ReviewMitochondrial malfunction and Ca2+ dyshomeostasis drive neuronal pathology 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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