Publications by authors named "Mai Tsukikawa"

13 Publications

  • Page 1 of 1

Incidence of and Risk Factors for Steroid Response After Cataract Surgery in Patients With and Without Glaucoma.

J Glaucoma 2021 04;30(4):e159-e163

Department of Ophthalmology, University of Washington.

Precis: Steroid response after cataract surgery was more frequent in glaucoma patients than nonglaucoma patients. Longer axial length and more preoperative medications were risk factors for steroid response in glaucoma patients.

Purpose: The aim was to evaluate incidence and risk factors for topical steroid response after uneventful cataract surgery in patients with and without glaucoma.

Setting: Academic glaucoma clinics.

Design: This was a retrospective review.

Participants: Consecutive patients with and without glaucoma and no prior incisional glaucoma surgery undergoing cataract surgery between March 2007 and September 2016. All patients routinely received topical prednisolone acetate 1% postoperatively.

Methods: Pertinent clinical information was recorded. Steroid response was defined as intraocular pressure >50% above the baseline intraocular pressure measurement, occurring at or after the second postoperative week.

Results: We included 472 eyes of 472 nonglaucoma patients and 191 eyes of 191 glaucoma patients. Ten (2.1%) nonglaucoma eyes and 16 (8.4%) glaucoma eyes were diagnosed as steroid responders (relative risk=3.72; 95% confidence interval: 1.71-8.07; P<0.001). Logistic regression showed that for nonglaucoma, longer axial length (AL) and younger age were associated with a higher incidence of steroid response (P≤0.003), while for glaucoma patients, longer AL and more preoperative medications were associated with steroid response (P≤0.030). An AL ≥26 mm was associated with steroid response for both groups (P≤0.024).

Conclusion: Although glaucoma patients were 3.72 times more likely to have steroid response after uneventful cataract surgery, the incidence of steroid response with prednisolone acetate 1% was relatively low after phacoemulsification in both nonglaucoma and glaucoma eyes. Steroid response was associated with longer AL in both groups and with more preoperative medications in glaucoma patients.
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http://dx.doi.org/10.1097/IJG.0000000000001785DOI Listing
April 2021

Adjuvant use of laser in eyes with macular retinoblastoma treated with primary intravenous chemotherapy.

Br J Ophthalmol 2020 Sep 15. Epub 2020 Sep 15.

Royal London Hospital, London, London, UK.

Background: Adjuvant use of laser with systemic chemotherapy for treatment of retinoblastoma may reduce recurrence rates while also causing local side effects. Information is lacking on the effect of laser on visual outcomes.

Methods: A retrospective review of two retinoblastoma centres in the United Kingdom was conducted. Patients were included if there was a macular tumour in at least one eye. Eyes that received chemotherapy alone were compared with eyes that received chemotherapy plus adjuvant laser.

Results: A total of 76 patients and 91 eyes were included in the study. Systemic chemotherapy alone was used in 71 eyes while chemotherapy plus laser was used in 20 eyes. Demographic characteristics of both groups were similar. Macular relapse rates were similar between groups: 22/71 (31%) eyes in chemotherapy group and 9/20 (45%) eyes in laser group (p=0.29). There was no increase in vitreous relapses in the laser group (2/20 eyes), compared with the chemotherapy group 10/71 eyes (p=0.99). Survival analysis demonstrated similar time to first relapse between groups. Final visual acuity was equal between groups with 6/15 or better present in 31.1% of eyes in the chemotherapy group and 37.5% of eyes in the laser group (p=0.76). Presence of tumour at the fovea was predictive of final visual acuity, regardless of treatment group.

Conclusion: Adjuvant laser in the treatment of retinoblastoma is safe and does not lead to increased rate of vitreous recurrence. Final visual acuity is determined by the presence of tumour at the fovea and not the use of laser.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316862DOI Listing
September 2020

A Review of Hypertensive Retinopathy and Chorioretinopathy.

Clin Optom (Auckl) 2020 5;12:67-73. Epub 2020 May 5.

Department of Ophthalmology, University of Washington, Seattle, WA 98104, USA.

Hypertensive retinopathy and choroidopathy have important short- and long-term implications on patients' overall health and mortality. Eye care professionals should be familiar with the severity staging of these entities and be able to readily recognize and refer patients who are in need of systemic blood pressure control. This paper will review the diagnosis, staging, treatment, and long-term implications for vision and mortality of patients with hypertensive retinopathy and choroidopathy.
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http://dx.doi.org/10.2147/OPTO.S183492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211319PMC
May 2020

Idiopathic Orbital Pseudotumor Preceding Systemic Inflammatory Disease in Children.

