Targeting of XJB-5-131 to Mitochondria Suppresses Oxidative DNA Damage and Motor Decline in a Mouse Model of Huntington’s Disease

Xun, Zhiyin; Rivera-Sánchez, Sulay; Ayala‐Peña, Sylvette; Lim, Jormay; Budworth, Helen; Skoda, Erin M.; Robbins, Paul D.; Niedernhofer, Laura J.; Wipf, Peter; McMurray, Cynthia T.

doi:10.1016/j.celrep.2012.10.001

Cited by 129 publications

(96 citation statements)

References 35 publications

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“…For example, small antioxidant molecules have been specifically targeted to the mitochondria by incorporating the Szeto-Schiller tetrapeptide sequence motif or the gramicidin S pentapeptide fragment. XBJ-5-131, an antioxidant that incorporates the mitochondrialtargeting peptide from gramicidin S, has been shown to improve the survival of neurons in a mouse model of Huntington disease 187 .…”

Section: Targets and Therapeutic Interventions For Mitochondrial Damagementioning

confidence: 99%

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

290

212

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Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches.Fibrosis as a pathogenic mechanism occurs in numerous organs and diseases. Fibrosis results from abnormal tissue repair and is associated with persistent and/or severe tissue damage and cellular stress. Epithelial and/or endothelial injury caused by various insults triggers interrelated wound-healing pathways to restore homeostasis 1 . Failure to adequately contain or eliminate inciting factors can exacerbate inflammation and chronic woundCorrespondence to A.L.M. anamora@pitt.edu. Competing interests statementThe authors declare competing interests: see Web version for details. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript healing responses, resulting in continued tissue damage and inadequate regeneration and, ultimately, fibrosis 2 . Although their aetiology and causative mechanisms differ, the various fibrotic diseases all have abnormal and exaggerated accumulation of extracellular matrix (ECM) components, mainly fibrillar collagens. The resulting fibrosis disturbs the normal architecture of affected organs, which ultimately leads to their dysfunction and failure. Nearly 45% of deaths in the developed world are attributable to some type of chronic fibroproliferative disease, including idiopathic pulmonary fibrosis (IPF) and end-stage fibrotic liver, kidney and heart disease 2 . The progressive nature of these diseases and the absence of effective treatments mean that a better understanding of the cellular and molecular mechanisms that contribute to the development of fibrosis is needed.Although IPF was originally thought to be an inflammation-driven disorder, clinical trials with a combination of anti-inflammatory drugs (prednisone, azathioprine and N-acetyl-Lcysteine (NAC)), failed to improve outcomes and instead increased mortality 3 . In 2014, two drugs, pirfenidone, a drug with poorly understood mechanisms, and nintedanib, a tyrosine kinase inhibitor, were approved for the treatment of IPF ...

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Section: Targets and Therapeutic Interventions For Mitochondrial Damagementioning

confidence: 99%

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

290

212

View full text Add to dashboard Cite

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“…Thus, protecting nerve endings from degeneration appears an important goal in order to achieve efficient neuroprotection in the brain. Although several approaches have been undertaken to specifically buffer axonal stress, such as treating with neurotrophins or increasing antioxidant defences 37 , they have yielded unequal success because of the dual role of these molecules in both axonal damage and signalling. Here, our data show that the X protein promotes a specific axoprotective effect and significant neuroprotection in a mouse model of PD, notably by modulating mitochondrial dynamics.…”

Section: Discussionmentioning

confidence: 99%

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

et al. 2014

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Mitochondrial dysfunction is a common feature of many neurodegenerative disorders, notably Parkinson's disease. Consequently, agents that protect mitochondria have strong therapeutic potential. Here, we sought to divert the natural strategy used by Borna disease virus (BDV) to replicate in neurons without causing cell death. We show that the BDV X protein has strong axoprotective properties, thereby protecting neurons from degeneration both in tissue culture and in an animal model of Parkinson's disease, even when expressed alone outside of the viral context. We also show that intranasal administration of a cellpermeable peptide derived from the X protein is neuroprotective. We establish that both the X protein and the X-derived peptide act by buffering mitochondrial damage and inducing enhanced mitochondrial filamentation. Our results open the way to novel therapies for neurodegenerative diseases by targeting mitochondrial dynamics and thus preventing the earliest steps of neurodegenerative processes in axons.

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“…Images were acquired on a Fluoview Olympus 1000 filter confocal microscope at 40x. Image J was used for image analysis (Xun et al 2012). …”

Section: Mitochondrial Volumementioning

confidence: 99%

“…Cells were then stained in 300 nM 4′,6-diamidino-2-phenylindole (DAPI) and 20 nM MitoTracker Deep Red 694. DAPI stains DNA in the nucleus, and MitoTracker DeepRed 694 is a far-red fluorescent dye (abs/em ~644/665 nm) that stains mitochondria in live cells (Xun et al 2012). Cells were fixed with 4 % paraformaldehyde directly after staining.…”

Section: Mitochondrial Volumementioning

confidence: 99%

The metabolic rate of cultured muscle cells from hybrid Coturnix quail is intermediate to that of muscle cells from fast-growing and slow-growing Coturnix quail

et al. 2015

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Growth rate is a fundamental parameter of an organism's life history and varies 30-fold across bird species. To explore how whole-organism growth rate and the metabolic rate of cultured muscle cells are connected, two lines of Japanese quail (Coturnix coturnix japonica), one that had been artificially selected for fast growth for over 60 generations and a control line were used to culture myoblasts. In line with previous work, myoblasts from the fast growth line had significantly higher rates of oxygen consumption, glycolytic flux, and higher mitochondrial volume than myoblasts from the control line, indicating that an increase in growth rate is associated with a concomitant increase in cellular metabolic rates and that mitochondrial density contributes to the differences in rates of metabolism between the lines. We reared chicks from two hybrid lines with reciprocal parental configurations for growth rate to explore the effect of maternally inherited mitochondrial DNA on rates of growth and metabolism. Growth rates of chicks, cellular basal oxygen consumption, glycolytic flux, and mitochondrial volume in myoblasts from chicks from both reciprocal crosses were intermediate to the fast and control lines. This indicates that genes in the nucleus have a strong influence on metabolic rates at the cellular level, compared with maternally inherited mitochondrial DNA.

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Targeting of XJB-5-131 to Mitochondria Suppresses Oxidative DNA Damage and Motor Decline in a Mouse Model of Huntington’s Disease

Cited by 129 publications

References 35 publications

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

The metabolic rate of cultured muscle cells from hybrid Coturnix quail is intermediate to that of muscle cells from fast-growing and slow-growing Coturnix quail

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