Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities - PubMed (original) (raw)
Review
Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities
William I Sivitz et al. Antioxid Redox Signal. 2010 Apr.
Abstract
Given their essential function in aerobic metabolism, mitochondria are intuitively of interest in regard to the pathophysiology of diabetes. Qualitative, quantitative, and functional perturbations in mitochondria have been identified and affect the cause and complications of diabetes. Moreover, as a consequence of fuel oxidation, mitochondria generate considerable reactive oxygen species (ROS). Evidence is accumulating that these radicals per se are important in the pathophysiology of diabetes and its complications. In this review, we first present basic concepts underlying mitochondrial physiology. We then address mitochondrial function and ROS as related to diabetes. We consider different forms of diabetes and address both insulin secretion and insulin sensitivity. We also address the role of mitochondrial uncoupling and coenzyme Q. Finally, we address the potential for targeting mitochondria in the therapy of diabetes.
Figures
FIG. 1.
Mitochondrial electron transport and ROS production. The schematic illustration depicts the convergent nature of electron donation at one of four sites: complex I (NADH ubiquinone reductase), complex II (succinate dehydrogenase), the electron-transfer flavoprotein (ETF), or a mitochondrial form of GAPDH. Reduced ubiquinone is processed through the Q-cycle in complex III, where protons are pumped and electrons passed to mobile cytochrome c and then cytochrome oxidase. ATP formation through ATP synthase (not shown) is coupled to mitochondrial potential generated by proton pumping at complexes I, III, and IV and offset by proton transfer in the opposite direction (proton leak), mediated in part by uncoupling proteins (UCPs). Superoxide (O2·−) produced at complex III in the Q-cycle results from electron leaks generated by the reactive semiquinone intermediate, O2·− (295). Superoxide is also produced at complex I (see text, section II.B), where it is released to the matrix. Note that superoxide is shown (dotted lines) to activate proton transfer by UCP. Red arrows, Electron transport. Blue arrows, H+ movement either away from (proton pumping) or back toward (proton leak) the matrix. Black arrows, Electron leaks leading to one-electron reduction of oxygen to O2·−.
FIG. 2.
Q-cycle at complex III. Mitochondrial inner membrane is depicted with (+) outside and (−) inside charge. bL and bH represent low- and high-potential cytochrome heme content. FeSIII represents non-heme iron–sulfur cluster of complex III. Electron (e−) flow follows along arrows, as depicted. Oxidation of CoQH2 directs electrons either to the iron–sulfur cluster and cytochrome c (Cyt C) or to generate the semiquinone form of CoQ, which passes electrons back through bL and bH to complete the cycle. Accompanying this process, two hydrogen ions are pumped outward from the negatively charged matrix.
FIG. 3.
Kinetics of the proton leak in mitochondria isolated from brown adipose tissue mitochondria of C57Bl/6 mice fed low-fat (LF) or high-fat (HF) diets. Leak kinetics were assessed in the presence or absence of the uncoupling protein 1 inhibitor GDP. Mitochondria from the high-fat–fed mice manifest greater GDP-inhibitable proton conductance, reflecting the UCP1-mediated proton leak. For both panels, the increased proton leak in the absence of GDP compared with the presence of GDP is evident as a shift in the curve of oxygen use versus potential upward and to the left.
FIG. 4.
H2O2 production by mitochondria isolated from mouse hindlimb muscle (A) or bovine aortic endothelial cells (B and C), measured as 10-acetyl-3,7-dihydroxyphenoxazine (DHPA) fluorescence. Mitochondria were incubated in the presence of the substrates or inhibitors shown (or both), including 5 m_M_ succinate (succ), 5 m_M_ glutamate + 1 m_M_ malate (glut + mal), 5 μ_M_ rotenone (rot), or 1 μ_M_ antimycin A (ant A). n = 4 to 6 mitochondrial preparations for each data point. *p < 0.01, †p < 0.05 by one-way ANOVA compared with succinate condition.
FIG. 5.
EPR spectra generated by using the spin-trap DMPO, which is specific for superoxide or the hydroxyl radical. Spectra were determined in the presence of bovine aortic endothelial cell mitochondria incubated in respiratory buffer plus the substrates or compounds indicated or both. Spectral signals were abolished by addition of MnSOD, demonstrating specificity for superoxide. Note the scale difference for the succinate + antimycin A condition. Additions consisted of 5 m_M_ succinate, 5 μ_M_ rotenone, 1 μ_M_ antimycin A, or 200 μg/ml manganese superoxide dismutase (SOD).
FIG. 6.
Schematic diagram depicting electron transport, the action of substrates and inhibitors, and proposed sites of ROS production, as detected with H2O2 fluorescence and EPR spectroscopy. Straight lines with arrows, Forward electron transport. Dashed lines, Reverse transport. Dashed-dotted lines, Diffusion of Q compounds in complex III or of H2O2 out from the matrix, as shown. Dotted boxes, Complexes I, II, and III. X, Sites of inhibition by rotenone (ROT), stigmatellin (STIG), or antimycin A (ANT A). Dark arrows, Direction of superoxide release or conversion to H2O2.
