The effect of small molecules on nuclear-encoded translation diseases

Soiferman, Devorah; Ayalon, Oshrat; Weissman, Sarah; Saada, Ann

doi:10.1016/j.biochi.2013.08.024

Cited by 24 publications

(29 citation statements)

References 59 publications

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“…Indeed, in the current study, fibroblasts of the CDs exhibited increased ROS production on DMEM-Glu, enhancing remarkably on DMEM-Gal, possibly due to COX-dysfunction and the increased mitochondrial mass. Our findings are consistent with previous observations showing elevated ROS levels in COX-deficient fibroblasts [39]. Supporting an increase in oxidative stress, we found the expression of the transcription factor NRF2, that facilitate cellular antioxidant response to oxidative stress [40] to be upregulated in fibroblasts of CDs rats.…”

Section: Discussionsupporting

confidence: 92%

Upregulation of Mitochondrial Content in Cytochrome c Oxidase Deficient Fibroblasts

et al. 2016

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Cytochrome-c-oxidase (COX) deficiency is a frequent cause of mitochondrial disease and is associated with a wide spectrum of clinical phenotypes. We studied mitochondrial function and biogenesis in fibroblasts derived from the Cohen (CDs) rat, an animal model of COX deficiency. COX activity in CDs-fibroblasts was 50% reduced compared to control rat fibroblasts (P<0.01). ROS-production in CDs fibroblasts increased, along with marked mitochondrial fragmentation and decreased mitochondrial membrane-potential, indicating mitochondrial dysfunction. Surprisingly, cellular ATP content, oxygen consumption rate (OCR) and the extracellular acidification rate (ECAR) were unchanged. To clarify the discrepancy between mitochondrial dysfunction and ATP production, we studied mitochondrial biogenesis and turnover. The content of mitochondria was higher in CDs-fibroblasts. Consistently, AMPK activity and the expression of NRF1-target genes, NRF2 and PGC1-α that mediate mitochondrial biogenesis were increased (P<0.01 vs control fibroblast). In CDs-fibrobalsts, the number of autophagosomes (LC3+ puncta) containing mitochondria in CDs fibroblasts was similar to that in control fibroblasts, suggesting that mitophagy was intact. Altogether, our findings demonstrate that mitochondrial dysfunction and oxidative stress are associated with an increase in mitochondrial biogenesis, resulting in preservation of ATP generation.

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Section: Discussionsupporting

confidence: 92%

Upregulation of Mitochondrial Content in Cytochrome c Oxidase Deficient Fibroblasts

et al. 2016

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“…During infection OmpA migrates to at least three subcellular locations within host cells: mitochondria, nuclei and cell-surfaces [62, 63]. Consistent with these findings, we identified OmpA interspecies interactions with a mitochondrial protein that affects reactive oxygen species generation (GFM-1) [64, 65], a nuclear protein involved in the DNA damage response[66] and circadian rhythm regulation[67] (SFPQ), and the obligate desmosomal adhesion protein DSP (Figure 3B). …”

Section: Discussionsupporting

confidence: 55%

Host-Microbe Protein Interactions during Bacterial Infection

Schweppe

Harding

Chavez

et al. 2015

Chemistry & Biology

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Summary Interspecies protein-protein interactions are essential mediators of infection. While bacterial proteins required for host cell invasion and infection can be identified through bacterial mutant library screens, information about host target proteins and interspecies complex structures has been more difficult to acquire. Using an unbiased chemical cross-linking/mass spectrometry approach, we identified interspecies protein-protein interactions in human lung epithelial cells infected with Acinetobacter baumannii. These efforts resulted in identification of 3076 total cross-linked peptide pairs and 46 interspecies protein-protein interactions. Most notably, the key A. baumannii virulence factor, OmpA, was identified cross-linked to host proteins involved in desmosomes, specialized structures that mediate host cell-to-cell adhesion. Co-immunoprecipitation and transposon mutant experiments were used to verify these interactions and demonstrate relevance for host cell invasion and acute murine lung infection. These results shed new light on A. baumannii-host protein interactions and their structural features and the presented approach is generally applicable to other systems.

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“…The significantly beneficial effect of AICAR on ATP content, and resveratrol on both ATP content and growth resembles the effect of these mitochondrial biogenesis inducers, on defects due to GFM1 and MRPS22, mutations in the mitochondrial translation machinery. 12 Notably, also ascorbate had a significant positive effect on both parameters without increasing mitochondrial content similar to the effect on cells with mutated mitochondrial elongation factor Ts. This effect could be due to its antioxidant properties 21 or its ability to donate electrons via cytochrome c. As vitamin C is regarded as a safe food supplement, it could be administered to patients.…”

Section: Discussionmentioning

confidence: 66%

“…Evaluation of compound was carried out essentially as we have previously described in 96-well microtiter plates. 12 Briefly, growth was evaluated by Figure 1. Head CT. Head CT performed at age 2 years shows prominent dilatation of the ventricles, VP shunt in the right occipital region, and of note is the very thin cortex.…”

Section: Tissue Culture and Evaluation Of Compoundsmentioning

confidence: 99%

Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy

et al. 2014

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Isolated cytochrome c oxidase (COX) deficiency is a prevalent cause of mitochondrial disease and is mostly caused by nuclear-encoded mutations in assembly factors while rarely by mutations in structural subunits. We hereby report a case of isolated COX deficiency manifesting with encephalomyopathy, hydrocephalus and hypertropic cardiomyopathy due to a missense p.R20C mutation in the COX6B1 gene, which encodes an integral, nuclear-encoded COX subunit. This novel mutation was predicted to be severe in silico. In accord, enzymatic activity was undetectable in muscle and fibroblasts, was severely decreased in lymphocytes and the COX6B1 protein was barely detectable in patient's muscle mitochondria. Complementation with the wild-type cDNA by a lentiviral construct restored COX activity, and mitochondrial function was improved by 5-aminoimidazole-4-carboxamide ribonucleotide, resveratrol and ascorbate in the patient's fibroblasts. We suggest that genetic analysis of COX6B1should be included in the investigation of isolated COX deficiency, including patients with cardiac defects. Initial measurement of COX activity in lymphocytes may be useful as it might circumvent the need for invasive muscle biopsy. The evaluation of ascorbate supplementation to patients with mutated COX6B1 is warranted.

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The effect of small molecules on nuclear-encoded translation diseases

Cited by 24 publications

References 59 publications

Upregulation of Mitochondrial Content in Cytochrome c Oxidase Deficient Fibroblasts

Upregulation of Mitochondrial Content in Cytochrome c Oxidase Deficient Fibroblasts

Host-Microbe Protein Interactions during Bacterial Infection

Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy

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