Calcium signaling-mediated endogenous protection of cell energetics in the acutely diabetic myocardiumThis article is one of a selection of papers published in a special issue on Advances in Cardiovascular Research (original) (raw)
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Energy Transfer in Acute Diabetic Rat Hearts
Annals of the New York Academy of Sciences, 2006
Objectives-Hearts of rats with diabetes mellitus (DM) are characterized by energy demands exceeding their energy production, but they might also exhibit decreased vulnerability to ischemia and calcium overload. This indicates adaptation in cardiac energetics (CE), where energy transport is not rate-limiting. Aim-This study was designed to elucidate the functional significance of the DM-induced adaptation in CE by investigating the formation of mitochondrial contact sites (MiCS), facilitating the Ca-dependent/high-capacity energy transfer from mitochondria, in conjunction with testing the ischemic tolerance (IT) of hearts. Methods-After 1 week of streptozotocin-induced DM (45 mg/kg iv), the hearts of male diabetic and age-matched control rats (C) were isolated and Langendorff-perfused with either 1.6 or 2.2 mmol/L of CaCl 2 . MiCS formation was assessed by cytochemical detection of mCPK octamers and was quantified stereologically as MiCS to mitochondrial surface ratio (S S ). IT was evaluated in anesthetized open-chest animals subjected to 30min occlusion of the LAD coronary artery followed by 4-h reperfusion, by monitoring ischemic arrhythmias and by measuring the size of infarction (tetrazolium double staining). Results-In C hearts, increasing Ca 2+ induced both positive inotropic response (dP/dt increase from 2270 ± 220 to 2955 ± 229, p < 0.01) and elevated MiCS formation (S S increase from 0.070 ± 0.011 to 0.123 ± 0.012, p < 0.01). In DM hearts, basic MiCS formation was already comparable with that induced by elevated Ca 2+ in C hearts and could not be further stimulated by Ca 2+ . In C, ventricular tachycardia represented 55.4% of the total arrhythmias and occurred in 90% of the animals. In DM rats, the 464 ANNALS NEW YORK ACADEMY OF SCIENCES arrhythmia profile was similar to that in C, and the incidence of tachyarrhythmias and their severity were not enhanced (arrhythmia score: 3.18 ± 0.4 vs. 3.30 ± 0.3 in C). The infarct size normalized to the size of area at risk was smaller in the DM than in C hearts (52.3 ± 5.8% vs. 69.2 ± 2.2%, respectively; p < 0.05). Conclusions-Ca-signaling represents the link between energy delivery from mitochondria (via MiCS) and energy requirements of the heart. In DM hearts, energy transport via MiCS is elevated to the maximum value. This contributes to increased resistance of DM hearts to irreversible cell damage.
2001
Type 2 diabetes (or non-insulin dependent diabetes mellitus, NIDDM) is a common metabolic disease in man. The Goto-Kakizaki (GK) rat has been designed as a NIDDM model. Previous studies with this strain have shown differences at the mitochondrial level. The mitochondrial permeability transition (MPT) is a widely studied phenomenon but yet poorly understood, that leads to mitochondrial dysfunction and cell death. The aim of this work was to compare the differences in susceptibility of induction of the MPT with calcium phosphate in GK and Wistar rats. Our results show that heart mitochondria from GK rats are less susceptible to the induction of MPT, and show a larger calcium accumulation before the overall loss of mitochondrial impermeability.
Mitochondrial Function and Diabetes: Consequences for Skeletal and Cardiac Muscle Metabolism
Antioxidants & Redox Signaling, 2016
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FEBS Letters, 2003
Cardiac dysfunction is associated with diabetes. It was previously shown that heart mitochondria from diabetic rats have a reduced calcium accumulation capacity. The objective of this work was to determine whether the reduction in calcium accumulation by cardiac mitochondria from diabetic rats is related to an enhanced susceptibility to induction of the mitochondrial permeability transition. Streptozotocin-induced diabetic rats were used as a model to study the alterations caused by diabetes in the permeability transition, 21 days after streptozotocin administration. Heart mitochondria were isolated to evaluate respiratory parameters and susceptibility to the calcium-dependent permeability transition. Our results show that streptozotocin diabetes facilitates the mitochondrial permeability transition in cardiac mitochondria, resulting in decreased mitochondrial calcium accumulation. We also observed that heart mitochondria from diabetic rats had depressed oxygen consumption during the phosphorylative state. The reduced mitochondrial calcium uptake observed in heart mitochondria from diabetic rats is related to an enhanced susceptibility to the permeability transition rather than to damage to the calcium uptake machinery. ß
Mitochondrial Function in Diabetes: Novel Methodology and New Insight
Diabetes, 2013
Interpreting mitochondrial function as affected by comparative physiologic conditions is confounding because individual functional parameters are interdependent. Here, we studied muscle mitochondrial function in insulin-deficient diabetes using a novel, highly sensitive, and specific method to quantify ATP production simultaneously with reactive oxygen species (ROS) at clamped levels of inner mitochondrial membrane potential (DC), enabling more detailed study. We used a 2-deoxyglucose (2DOG) energy clamp to set DC at fixed levels and to quantify ATP production as 2DOG conversion to 2DOG-phosphate measured by onedimensional 1 H and two-dimensional 1 H/ 13 C heteronuclear single quantum coherence nuclear magnetic resonance spectroscopy. These techniques proved far more sensitive than conventional 31 P nuclear magnetic resonance and allowed high-throughput study of small mitochondrial isolates. Over conditions ranging from state 4 to state 3 respiration, ATP production was lower and ROS per unit of ATP generated was greater in mitochondria isolated from diabetic muscle. Moreover, ROS began to increase at a lower threshold for inner membrane potential in diabetic mitochondria. Further, ATP production in diabetic mitochondria is limited not only by respiration but also by limited capacity to use DC for ATP synthesis. In summary, we describe novel methodology for measuring ATP and provide new mechanistic insight into the dysregulation of ATP production and ROS in mitochondria of insulin-deficient rodents.
