Diminished Superoxide Generation Is Associated With Respiratory Chain Dysfunction and Changes in the Mitochondrial Proteome of Sensory Neurons From Diabetic Rats

Akude, Eli; Zherebitskaya, Elena; Chowdhury, Subir; Smith, Daniel R.; Dobrowsky, Rick T.; Fernyhough, Paul

doi:10.2337/db10-0818

Cited by 129 publications

(150 citation statements)

References 40 publications

(83 reference statements)

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“…They discovered that the respiratory chain components of mitochondrial proteome were down-regulated in the DRG of diabetic rats. Consistent with decreased protein expression and impaired respiratory chain activity, as demonstrated by reduced mitochondrial membrane potential and reduced respiratory chain derived ROS generation (Akude et al, 2011).…”

Section: Mitochondrial Proteomics In T1dmmentioning

confidence: 81%

Mitochondria in the pathogenesis of diabetes: a proteomic view

2012

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Diabetes mellitus is a complex metabolic disorder characterized by chronic hyperglycemia due to absolute or relative lack of insulin. Though great efforts have been made to investigate the pathogenesis of diabetes, the underlying mechanism behind the development of diabetes and its complications remains unexplored. Cumulative evidence has linked mitochondrial modification to the pathogenesis of diabetes and its complications and they are also observed in various tissues affected by diabetes. Proteomics is an attractive tool for the study of diabetes since it allows researchers to compare normal and diabetic samples by identifying and quantifying the differentially expressed proteins in tissues, cells or organelles. Great progress has already been made in mitochondrial proteomics to elucidate the role of mitochondria in the pathogenesis of diabetes and its complications. Further studies on the changes of mitochondrial protein specifically post-translational modifications during the diabetic state using proteomic tools, would provide more information to better understand diabetes.

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Section: Mitochondrial Proteomics In T1dmmentioning

confidence: 81%

Mitochondria in the pathogenesis of diabetes: a proteomic view

2012

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“…Evidence indicates that in neurons, diabetes decreases the expression of mitochondrial proteins 174 , the inner membrane potential 175 and the spare respiratory capacity 77 of otherwise functional mitochondria as a result of disruption to the AMPK-PGC1 pathway, which serves as a nutrient sensor and mitochondrial regulator 176 . These effects leave the neuron energetically viable but restricted in its capacity to respond to the increased energy demand of regrowth after physical injury, and to survive diseasemediated stress.…”

Section: Towards a New Understandingmentioning

confidence: 99%

Schwann cell interactions with axons and microvessels in diabetic neuropathy

et al. 2017

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The incidence of diabetes mellitus has increased dramatically over the past two to three decades. According to the International Diabetes Federation Diabetes Atlas, 415 million people worldwide had diabetes in 2015, and this number is expected to grow by 5% annually, predominantly as a result of increasing prevalence of type 2 diabetes. Furthermore, an estimated 100 million Europeans and 80 million Americans have impaired glucose tolerance or prediabetes. Few people die from acute diabetes in countries with comprehensive health care systems, but the disease is inflicting a huge medical, social and economic burden on society owing to the need for lifelong treatment of its systemic consequences and the insidious development of multi-organ damage.Peripheral neuropathy (BOXES 1,2) is a common but often neglected complication of long-term diabetes, and the lack of treatment options reflects an incomplete understanding of the pathogenic mechanisms. Hyperglycaemia is generally accepted as the primary pathogenic insult in type 1 and type 2 diabetic neuropathy, although roles are emerging for other factors, such as impaired insulin signalling, hypertension and dyslipidaemia (particularly for type 2 diabetes), which might precede overt hyperglycaemia 1 . Many preclinical studies, and occasional clinical studies, have indicated that diabetic neuropathy -like diabetic nephropathy and retinopathy -results from microvascular disease, with a focus on axonal degeneration as a consequence of ischaemia and/or hypoxia. This mechanism, however, is likely to be only one aspect of a more complex pathogenesis.The earliest descriptions of pathology in diabetic neuropathy indicated that Schwannopathy accompanied axonal degeneration. The majority of clinical and basic research in diabetic neuropathy since then has focused on the effects on neurons. However, accumulating data from research into the development and regeneration of the PNS has identified Schwann cells as equally indispensable components that maintain neuronal structure and function, nourish axons, and promote survival and growth upon injury. The early reports from 1979 that demonstrated morphological changes in Schwann cells in human diabetic neuropathy 2 are now supported by an increased awareness of molecular alterations in Schwann cells during diabetes 3 . Schwann cells express a wide range of receptors and, when they sense insults or danger signals, they upregulate synthesis and secretion of factors that stimulate neuroprotection, regrowth and remyelination, or factors that aggravate disease phenotypes 4 . The most recent studies have demonstrated that Schwann cells regulate many aspects of axonal function, so that disruption of their metabolism by diabetes results in the accumulation of neurotoxic intermediates and compromises production of neuronal support factors, contributing to axonal degeneration, endothelial dysfunction and diabetic neuropathy. Abstract | The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annu...

