Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis

Witte, Maarten E.; Mahad, Don J.; Lassmann, Hans; Horssen, Jack van

doi:10.1016/j.molmed.2013.11.007

Cited by 245 publications

(200 citation statements)

References 85 publications

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“…30 RSV has been proven to improve the overall metabolic health status in clinical trials for patients with metabolic disorders, 32 which may or may not be confirmed in currently ongoing clinical trials for AD and Friedreich ataxia (NCT01339884, NCT01504854, NCT00743743, NCT00678431). Therapeutic implications derived from this work may be potentially extended to other diseases such as multiple sclerosis, 65 amyotrophic lateral sclerosis 66 and some forms of HSP such as SPG7, 54 which share axonal degeneration as a primary component of clinical disability and oxidative stress/mitochondria impairment as the primary or early contributing pathogenic factors. Mouse strains.…”

Section: Discussionmentioning

confidence: 98%

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

et al. 2015

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Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired. Cell Death and Differentiation (2015) 22, 1742-1753 doi:10.1038/cdd.2015; published online 27 March 2015Sirtuins are highly conserved NAD + -dependent deacetylases with a critical impact on metabolic adaptive responses. In mammals, among the seven members of the sirtuin family (SIRT1-SIRT7), SIRT1 has been the most extensively characterized. 1 SIRT1 promotes the generation of new mitochondria through the activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), which orchestrates the mitochondrial biogenesis program through the transcriptional activation of nuclear respiratory factors (NRF-1 and NRF-2) and mitochondrial transcription factor A (TFAM). 2 SIRT1 activity is finely regulated not only by gene expression and protein levels but also by posttranslational modifications, its oligomeric status, the interaction with the DBC1 and AROS proteins, and the levels of NAD + /NADH/NAM. 3 In addition, SIRT1 activity is modulated by several synthetic or natural molecules such as the polyphenol resveratrol (3,4',5-trihydroxystilbene: RSV). 4 The activation of SIRT1 by transgenic overexpression or pharmacologically with RSV has been shown to prevent the pathology in diseases commonly associated with mitochondrial dysfunction such as the metabolic syndrome and neurodegenerative disorders, 1,5,6 albeit recent findings cast doubts on the universal validity of the results. 7,8 Although prominent axonal pathology often precedes cell body loss in many neurodegenerative diseases, 9 the potential of SIRT1 activation in axonal degeneration has not been addressed in depth. In this work, we take advantage of the cellular and animal models of the rare monogenic neurodegenerative disease named X-linked adrenoleukodystrophy (X-ALD, (McKusick No.300100)) to evaluate the impact of SIRT1 function on axonal degeneration. X-ALD is the most prevalent peroxisomal disorder (minimum incidence 1:17 000 newborns), characterized by brain inflammatory demyelination and/or axonopathy of long tracts in spinal cords, adrenal insufficiency and a pathognomonic accumulation of very longchain fatty acids (VLCFA) in plasma and tissues, in particular hexacosanoic acid (C26:0). 10,11 The disease phenotypes range from adrenal ...

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Section: Discussionmentioning

confidence: 98%

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

et al. 2015

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“…10 Dysfunctional mitochondria were recently shown to be implicated in both early and chronic stages of MS pathology, actively contributing to both axonal and neuronal injury. [11][12][13] The cause of mitochondrial dysfunction in patients with MS has been debated, but evidence is emerging that ROS production by macrophages/microglia might induce mitochondrial dysfunction in patients with MS, 10,13 possibly via oxidative damage to mitochondrial DNA. 12 Oxidative damage contribution to MS lesion formation In the initial phase of MS lesion formation, locally produced ROS can induce blood-brain barrier (BBB) disruption and promote leukocyte migration.…”

Section: Introductionmentioning

confidence: 99%

Glutathione in multiple sclerosis: More than just an antioxidant?

et al. 2014

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Abstract:Oxidative stress has been strongly implicated in both the inflammatory and neurodegenerative pathological mechanisms in multiple sclerosis (MS). In response to oxidative stress, cells increase and activate their cellular antioxidant mechanisms. Glutathione (GSH) is the major antioxidant in the brain, and as such plays a pivotal role in the detoxification of reactive oxidants. Previous research has shown that GSH homeostasis is altered in MS. In this review, we provide a comprehensive overview on GSH metabolism in brain cells, with a focus on its involvement in MS. The potential of GSH as an in vivo biomarker in MS is discussed, along with a short overview of improvements in imaging methods that allow non-invasive quantification of GSH in the brain. These methods might be instrumental in providing realtime measures of GSH, allowing the assessment of the oxidative state in MS patients and the monitoring of disease progression. Finally, the therapeutic potential of GSH in MS is discussed.

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“…Mitochondrial disturbances cause many neurodegenerative processes, including DNA damage, insufficient mitochondrial enzyme activity, abnormal mitochondrial gene expression, and defective DNA repair mechanism (22). As a result, mitochondrial damage in MS was considered to play an important role in disease progression (23,24).OS leads to mitochondrial damage, thus disrupting transport of adenosine triphosphate along axons, resulting in neurodegeneration (25)(26)(27). Faulty mitochondrial DNA was reported as the consequence of oxidative and nitrosative stress (28).…”

Section: The Mitochondrial Dysfunction Theory In Msmentioning

confidence: 99%

Novel Approaches of Oxidative Stress Mechanisms in the Multiple Sclerosis Pathophysiology and Therapy

Adamczyk

Niedziela

Adamczyk-Sowa

2017

Multiple Sclerosis: Perspectives in Treatment and Pathogenesis

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Abstract:It is suspected that the development of multiple sclerosis (MS) can be affected by oxidative stress (OS). In the acute phase of the disease, OS is responsible for initiating inflammation, whereas in the chronic phase it sustains neurodegenerative process. Redox processes in MS are related to dysregulation of axonal bioenergetics, cerebral iron accumulation, mitochondrial dysfunction, impaired oxidant/antioxidant balance, and OS memory. This chapter gives an overview of the role of OS in MS.

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Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis

Cited by 245 publications

References 85 publications

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

Glutathione in multiple sclerosis: More than just an antioxidant?

Novel Approaches of Oxidative Stress Mechanisms in the Multiple Sclerosis Pathophysiology and Therapy

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