Elsevier

Cell Calcium

Volume 44, Issue 1, July 2008, Pages 112-122
Cell Calcium

Review
Mitochondrial malfunction and Ca2+ dyshomeostasis drive neuronal pathology in diabetes

https://doi.org/10.1016/j.ceca.2007.11.010Get rights and content

Summary

The World Health Organization (WHO) predicts there will be 300 million people world-wide with diabetes mellitus by 2025. Currently it is estimated that there are 20 and 60 million people suffering from diabetes mellitus in North America and Europe, respectively. Within this huge population of diabetic persons approximately 50% will develop some form of sensory polyneuropathy, which involves the dying back of distal axons and a failure of axons to regenerate. This leads to incapacitating pain, sensory loss and poor wound healing. The end result is lower extremity amputation with approximately 90,000 diabetes-related amputations occurring each year in North America and the expectation of a 5-fold increase over the next 10 years due to increased incidence of type 2 diabetes.

Abnormal neuronal Ca2+ homeostasis and impaired mitochondrial function have been implicated in numerous CNS and PNS diseases including diabetic sensory neuropathy. The endoplasmic reticulum (ER), in part, regulates cellular Ca2+ homeostasis and this process is linked to regulation of mitochondrial function and activity of anti-apoptotic signal transduction pathways. Here we review the current state of research regarding role of Ca2+ dyshomeostasis and mitochondrial physiology in neuronal dysfunction in diabetes. The central impact of diabetes-induced alteration of Ca2+ handling on sensory neurone function is discussed and related to abnormal ER performance. New results are presented showing suboptimal Ca2+ concentration in the ER lumen in association with reduced SERCA2 expression in sensory neurones from type 1 diabetic rats. We hypothesize that deficits in neurotrophic factor support, specifically linked to diabetes-induced lowered expression of insulin and neurotrophin-3, triggers alterations of sensory neurone phenotype that are critical for the development of abnormal Ca2+ homeostasis and associated mitochondrial dysfunction. The role of hyperglycaemia in diabetes is also discussed and we propose that high glucose concentration may impact at other sites to contribute to the heterogeneous aetiology of nerve damage in diabetes.

Introduction

Diabetes mellitus in humans may lead to a number of complications, which determine the clinical progression of the disease and affect various tissues, including heart muscle, retina, secretory glands, kidneys and peripheral nerves. Chronic metabolic stress induced by hyperglycaemia resulting from either low insulin production in type 1 diabetes or decreased peripheral sensitivity to insulin in type 2 diabetes affects cellular homeostasis in virtually all cell types.

At the same time the cellular pathophysiology of diabetes-induced impairments remain controversial. Conceptually, the leading mechanism driving cellular pathology is believed to be associated with accumulation of extracellular glucose, with subsequent metabolic and osmotic stress, generation of reactive oxygen species (ROS), which all damage membrane systems, thereby triggering pathological outcomes [1], [2].

Recent experimental studies however, have revealed very early impairment of two intimately connected intracellular signalling/integrative systems, namely Ca2+ homeostatic/signalling and mitochondria. These changes are similar in very different cell types, and may be regarded as a common pathologically relevant pathway. Here we summarise our own data and data produced by other groups, which show similar changes in Ca2+ homeostasis and mitochondrial dysfunction in peripheral neurones, and propose a leading role of these changes in cellular pathophysiology of complications associated with diabetes mellitus.

Section snippets

Clinical impact of diabetes and diabetic sensory neuropathy

The World Health Organization (WHO) predicts that by 2025 there will be 300 million people with diabetes. In Europe and North America it is estimated that 60 and 20 million people, respectively, currently have diabetes which has an incidence of 6% and rising (see ADA, IDF and CDA web sites of International Diabetes Federation; http://www.idf.org/webdata/docs/StakeholderPresentation.pdf; American Diabetes Association; http://www.diabetes.org/diabetes-statistics.jsp or Canadian Diabetes

Neurodegeneration in diabetic sensory neuropathy

Diabetic neuropathy in type 1 and 2 diabetes in both humans and animal models is associated with reduction of motor and sensory nerve conduction velocity and structural changes in peripheral nerve including endoneurial microangiopathy, abnormal Schwann cell pathology, axonal degeneration, paranodal demyelination and loss of myelinated and unmyelinated fibers—the latter due to a dying-back of distal axons that presents clinically as reduced epidermal nerve fiber density [8], [9], [10]. All

Calcium homeostatic/signalling system

The Ca2+ homeostatic/signalling system is, in all probability, the most ancient one, which determined the survival of proto-cells in the primordial ocean [22]. Being crucially important for cell viability, the Ca2+ homeostatic/signalling cascades are naturally implicated in cell death, because the majority of extinction pathways employ Ca2+ as an ultimate executioner, which severs the string of life and sends the cell towards the unknown realm of death [23]. Molecular cascades, responsible for

Calcium dyshomeostasis in diabetic neurones

Abnormal cellular Ca2+ homeostasis/signalling are a common feature of type 1 and 2 diabetes. Altered Ca2+ handling and Ca2+ signalling were detected in a huge variety of preparations isolated from animals with experimentally induced diabetes as well as from patients suffering from the disease. Ca2+ homeostasis abnormalities were found in virtually every tissue studied, for example in skeletal, cardiac and smooth muscle, in secretory cells, in blood cells, in kidney, in osteoblasts, etc. (see

Mitochondrial depolarisation in diabetes

The ultimate mitochondrial function, production of ATP, is driven by a host of proteins residing in the inner mitochondrial membrane, which form the electron transport chain (ETC). Energy, released in the process of electron transfer is utilised to pump protons out of the matrix (each complex in the ETC will pump protons independently) and thus generating an electrochemical gradient, expressed both as a pH gradient (alkalinisation of the mitochondrial matrix) and a mitochondrial membrane

Mitochondrial dysfunction and Ca2+ dyshomeostasis can be prevented by insulin and neurotrophic factors

Both alterations of Ca2+ homeostasis and mitochondrial membrane depolarisation in adult sensory neurones occur early (3–14 weeks) in experimental STZ-diabetes and db/db diabetes, and therefore can be identified as potential key steps in the development of sensory neuropathy. What is the pathological stressor which may trigger these events? It turned out that the critical factor determining mitochondrial dysfunction is not the hyperglycaemia, but rather absence of insulin-dependent neurotrophic

Impairment of Ca2+ homeostasis and mitochondrial function drives pathogenesis of diabetic sensory neuropathy

Neurological impairments in diabetes are many; diabetic status triggers neurodegeneration and neuronal remodelling in the CNS, which leads to diabetic encephalopathies manifested by cognitive and behavioural deficits [105]. In the periphery, diabetes almost invariably affects sensory pathways resulting in symmetrical sensory polyneuropathy. Initially, diabetic status diminishes the nerve conductance velocity; in the later stages diabetic patients may experience various symptoms ranging from

Acknowledgements

The authors thank the Juvenile Diabetes Research Foundation, Diabetes UK, St. Boniface Hospital and Research Foundation, Canadian Institutes for Health Research and Alzheimer Research Trust UK for grant support for these studies. We thank our colleagues, Drs. Natasha Solovyova, T.-J. Huang and Zuocheng Wang, for providing data that contributed towards this article.

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