The role of mitochondria in the pathogenesis of type 2 diabetes
ABSTRACT The pathophysiology of type 2 diabetes mellitus (DM) is varied and complex. However, the association of DM with obesity and inactivity indicates an important, and potentially pathogenic, link between fuel and energy homeostasis and the emergence of metabolic disease. Given the central role for mitochondria in fuel utilization and energy production, disordered mitochondrial function at the cellular level can impact whole-body metabolic homeostasis. Thus, the hypothesis that defective or insufficient mitochondrial function might play a potentially pathogenic role in mediating risk of type 2 DM has emerged in recent years. Here, we summarize current literature on risk factors for diabetes pathogenesis, on the specific role(s) of mitochondria in tissues involved in its pathophysiology, and on evidence pointing to alterations in mitochondrial function in these tissues that could contribute to the development of DM. We also review literature on metabolic phenotypes of existing animal models of impaired mitochondrial function. We conclude that, whereas the association between impaired mitochondrial function and DM is strong, a causal pathogenic relationship remains uncertain. However, we hypothesize that genetically determined and/or inactivity-mediated alterations in mitochondrial oxidative activity may directly impact adaptive responses to overnutrition, causing an imbalance between oxidative activity and nutrient load. This imbalance may lead in turn to chronic accumulation of lipid oxidative metabolites that can mediate insulin resistance and secretory dysfunction. More refined experimental strategies that accurately mimic potential reductions in mitochondrial functional capacity in humans at risk for diabetes will be required to determine the potential pathogenic role in human insulin resistance and type 2 DM.
- SourceAvailable from: Michael Paillasse
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- "Apart from ROS accumulation, dysfunctional mitochondria impair oxidative metabolism (e.g. ATP production, fatty acid and glucose oxidation) provoking increased visceral adiposity, blood glucose and insulin resistance  . These metabolic changes are deleterious to organs maintenance. "
ABSTRACT: The development of innovative anti-aging strategy is urgently needed to promote healthy aging and overcome the occurrence of age-related diseases such as cancer, diabetes, cardiovascular and neurodegenerative diseases. Genomic instability, deregulated nutrient sensing and mitochondrial dysfunction are established hallmark of aging. Interestingly, the orphan nuclear receptors NR4A subfamily (NR4A1, NR4A2 and NR4A3) are nutrient sensors that trigger mitochondria biogenesis and improve intrinsic mitochondrial function. In addition, NR4A receptors are components of DNA repair machinery and promote DNA repair. Members of the NR4A subfamily should also be involved in anti-aging properties of hormesis since these receptors are induced by various form of cellular stress and stimulate protective cells response such as anti-oxidative activity and DNA repair. Previous studies reported that NR4A nuclear receptors subfamily is potential therapeutic targets for the treatment of age related disorders (e.g. metabolic syndromes, diabetes and neurodegenerative diseases). Consequently, we propose that targeting NR4A receptors might constitute a new approach to delay aging and the onset of diseases affecting our aging population. Copyright © 2014 Elsevier Ltd. All rights reserved.Medical Hypotheses 12/2014; 84(2). DOI:10.1016/j.mehy.2014.12.003 · 1.15 Impact Factor
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- "The increase in the supply of reducing equivalents (i.e. NADH and FADH 2 ) to the electron transport chain (ETC), without a parallel increase in the oxidative phosphorylation (OXPHOS) capacity, might result in the loss of electrons from the ETC and subsequently, the generation of reactive oxygen species (ROS) . In turn, increased ROS may promote mitochondrial uncoupling     , as a mechanism to reduce the electrochemical proton gradient required for ROS formation, which will however result in lower ATP generation. "
ABSTRACT: Obesity is often associated with abnormalities in cardiac morphology and function. This study tested the hypothesis that obesity-related cardiomyopathy is caused by impaired cardiac energetics. In a mouse model of high-fat diet (HFD)-induced obesity, we applied in vivo cardiac 31P magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) to investigate cardiac energy status and function, respectively. The measurements were complemented by ex vivo determination of oxygen consumption in isolated cardiac mitochondria, the expression of proteins involved in energy metabolism, and markers of oxidative stress and calcium homeostasis. We also assessed whether HFD induced myocardial lipid accumulation using in vivo 1H MRS, and if this was associated with apoptosis and fibrosis. Twenty weeks of HFD feeding resulted in early stage cardiomyopathy, as indicated by diastolic dysfunction and increased left ventricular mass, without any effects on systolic function. In vivo cardiac phosphocreatine-to-ATP ratio and ex vivo oxygen consumption in isolated cardiac mitochondria were not reduced after HFD feeding, suggesting that the diastolic dysfunction was not caused by impaired cardiac energetics. HFD feeding promoted mitochondrial adaptations for increased utilization of fatty acids, which was however not sufficient to prevent the accumulation of myocardial lipids and lipid intermediates. Myocardial lipid accumulation was associated with oxidative stress and fibrosis, but not apoptosis. Furthermore, HFD feeding strongly reduced the phosphorylation of phospholamban, a prominent regulator of cardiac calcium homeostasis and contractility. In conclusion, HFD-induced early stage cardiomyopathy in mice is associated with lipotoxicity-associated oxidative stress, fibrosis, and disturbed calcium homeostasis, rather than impaired cardiac energetics.Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 10/2014; 1841(10). DOI:10.1016/j.bbalip.2014.07.016 · 4.50 Impact Factor
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- "Among many contributing factors to ageing is the gradual decline of mitochondrial function with age leading to progressive tissue damage via oxidative stress. Mutations in mitochondrial DNA result in a variety of phenotypes including myopathies, neuropathies, diabetes, as well as premature signs of ageing and reduced lifespan (Larsson 2010; Patti and Corvera 2010; Lee and Wei 2012). Mitochondrial dysfunction occurs at an organ-specific level in many age-related diseases including type 2 diabetes and obesity. "
ABSTRACT: Ageing can be characterised by a general decline in cellular function, which affects whole-body homoeostasis with metabolic dysfunction-a common hallmark of ageing. The identification and characterisation of the genetic pathways involved are paramount to the understanding of how we age and the development of therapeutic strategies for combating age-related disease. Furthermore, in addition to understanding the ageing process itself, we must understand the interactions ageing has with genetic variation that results in disease phenotypes. The use of model systems such as the mouse, which has a relatively short lifespan, rapid reproduction (resulting in a large number of offspring), well-characterised biology, a fully sequenced genome, and the availability of tools for genetic manipulation is essential for such studies. Here we review the relationship between ageing and metabolism and highlight the need for modelling these processes.Mammalian Genome 08/2014; 25(9-10). DOI:10.1007/s00335-014-9539-6 · 2.88 Impact Factor