Section III : Mitochondria ,-Cell Function , and Type 2 Diabetes Roles of Mitochondria in Health and Disease

Mitochondria play a central role in cell life and cell death. An increasing number of studies place mitochondrial dysfunction at the heart of disease, most notably in the heart and the central nervous system. In this article, I review some of the key features of mitochondrial biology and focus on the pathways of mitochondrial calcium accumulation. Substantial evidence now suggests that the accumulation of calcium into mitochondria may play a key role as a trigger to mitochondrial pathology, especially when that calcium uptake is accompanied by another stressor, in particular nitrosative or oxidative stress. The major process involved is the opening of the mitochondrial permeability transition pore, a large conductance pore that causes a collapse of the mitochondrial membrane potential, leading to ATP depletion and necrotic cell death or to cytochrome c release and apoptosis, depending on the rate of ATP consumption. I discuss two models in particular in which these processes have been characterized. The first is a model of oxidative stress in cardiomyocytes, in which reperfusion after ischemia causes mitochondrial calcium overload, and oxidative stress. Recent experiments suggest that cardioprotection by hypoxic preconditioning or exposure to the ATP-dependent K channel opener diazoxide increases mitochondrial resistance to oxidative injury. In a second model, of calcium overload in neurons, the neurotoxicity of glutamate depends on mitochondrial calcium uptake, but the toxicity to mitochondria also requires the generation of nitric oxide. Glutamate toxicity after activation of N-methyl-D-aspartate (NMDA) receptors results from the colocalization of NMDA receptors with neuronal nitric oxide synthase (nNOS). The calcium increase mediated by NMDA receptor activation is thus associated with nitric oxide generation, and the combination leads to the collapse of mitochondrial membrane potential followed by cell death. Diabetes 53 (Suppl. 1):S96–S102, 2004 The mitochondrion lies at the heart of cell life and cell death. That we must breathe oxygen to stay alive is simply the consequence of the demand of our mitochondria for oxygen. About 98% of inhaled oxygen is consumed by mitochondria, and without mitochondria, we would have no need of the oxygen transfer machinery of the lungs, red cells, hemoglobin, or even the circulatory system that delivers oxygen to the tissues. Similarly, the organization of food intake, digestion, and processing is designed primarily to supply substrates destined for mitochondrial oxidation. Consider then how much of the physiology of higher organisms is dictated by the demand of our mitochondria for a supply of oxygen. And yet without the supply of energy provided by mitochondria as ATP, the evolution of higher organisms would not have been possible. Mitochondria are essential in maintaining the battle against entropy necessary to sustain life. They provide the energy required for almost all cellular processes—to allow muscle to contract (cardiac muscle and smooth muscle in the gut, the vasculature, and the lungs), to maintain ionic gradients in excitable cells, to allow the accumulation of secreted material into vesicles, and to permit the vesicle fusion and cycling necessary for the secretion of hormones and neurotransmitters (all the processes central to sophisticated life). And so it follows inevitably that impaired mitochondrial function will lead to disease, ranging from subtle alterations in cell function to cell death and from minor to major disability, or to death. Quite apart from the provision of ATP, mitochondria play important roles in aspects of normal physiology. These include the transduction pathway that underlies the secretion of insulin in response to glucose by -cells and (possibly but controversially) in the sensing of oxygen tension necessary for oxygen sensing in the carotid body and the pulmonary vasculature. Mitochondria also house key enzyme systems quite distinct from those required for intermediary metabolism—the rate-limiting enzymes in steroid biosynthesis, the synthesis of haem, and even the carbonic anhydrase required for acid secretion in the stomach. By accumulating calcium when cytosolic calcium levels are high, mitochondria play subtle roles in coordinating the complexities of intracellular calciumsignaling pathways, as least in some cell types, in which their contribution may be extremely important in the finer aspects of cell regulation. The physiological “uncoupling” From the Department of Physiology, University College London, London, U.K. Address correspondence and reprint requests to Michael R. Duchen, Mitochondrial Biology Group, Department of Physiology, University College London, Gower St., London WC1E 6BT. E-mail: m.duchen@ucl.ac. uk. Received for publication 18 March 2003 and accepted in revised form 30 May 2003. This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Les Laboratoires Servier. ANT, adenine nucleotide translocase; ER, endoplasmic reticulum; Icrac, influx of calcium through capacitative influx channels; KATP channel, ATPdependent K channel; mPTP, mitochondrial permeability transition pore; NMDA, N-methyl-D-aspartate; nNos, neuronal nitric oxide synthase; ROS, reactive oxygen species; SR, sarcoplasmic reticulum; TCA, tricarboxylic acid. © 2004 by the American Diabetes Association.