Posts Categorized: Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION



New disorder of mitochondrial tRNA processing

Posted by & filed under New IEM, Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION.

Metodiev and colleagues (AJHG, 98(5), p993–1000, 5 May 2016 ) recently reported a new mitochondrial disorder of mt-tRNA processing. Pathogenic variants were found in in TRMT10C in  2 unrelated probands via whole exome sequencing protein. Clinical features of the probands included neonatal lactic acidosis, hypotonia, feeding difficulties, deafness, and early death from respiratory failure. TRMT10C encodes  mitochondrial RNase P […]



mtDNA variants and LHON

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION.

While several different mtDNA variants are known to be associated with Leber’s hereditary optic neuropathy (LHON), penetrance is not 100%, and many of the factors contributing to increased penetrance have not been solved. One theory is that additive mitochondrial dysfunction caused by multiple LHON associated mtDNA variants could contribute to increased severity and/or penetrance of LHON. […]



Hypoxia as a therapy for mitochondrial disease

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION.

Jain et al. performed a genome-wide, Cas9-mediated screen using the human leukemic suspension cell line, K562, to identify factors that are protective during mitochondrial respiratory chain (RC) inhibition. Hypoxia response, an endogenous program evolved to adapt to limiting oxygen availability, was a very interesting finding. Genetic or small molecule activation of the hypoxia response appears […]



DNA methylation in mtDNA

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I was recently reviewing evidence for epigenetic control in mitochondrial DNA and came across a nice review by Iacobazzi et al (Mol Gen Metab 2013, 110(2) 25-34). In this review, the authors describe evidence for methylation and other mechanisms for epigenetic control of mtDNA, and methodology for exploration of this. They also discuss evidence for this […]



Defects of the mitochondrial S-adenosylmethionine transporter cause intramitochondrial methylation deficiency

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

Mutations in SLC25A26, encoding the mitochondrial S-adenosylmethionine (SAM) transporter, were identified in patients in three families though homozygosity mapping and exome sequencing. Clinical manifestations ranged from foetal hydrops to episodes of lactic acidosis and cardiopulmonary collapse in childhood with chronic progressive muscle weakness. The authors showed that the defect of SAM import into mitochondria causes […]



LONP1 mutations in CODAS Syndrome

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Dikoglu et al (AJMG 2015 Volume 167,  Issue 7, pages 1501–1509) report the identification of the gene responsible for CODAS syndrome, an ultra- rare syndrome named for its’ cardinal features: Cerebral, ocular, dental, auricular, and skeletal anomalies. The responsible gene, LONP1, likely plays a role in protein turnover within the mitochondrial matrix. Thus, this represents another unique mechanism for a primary disorder […]



Mitochondrial metabolism and the circadian clock

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Biochemical consequences in primary inborn errors of metabolism are often clear and predictable (i.e. elevated plasma phenylalanine in phenylalanine hydroxylase deficiency). However, potential biochemical consequences of genetic aberrations that do not have an obvious connection to metabolic pathways are much more difficult to understand. Kohsaka et al. (PLOS One, 2014 9(11): 1-16) described cardiac mitochondrial abnormalities in a mouse model with cardiac targeted disruption of the circadian clock […]



Potential therapy for MTO1 abnormalities

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Mitochondrial tRNA modification abnormalities are a recently recognized pathologic mechanism leading to defects in oxidative phosphorylation. Genes involved in these modifications include GTPBP3, and MTO1. Tischner et al (Hum. Mol. Genet. (2015) 24 (8):2247-2266.doi: 10.1093/hmg/ddu743) recently described experiments with a mouse model for MTO1 deficiency, in which implementation of a ketogenic diet was found to subvert the oxidative phosphorylation defect, with […]



SS-31 and cardiolipin oxidative stress

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We are increasingly aware of the role that oxidative stress plays in cellular pathophysiology. Cardiolipin, a phospholipid abundant in the inner mitochondrial  membrane, has been shown to be particularly susceptible to oxidative stress and peroxidation. This is particularly relevant due to the role that cardiolipin plays in cytochrome c activity. A recent antioxidant compound, SS-31 […]



Natural history of Leigh disease

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION, Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT.

Leigh syndrome is a neurodegenerative disease associated with primary or secondary mitochondrial dysfunction at the level of oxidative phosphorylation. Sofou et al. published a retrospective study describing patients with Leigh syndrome (n=130; 77 with pathogenic mutations) from eight European centers specializing in mitochondrial diseases. They described the natural history of Leigh syndrome and identified novel […]