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“…In neurons derived from the DRG of diabetic rats (22 weeks after STZ) compared with healthy controls and maintained in culture with high and normal glucose media, respectively, there was significant downregulation of proteins related to oxidative phosphorylation and the tricarboxylic (TCA) cycle in diabetes/ high glucose (9). In contrast, Schwann cells derived from the SN of neonatal rats and cultured in high glucose for 2, 6, or 16 days compared with normal glucose showed upregulation of oxidative phosphorylation and the TCA cycle at all time points (10).…”

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confidence: 99%

Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy

et al. 2015

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High glucose levels in the peripheral nervous system (PNS) have been implicated in the pathogenesis of diabetic neuropathy (DN). However, our understanding of the molecular mechanisms that cause the marked distal pathology is incomplete. We performed a comprehensive, system-wide analysis of the PNS of a rodent model of DN. We integrated proteomics and metabolomics from the sciatic nerve (SN), the lumbar 4/5 dorsal root ganglia (DRG), and the trigeminal ganglia (TG) of streptozotocin-diabetic and healthy control rats. Even though all tissues showed a dramatic increase in glucose and polyol pathway intermediates in diabetes, a striking upregulation of mitochondrial oxidative phosphorylation and perturbation of lipid metabolism was found in the distal SN that was not present in the corresponding cell bodies of the DRG or the cranial TG. This finding suggests that the most severe molecular consequences of diabetes in the nervous system present in the SN, the region most affected by neuropathy. Such spatial metabolic dysfunction suggests a failure of energy homeostasis and/or oxidative stress, specifically in the distal axon/Schwann cell-rich SN. These data provide a detailed molecular description of the distinct compartmental effects of diabetes on the PNS that could underlie the distal-proximal distribution of pathology.Diabetic neuropathy (DN) will develop in ;30-50% of patients with diabetes. DN typically presents with sensory symptoms in a distal glove-and-stocking distribution (1,2). It is a poorly understood complication of diabetes, and currently, few treatments are available (3). Raised glucose has long been believed to instigate pathology in DN either through direct neurotoxicity or from the activation of secondary pathways (4,5). However, exactly how these pathways cause nerve conduction velocity deficits, neuropathic pain, distal axonopathy, and numbness in the extremities continues to elude us, and many clinical trials aimed at specific targets have failed due to lack of efficacy (3).Crossover exists between proposed pathogenic pathways in DN, but how these interact is unclear. This question can be approached by implementing extensive -omic technologies to measure many transcripts, proteins, or metabolites in parallel. Gene microarrays were among the first of these technologies to be used, and transcriptomic analyses have been performed on tissues such as the dorsal root ganglia (DRG) from streptozotocin (STZ)-diabetic rats compared with healthy controls (6), the sciatic nerve (SN) of db/db mice compared with those from db/+ mice (7), and sural nerve biopsy specimens from human patients whose neuropathy progressed over 1 year compared with those whose neuropathy did not (based on myelinated fiber density loss) (8). Common changes across these gene array studies highlight altered carbohydrate and lipid metabolism.Because gene transcript levels do not always correlate with protein expression due to varying transcriptional/translational

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Diminished Superoxide Generation Is Associated With Respiratory Chain Dysfunction and Changes in the Mitochondrial Proteome of Sensory Neurons From Diabetic Rats

Cited by 129 publications

References 40 publications

Mitochondria in the pathogenesis of diabetes: a proteomic view

Mitochondria in the pathogenesis of diabetes: a proteomic view

Schwann cell interactions with axons and microvessels in diabetic neuropathy

Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy

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