J Pediatr Ophthalmol Strabismus 2019 Nov;56(6):373-377

Purpose: To describe four pediatric cases in which isolated orbital pseudotumor preceded the development of a systemic inflammatory disease by months to years.

Methods: The medical records of all patients with the clinical diagnosis of orbital pseudotumor seen at the Ocular Oncology Service of Wills Eye Hospital and Northern Virginia Ophthalmology Associates from 2010 to 2015 were reviewed retrospectively, and those associated with systemic inflammatory disease were selected for further study. Data were retrospectively collected from medical record review regarding patient demographics and clinical features, time to development of systemic inflammatory disease, and medical management.

Results: In four pediatric patients, isolated orbital pseudotumor preceded the development of a systemic inflammatory disease, including pauciarticular juvenile idiopathic arthritis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), granulomatosis with polyangiitis (Wegener's granulomatosis), and Crohn's disease.

Conclusions: Orbital pseudotumor may be an antecedent to systemic inflammatory disease in children. Because this was a small case series, the authors are not ready to suggest that a full systemic work-up for systemic inflammatory disease is warranted for every patient with orbital pseudotumor. However, close observation and suspicion for systemic inflammatory conditions may be reasonable in children who present with idiopathic orbital pseudotumor. [J Pediatr Ophthalmol Strabismus. 2019;56(6):373-377.].
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http://dx.doi.org/10.3928/01913913-20190923-02DOI Listing
November 2019

Optical Coherence Tomography in Knobloch Syndrome.

Ophthalmic Surg Lasers Imaging Retina 2019 08;50(8):e203-e210

Background And Objective: Knobloch syndrome is a genetic disorder defined by occipital defect, high myopia, and vitreoretinal degeneration. The authors studied retinal changes in patients with Knobloch syndrome using optical coherence tomography (OCT).

Patients And Methods: The authors report patients with Knobloch syndrome who received OCT testing during their care from 2011 to 2016. Diagnosis was based on high myopia, characteristic fundus, and occipital scalp or skull abnormalities with/without featureless irides and/or ectopia lentis. When available, diagnosis was confirmed by the detection of COL18A1 mutations.

Results: The authors studied eight eyes from five patients. Two eyes were excluded due to chronic retinal detachment. OCT findings included epiretinal membrane, peripapillary vitreoretinal traction with retinoschisis, absent or rudimentary foveal pits, mean macular thickness of 113.4 μm, poor lamination, retinal pigment epithelium (RPE) atrophy, photoreceptor depletion, and mean choroidal thickness of 168.5 μm with enlarged choroidal vessels.

Conclusion: OCT findings in Knobloch syndrome include abnormal vitreoretinal traction, poor foveal differentiation, poor retinal lamination, retinal thinning, RPE attenuation, myopic choroidal thinning, and pachychoroid. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e203-e210.].
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http://dx.doi.org/10.3928/23258160-20190806-13DOI Listing
August 2019

Ophthalmic manifestations of Heimler syndrome due to PEX6 mutations.

Ophthalmic Genet 2018 06;39(3):384-390

a Wills Eye Hospital , Philadelphia , PA , USA.

Background/aims: Pigmentary retinal dystrophy and macular dystrophy have been previously reported in Heimler syndrome due to mutations in PEX1. Here we reported the ocular manifestations in Heimler syndrome due to mutations in PEX6.

Materials And Methods: Medical records were reviewed to identify patient demographics, ophthalmic and systemic findings, and results of diagnostic testing including whole genome sequencing.

Results: Patient 1 is 12-year-old boy with a novel mutation c.275T>G (p.Val92Gly) and known mutation c.1802G>A (p.Arg601Gln) in PEX6. Patient 2 is a 7-year-old girl with the same known c.1802G>A (p.Arg601Gln) mutation and another novel missense mutation c.296G>T (p.Arg99Leu). Both patients exhibited a pigmentary retinopathy. Visual acuity in patient 1 was 20/80 and 20/25 following treatment of intraretinal cystoid spaces with carbonic anhydrase inhibitors, while patient 2 had visual acuity of 20/20 in both eyes without intraretinal cysts. Fundus autofluorescence showed a multitude of hyperfluorescent deposits in the paramacular area of both eyes. OCTs revealed significant depletion of photoreceptors in both patients and macular intraretinal cystoid spaces in one patient. Full field electroretinograms showed normal or abnormal photopic but normal scotopic responses. Multifocal electroretinograms were abnormal.

