metabolic pathways are required for efficient energy production in eukaryotic cells: the electron transfer chain (ETC), fatty acid -oxidation (FAO), and the tricarboxylic acid cycle. The ETC is organized into inner mitochondrial membrane supercomplexes that promote substrate channeling and catalytic efficiency. Although previous studies have suggested functional interaction between FAO and the ETC, their physical interaction has never been demonstrated. In this study, using blue native gel and two-dimensional electrophoreses, nano-LC-MS/MS, immunogold EM, and stimulated emission depletion microscopy, we show that FAO enzymes physically interact with ETC supercomplexes at two points. We found that the FAO trifunctional protein (TFP) interacts with the NADH-binding domain of complex I of the ETC, whereas the electron transfer enzyme flavoprotein dehydrogenase interacts with ETC complex III. Moreover, the FAO enzyme verylong-chain acyl-CoA dehydrogenase physically interacted with TFP, thereby creating a multifunctional energy protein complex. These findings provide a first view of an integrated molecular architecture for the major energy-generating pathways in mitochondria that ensures the safe transfer of unstable reducing equivalents from FAO to the ETC. They also offer insight into clinical ramifications for individuals with genetic defects in these pathways. Mitochondrial fatty acid -oxidation (FAO), 2 the electron transport chain (ETC), and the tricarboxylic acid (TCA) cycle
In Sickle Cell Anemia (SCA) patient blood transfusions are an important part of treatment for stroke and its prevention. However, blood transfusions can also lead to complications such as Reversible Posterior Leukoencephalopathy Syndrome (RPLS). This brief report highlights two cases of SCA who developed such neurological complications after a blood transfusion. RLPS should be considered as the cause of neurologic finding in patients with SCA and hypertension following a blood transfusion.
PreTesT1. What clinical features should increase suspicion for underlying mitochondrial hepatopathy? 2. How are mitochondrial hepatopathies diagnosed? 3. How are mitochondrial hepatopathies treated?Mitochondria play critical roles in energy, calcium, iron, and reduction/oxidation homeostasis, as well as regulation of apoptosis. They are the only organelle that contains its own circular genomes (mitochondrial DNA [mtDNA]). Maternally inherited mtDNA houses 37 genes encoding mitochondrial transfer RNAs (tRNAs), ribosomal RNA, and 13 proteins that exclusively function as subunits of the oxidative-phosphorylation machinery. Additional proteins critical to mitochondrial structure and function are encoded by the nuclear genome.Mitochondrial disorders include defects in oxidativephosphorylation complexes, mtDNA maintenance, and mtDNA transcription and translation and can result from mitochondrial or nuclear mutations and yield disease involving virtually every organ system, including the liver. Mitochondrial hepatopathies are heterogenous and individually rare, but collectively they comprise an important cause of early liver failure. In two studies of infants with acute liver failure, about 20% of cases were attributable to mitochondrial pathology. 1,2
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