Posts Categorized: Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION



FGF21 is an endocrine signal of protein restriction

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Several studies have proposed serum fibroblast growth factor 21 (FGF21) levels as a sensitive biomarker of mitochondrial diseases. Serum FGF21 are the best predictor of these disorders when compared to serum levels of classical indicators: creatine kinase, lactate, pyruvate, and the lactate to pyruvate ratio. Enhanced FGF21 production and circulation has been linked to the metabolic adaptation to […]



Deoxypyrimidine monophosphate therapy for thymidine kinase 2 deficiency

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Autosomal recessive mutations in the thymidine kinase 2 gene (TK2) cause mitochondrial DNA depletion and/or multiple deletions due to loss of TK2 enzyme activity and unbalanced deoxynucleotide triphosphate (dNTP) pools. To bypass Tk2 deficiency, Dr. Michio Hirano’s group administered deoxycytidine and deoxythymidine monophosphates (dCMP+dTMP) to the Tk2?/? knock-in mouse model from postnatal day 4, when mutant mice […]



Nuclear Pyruvate Dehydrogenase Complex Generates Acetyl-CoA for Histone Acetylation

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The mitochondrial pyruvate dehydrogenase complex (PDC) is a key enzyme in metabolism but also has a newly recognized functional role in the nucleus of mammalian cells.  Sutendra and colleagues have discovered that PDC translocates from the mitochondria to the nucleus  in a cell-cycle-dependent manner and in response to serum, epidermal growth factor, or mitochondrial stress.  Inhibition of nuclear PDC […]



VARS2 and TARS2 mutations associated with mitochondrial disease

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Increasingly, whole exome sequencing has been critical in resolving molecular causes of unknown metabolic or mitochondrial disorders. Diodato et al (Hum Mutat. 2014 Aug;35(8):983-9) used WES to identify homozygous mutations in VARS2 (Valyl tRNA synthetase)  in one patient seizures and deficiency mitochondrial respiratory chain complex I, and compound heterozygous mutations in TARS2 (threonyl-tRNA synthetase) in siblings with hypotonia, severe psychomotor delay and multiple […]



Sodium pyruvate for the treatment of disorders of oxidative phosphorylation

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Fujii T, Nozaki F, Saito K, Hayashi A, Nishigaki Y, Murayama K, Tanaka M, Koga Y, Hiejima I, Kumada T. Efficacy of pyruvate therapy in patients with mitochondrial disease: a semi-quantitative clinical evaluation study. Mol Genet Metab. 2014 Jun;112(2):133-8.  Tanaka M, Nishigaki Y, Fuku N, Ibi T, Sahashi K, Koga Y. Therapeutic potential of pyruvate therapy for mitochondrial diseases. Mitochondrion. 2007 Dec;7(6):399-401.   In 2007, Tanaka et al formulated the […]



Valproic acid and hepatotoxicity

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It is well known that in some individuals, administration of valproic acid leads to hepatotoxicity. The causes for this are not completely understood, though mutations in POLG are a well known risk factor. In a fibroblast model, Luis et al (JIMD, (2014) 37 353-357) found that Valproyl-CoA inhibited the activities of both GTP- and ATP-specific […]



MELAS and citrulline supplementation

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Impaired nitric oxide production has been implicated in the pathogenesis of mitochondrial encephalomyopathy, lactic acidosis and stroke like episiodes (MELAS). Arginine supplementation is often employed as a precursor for nitric oxide and can have therapeutic effects in stroke-like episodes associated with MELAS. El-Hattab et al  (Mol Gen Metab 105 (2012) 607-614) reported that citrulline has an […]



mitochondrial tRNA synthetases

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To date, nine nuclear encoded mitochondrial tRNA synthetases have been implicated in human disease, including DARS2 causing leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, HARS2 with Perrault Syndrome, and AARS2 causing fatal infantile cardiomyopathy. Recently, two groups have reported mutations in mitochondrial phenylalanyl–tRNAsynthetase (FARS2) leading to  infantile onset epilepsy, and a fatal Alpers-like encephalopathy […]



Repeat sequences in the genomic DNA of the TAZ gene

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Barth syndrome, a disorder of dilated cardiomyopathy and neutropenia, is caused by mutations in TAZ on chromosome Xq28. Analysis of the genomic sequence of this gene has revealed that about 45% of the sequence is composed of SINES and LINES and three quarters of these interspersed repeat sequences are Alu sequences. Ferri et al. (Orphanet J Rare Dis, 2013, 8(1): 27) […]



3-hydroxy-isobutyryl-CoA hydrolase deficiency causing deficiency of multiple mitochondrial respiratory chain enzymes and of the pyruvate dehydrogenase complex

Posted by & filed under Part 09: ORGANIC ACIDS, Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION, _.

Ferdinandusse S et al. HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase. Orphanet J Rare Dis. 2013 Dec 4;8:188.   Ferdinandusse et al describe two new patients (for a total of four patients described on the literature) with 3-hydroxy-isobutyryl-CoA hydrolase deficiency, a disorder of valine […]