Conclusions: Heimler syndrome due to biallelic PEX6 mutations demonstrates a macular dystrophy with characteristic fundus autofluorescence and may be complicated by intraretinal cystoid spaces.
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http://dx.doi.org/10.1080/13816810.2018.1432063DOI Listing
June 2018

N-acetylcysteine and vitamin E rescue animal longevity and cellular oxidative stress in pre-clinical models of mitochondrial complex I disease.

Mol Genet Metab 2018 04 23;123(4):449-462. Epub 2018 Feb 23.

Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address:

Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials. Here, lifespan effects of N-acetylcysteine (NAC), vitamin E, vitamin C, coenzyme Q10 (CoQ10), mitochondrial-targeted CoQ10 (MS010), lipoate, and orotate were evaluated as the primary outcome in a well-established, short-lived C. elegans gas-1(fc21) animal model of RC complex I disease. Healthspan effects were interrogated to assess potential reversal of their globally disrupted in vivo mitochondrial physiology, transcriptome profiles, and intermediary metabolic flux. NAC or vitamin E fully rescued, and coenzyme Q, lipoic acid, orotic acid, and vitamin C partially rescued gas-1(fc21) lifespan toward that of wild-type N2 Bristol worms. MS010 and CoQ10 largely reversed biochemical pathway expression changes in gas-1(fc21) worms. While nearly all drugs normalized the upregulated expression of the "cellular antioxidant pathway", they failed to rescue the mutant worms' increased in vivo mitochondrial oxidant burden. NAC and vitamin E therapeutic efficacy were validated in human fibroblast and/or zebrafish complex I disease models. Remarkably, rotenone-induced zebrafish brain death was preventable partially with NAC and fully with vitamin E. Overall, these pre-clinical model animal data demonstrate that several classical antioxidant drugs do yield significant benefit on viability and survival in primary mitochondrial disease, where their major therapeutic benefit appears to result from targeting global cellular, rather than intramitochondria-specific, oxidative stress. Clinical trials are needed to evaluate whether the two antioxidants, NAC and vitamin E, that show greatest efficacy in translational model animals significantly improve the survival, function, and feeling of human subjects with primary mitochondrial RC disease.
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http://dx.doi.org/10.1016/j.ymgme.2018.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891356PMC
April 2018

Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach.

J Clin Invest 2018 01 20;128(1):190-206. Epub 2017 Nov 20.

Department of Ophthalmology Pathology & Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.

Retinitis pigmentosa (RP) is a major cause of blindness that affects 1.5 million people worldwide. Mutations in cyclic nucleotide-gated channel β 1 (CNGB1) cause approximately 4% of autosomal recessive RP. Gene augmentation therapy shows promise for treating inherited retinal degenerations; however, relevant animal models and biomarkers of progression in patients with RP are needed to assess therapeutic outcomes. Here, we evaluated RP patients with CNGB1 mutations for potential biomarkers of progression and compared human phenotypes with those of mouse and dog models of the disease. Additionally, we used gene augmentation therapy in a CNGβ1-deficient dog model to evaluate potential translation to patients. CNGB1-deficient RP patients and mouse and dog models had a similar phenotype characterized by early loss of rod function and slow rod photoreceptor loss with a secondary decline in cone function. Advanced imaging showed promise for evaluating RP progression in human patients, and gene augmentation using adeno-associated virus vectors robustly sustained the rescue of rod function and preserved retinal structure in the dog model. Together, our results reveal an early loss of rod function in CNGB1-deficient patients and a wide window for therapeutic intervention. Moreover, the identification of potential biomarkers of outcome measures, availability of relevant animal models, and robust functional rescue from gene augmentation therapy support future work to move CNGB1-RP therapies toward clinical trials.
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http://dx.doi.org/10.1172/JCI95161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749539PMC
January 2018

Novel ABCA4 mutation leads to loss of a conserved C-terminal motif: implications for predicting pathogenicity based on genetic testing.

Eur J Ophthalmol 2018 Jan 19;28(1):123-126. Epub 2018 Feb 19.

3 Departments of Pediatrics and Ophthalmology, Sydney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania - USA.

Purpose: Mutations in the ABCA4 gene result in a broad spectrum of severe retinal degeneration, including Stargardt macular dystrophy, fundus flavimaculatus, autosomal recessive retinitis pigmentosa, and cone-rod dystrophy. In addition to the detection of well-characterized mutations, genetic testing frequently yields novel variants of unknown significance. The purpose of this report is to describe an approach to aid in the assessment of genetic variants of unknown significance.