FIG. 7.
Effect of mitochondrial dysfunction to inhibit insulin signaling in GLU4-expressing muscle cells. The schematic diagram depicts major steps in insulin signal transduction as well as the consequences of excess fatty acyl-CoA and ROS production on insulin signaling. Insulin interacts with α-subunits of its receptor (IR), which extends outward from the cell membrane. In response to an induced conformational change in the internal or β-subunits of the receptor, tyrosine residues undergo autophosphorylation, and the IR acquires tyrosine kinase activity. This leads to phosphorylation of insulin-receptor substrate-1 (IRS-1), triggering a downstream cascade leading to activation of Akt and translocation of the glucose transporter type 4 (GLUT4) to the cell membrane. GLUT-4 fusion with the membrane results in glucose uptake by facilitated diffusion. Mitochondrial dysfunction is depicted to oppose insulin signaling in two ways: first, by interfering with oxidation of fatty acyl-CoA and consequent accumulation of intracellular lipid and diacylglycerol, and second, through generation of ROS. Both processes activate serine kinase reactions, leading to serine phosphorylation of IRS-1 and interference with insulin signal transduction. IRS-1, insulin receptor substrate-1; GLUT4, glucose transporter 4; FA, fatty acid; FATPs, various transport proteins that have been described as active in fatty acid uptake.
FIG. 8.
Role of mitochondria in regulating insulin secretion. As shown, glucose sensing and glucose-induced insulin release is dependent on mitochondrial ATP generation and affected by both mitochondrial ROS and UCP2. ATP is essential for opening of potassium ATP channels and, therefore, for entry of calcium and insulin release from storage granules. Under conditions of hyperglycemia, it is possible that excess ROS may lead to oxidative damage, gradually impairing insulin secretion over time, with worsening of the diabetic state. +, Positive effect. Dash, Negative effect. VDCC, voltage dependent calcium channel; GK, glucokinase.
FIG. 9.
Events associated with diabetic cardiomyopathy contributing to the incongruity between glucose need and glucose oxidation (rectangular boxes). Ischemia, pressure load (often related to hypertension), and lipid overload all contribute to greater oxygen demand. This is compounded by ROS and fatty acid–induced uncoupling, which increases the oxygen requirement for a given degree of ADP conversion to ATP. These events might be offset if the myocardium could more efficiently use glucose rather than fat, because the former requires less oxygen per molecule ATP produced. Unfortunately, insulin resistance or defective insulin secretion or both, as well as excess lipid supply, all decrease the capacity of the heart to use glucose when it is needed most.
FIG. 10.
Self-perpetuating vicious cycle wherein excess nutrient supply to islet cells and insulin-sensitive myocytes leads to worsening of insulin secretion and insulin action. Concurrently worsening glycemia and elevated free fatty acids (FFAs) lead to worsening diabetic complications.
FIG. 11.
Antioxidant role of UCP3. By reducing membrane potential in the face of high substrate flux to mitochondria and consequent ROS production, UCP3 may act to effect a type of feedback inhibition. As shown, ROS would activate UCP3, thereby triggering UCP3-mediated uncoupling and close the loop.
FIG. 12.
Possible role of UCP3 to export excess mitochondrial fatty acids. Under conditions of high availability, fatty acid anions might accumulate in the mitochondrial matrix in two ways. One is through the flip-flop phenomenon (136). The other is through the carnitine palmitoyl transferase (CPT) system, followed by conversion of excess fatty acyl-CoAs to fatty acid anions and coenzyme A by mitochondrial thioesterase-1 (MTE-1) (289). In both cases, UCP3 would function to export the resultant trapped fatty acid anion protecting mitochondria from excess accumulation of fat and lipid peroxides. FAO, fatty acid oxidation.
FIG. 13.
Examples representing molecular targets for mitochondrial therapy directed at diabetes, insulin resistance, and obesity.
FIG. 14.
Structures of ubiquinone (CoQ10), mitochondrial targeted CoQ (mitoQ), and related compounds.
FIG. 15.
Dose-dependent effect of mitoquinone on fuel selectivity in bovine endothelial cells. BAE cells were incubated overnight (16 h) in the presence of culture medium with 5.5 m_M_ glucose. 1-[14C]oleic acid or
d
-[14C(U)]glucose was added along with 50 μ_M_ oleate, and cells were incubated for 120 min before trapping of CO2. Data are expressed relative to incubation in the presence of vehicle alone (0 point on x-axis, otherwise depicted on log scale). Data represent mean ± SEM (n = 4 for each determination). *p < 0.05 or **p < 0.01 compared with vehicle by one-way ANOVA with repeated measures. The absolute values for glucose and oleate oxidation in the presence of vehicle were 6.21 ± 0.54 nmol/well and 71 ± 18 pmol/well, respectively.
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