Case Report: We report an 11-year-old girl with Stargardt disease harboring novel compound heterozygous deletions of ABCA4 (c.850_857delATTCAAGA and c.6184_6187delGTCT). The pathogenicity of these variants was otherwise unknown. Both deletions introduce premature stop codons and are localized within the open reading frame of ABCA4. The c.850_857delATTCAAGA occurs early in the gene and leads to a significantly truncated protein of only 317 amino acids. The c.6184_6187delGTCT, is localized to the 3' terminus of the ORF and results in removal of the last 161 out of 2,273 amino acids of ABCA4, including the VFVNFA motif, which has been shown to be critical in ABCA4 protein function. Homology-based protein modeling of ABCA4 harboring this deletion suggests significant alterations in the protein structure and function.

Conclusions: Our analyses allowed us to classify novel variants in ABCA4 as being clearly loss-of-function mutations, and thus pathogenic variants. In cases of variants of unknown significance, appraising the protein structure-function consequences of genetic mutations using in silico tools may help to predict the clinical importance of variants of uncertain pathogenicity.
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http://dx.doi.org/10.5301/ejo.5001019DOI Listing
January 2018

Inhibiting cytosolic translation and autophagy improves health in mitochondrial disease.

Hum Mol Genet 2015 Sep 3;24(17):4829-47. Epub 2015 Jun 3.

Division of Human Genetics, Department of Pediatrics and

Mitochondrial respiratory chain (RC) disease therapies directed at intra-mitochondrial pathology are largely ineffective. Recognizing that RC dysfunction invokes pronounced extra-mitochondrial transcriptional adaptations, particularly involving dysregulated translation, we hypothesized that translational dysregulation is itself contributing to the pathophysiology of RC disease. Here, we investigated the activities, and effects from direct inhibition, of a central translational regulator (mTORC1) and its downstream biological processes in diverse genetic and pharmacological models of RC disease. Our data identify novel mechanisms underlying the cellular pathogenesis of RC dysfunction, including the combined induction of proteotoxic stress, the ER stress response and autophagy. mTORC1 inhibition with rapamycin partially ameliorated renal disease in B6.Pdss2(kd/kd) mice with complexes I-III/II-III deficiencies, improved viability and mitochondrial physiology in gas-1(fc21) nematodes with complex I deficiency, and rescued viability across a variety of RC-inhibited human cells. Even more effective was probucol, a PPAR-activating anti-lipid drug that we show also inhibits mTORC1. However, directly inhibiting mTORC1-regulated downstream activities yielded the most pronounced and sustained benefit. Partial inhibition of translation by cycloheximide, or of autophagy by lithium chloride, rescued viability, preserved cellular respiratory capacity and induced mitochondrial translation and biogenesis. Cycloheximide also ameliorated proteotoxic stress via a uniquely selective reduction of cytosolic protein translation. RNAseq-based transcriptome profiling of treatment effects in gas-1(fc21) mutants provide further evidence that these therapies effectively restored altered translation and autophagy pathways toward that of wild-type animals. Overall, partially inhibiting cytosolic translation and autophagy offer novel treatment strategies to improve health across the diverse array of human diseases whose pathogenesis involves RC dysfunction.
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http://dx.doi.org/10.1093/hmg/ddv207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527487PMC
September 2015

Mitochondrial DNA variant in COX1 subunit significantly alters energy metabolism of geographically divergent wild isolates in Caenorhabditis elegans.

J Mol Biol 2014 May 14;426(11):2199-216. Epub 2014 Feb 14.

Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. Electronic address:

Mitochondrial DNA (mtDNA) sequence variation can influence the penetrance of complex diseases and climatic adaptation. While studies in geographically defined human populations suggest that mtDNA mutations become fixed when they have conferred metabolic capabilities optimally suited for a specific environment, it has been challenging to definitively assign adaptive functions to specific mtDNA sequence variants in mammals. We investigated whether mtDNA genome variation functionally influences Caenorhabditis elegans wild isolates of distinct mtDNA lineages and geographic origins. We found that, relative to N2 (England) wild-type nematodes, CB4856 wild isolates from a warmer native climate (Hawaii) had a unique p.A12S amino acid substitution in the mtDNA-encoded COX1 core catalytic subunit of mitochondrial complex IV (CIV). Relative to N2, CB4856 worms grown at 20°C had significantly increased CIV enzyme activity, mitochondrial matrix oxidant burden, and sensitivity to oxidative stress but had significantly reduced lifespan and mitochondrial membrane potential. Interestingly, mitochondrial membrane potential was significantly increased in CB4856 grown at its native temperature of 25°C. A transmitochondrial cybrid worm strain, chpIR (M, CB4856>N2), was bred as homoplasmic for the CB4856 mtDNA genome in the N2 nuclear background. The cybrid strain also displayed significantly increased CIV activity, demonstrating that this difference results from the mtDNA-encoded p.A12S variant. However, chpIR (M, CB4856>N2) worms had significantly reduced median and maximal lifespan relative to CB4856, which may relate to their nuclear-mtDNA genome mismatch. Overall, these data suggest that C. elegans wild isolates of varying geographic origins may adapt to environmental challenges through mtDNA variation to modulate critical aspects of mitochondrial energy metabolism.
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http://dx.doi.org/10.1016/j.jmb.2014.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067970PMC
May 2014

Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.

Am J Hum Genet 2013 Sep 29;93(3):482-95. Epub 2013 Aug 29.

Department of Molecular Pharmacology and Therapeutics, Loyola University Stritch School of Medicine, Maywood, IL 60153, USA.

Whole-exome sequencing and autozygosity mapping studies, independently performed in subjects with defective combined mitochondrial OXPHOS-enzyme deficiencies, identified a total of nine disease-segregating FBXL4 mutations in seven unrelated mitochondrial disease families, composed of six singletons and three siblings. All subjects manifested early-onset lactic acidemia, hypotonia, and developmental delay caused by severe encephalomyopathy consistently associated with progressive cerebral atrophy and variable involvement of the white matter, deep gray nuclei, and brainstem structures. A wide range of other multisystem features were variably seen, including dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosis, seizures, and episodic metabolic failure. Mitochondrial respiratory chain deficiency was present in muscle or fibroblasts of all tested individuals, together with markedly reduced oxygen consumption rate and hyperfragmentation of the mitochondrial network in cultured cells. In muscle and fibroblasts from several subjects, substantially decreased mtDNA content was observed. FBXL4 is a member of the F-box family of proteins, some of which are involved in phosphorylation-dependent ubiquitination and/or G protein receptor coupling. We also demonstrate that FBXL4 is targeted to mitochondria and localizes in the intermembrane space, where it participates in an approximately 400 kDa protein complex. These data strongly support a role for FBXL4 in controlling bioenergetic homeostasis and mtDNA maintenance. FBXL4 mutations are a recurrent cause of mitochondrial encephalomyopathy onset in early infancy.
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http://dx.doi.org/10.1016/j.ajhg.2013.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769923PMC
September 2013

Primary respiratory chain disease causes tissue-specific dysregulation of the global transcriptome and nutrient-sensing signaling network.

PLoS One 2013 24;8(7):e69282. Epub 2013 Jul 24.

Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. Mechanism(s) by which RC dysfunction causes global cellular sequelae are poorly understood. To identify a common cellular response to RC disease, integrated gene, pathway, and systems biology analyses were performed in human primary RC disease skeletal muscle and fibroblast transcriptomes. Significant changes were evident in muscle across diverse RC complex and genetic etiologies that were consistent with prior reports in other primary RC disease models and involved dysregulation of genes involved in RNA processing, protein translation, transport, and degradation, and muscle structure. Global transcriptional and post-transcriptional dysregulation was also found to occur in a highly tissue-specific fashion. In particular, RC disease muscle had decreased transcription of cytosolic ribosomal proteins suggestive of reduced anabolic processes, increased transcription of mitochondrial ribosomal proteins, shorter 5'-UTRs that likely improve translational efficiency, and stabilization of 3'-UTRs containing AU-rich elements. RC disease fibroblasts showed a strikingly similar pattern of global transcriptome dysregulation in a reverse direction. In parallel with these transcriptional effects, RC disease dysregulated the integrated nutrient-sensing signaling network involving FOXO, PPAR, sirtuins, AMPK, and mTORC1, which collectively sense nutrient availability and regulate cellular growth. Altered activities of central nodes in the nutrient-sensing signaling network were validated by phosphokinase immunoblot analysis in RC inhibited cells. Remarkably, treating RC mutant fibroblasts with nicotinic acid to enhance sirtuin and PPAR activity also normalized mTORC1 and AMPK signaling, restored NADH/NAD(+) redox balance, and improved cellular respiratory capacity. These data specifically highlight a common pathogenesis extending across different molecular and biochemical etiologies of individual RC disorders that involves global transcriptome modifications. We further identify the integrated nutrient-sensing signaling network as a common cellular response that mediates, and may be amenable to targeted therapies for, tissue-specific sequelae of primary mitochondrial RC disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069282PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3722174PMC
February 2014
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