Mitochondrial inefficiencies and anoxic ATP hydrolysis capacities in diabetic rat heart
American journal of physiology. Cell physiology, 2014
As ~80% of diabetic patients die from heart failure, an understanding of diabetic cardiomyopathy is crucial. Mitochondria occupy 35-40% of the mammalian cardiomyocyte volume and supply 95% of the heart's ATP, and diabetic heart mitochondria show impaired structure, arrangement, and function. We predict that bioenergetic inefficiencies are present in diabetic heart mitochondria; therefore, we explored mitochondrial proton and electron handling by linking oxygen flux to steady-state ATP synthesis, reactive oxygen species (ROS) production, and mitochondrial membrane potential (ΔΨ) within rat heart tissues. Sprague-Dawley rats were injected with streptozotocin (STZ, 55 mg/kg) to induce type 1 diabetes or an equivalent volume of saline (control, n = 12) and fed standard rat chow for 8 wk. By coupling high-resolution respirometers with purpose-built fluorometers, we followed Magnesium Green (ATP synthesis), Amplex UltraRed (ROS production), and safranin-O (ΔΨ). Relative to control rat...
American journal of physiology. Cell physiology, 2016
Diabetic cardiomyopathy is associated with metabolic changes including decreased glucose oxidation (Gox) and increased fatty acid oxidation (FAox), which result in cardiac energetic deficiency. Diabetic hyperglycemia is a pathophysiological mechanism that triggers multiple maladaptive phenomena. The mitochondrial calcium uniporter (MCU) is the channel responsible for Ca(2+) uptake in mitochondria and free mitochondrial calcium concentration ([Ca(2+)]m) regulates mitochondrial metabolism. Experiments with cardiac myocytes (CM) exposed to simulated hyperglycemia revealed both reduced [Ca(2+)]m and MCU protein levels. Therefore, we investigated whether returning [Ca(2+)]m to normal levels in CM by expressing MCU could lead to normalization of Gox and FAox with no detrimental effects. Mouse neonatal CM were exposed for 72 h to either normal glucose (5.5 mM glucose plus 19.5 mM manitol, NG), high glucose (25 mM glucose, HG), or HG plus adenoviral MCU expression. Gox and FAox, [Ca(2+)]m, ...
Protective mechanisms of mitochondria and heart function in diabetes
Antioxidants & Redox Signaling, 2015
Significance: The heart depends on continuous mitochondrial ATP supply and maintained redox balance to properly develop force, particularly under increased workload. During diabetes, however, myocardial energeticredox balance is perturbed, contributing to the systolic and diastolic dysfunction known as diabetic cardiomyopathy (DC). Critical Issues: How these energetic and redox alterations intertwine to influence the DC progression is still poorly understood. Excessive bioavailability of both glucose and fatty acids (FAs) play a central role, leading, among other effects, to mitochondrial dysfunction. However, where and how this nutrient excess affects mitochondrial and cytoplasmic energetic/redox crossroads remains to be defined in greater detail. Recent Advances: We review how high glucose alters cellular redox balance and affects mitochondrial DNA. Next, we address how lipid excess, either stored in lipid droplets or utilized by mitochondria, affects performance in diabetic hearts by influencing cardiac energetic and redox assets. Finally, we examine how the reciprocal energetic/redox influence between mitochondrial and cytoplasmic compartments shapes myocardial mechanical activity during the course of DC, focusing especially on the glutathione and thioredoxin systems. Future Directions: Protecting mitochondria from losing their ability to generate energy, and to control their own reactive oxygen species emission is essential to prevent the onset and/or to slow down DC progression. We highlight mechanisms enforced by the diabetic heart to counteract glucose/FAs surplus-induced damage, such as lipid storage, enhanced mitochondria-lipid droplet interaction, and upregulation of key antioxidant enzymes. Learning more on the nature and location of mechanisms sheltering mitochondrial functions would certainly help in further optimizing therapies for human DC. Antioxid. Redox Signal. 00, 000-000.
Diabetes impairs heart mitochondrial function without changes in resting cardiac performance
The International Journal of Biochemistry & Cell Biology, 2016
Diabetes is a chronic disease associated to a cardiac contractile dysfunction that is not attributable to underlying coronary artery disease or hypertension, and could be consequence of a progressive deterioration of mitochondrial function. We hypothesized that impaired mitochondrial function precedes Diabetic Cardiomyopathy. Thus, the aim of this work was to study the cardiac performance and heart mitochondrial function of diabetic rats, using an experimental model of type I Diabetes. Rats were sacrificed after 28 days of Streptozotocin injection (STZ, 60 mg kg −1 , ip.). Heart O 2 consumption was declined, mainly due to the impairment of mitochondrial O 2 uptake. The mitochondrial dysfunction observed in diabetic animals included the reduction of state 3 respiration (22%), the decline of ADP/O ratio (∼15%) and the decrease of the respiratory complexes activities (22-26%). An enhancement in mitochondrial H 2 O 2 (127%) and NO (23%) production rates and in tyrosine nitration (58%) were observed in heart of diabetic rats, with a decrease in Mn-SOD activity (∼50%). Moreover, a decrease in contractile response (38%), inotropic (37%) and lusitropic (58%) reserves were observed in diabetic rats only after a -adrenergic stimulus. Therefore, in conditions of sustained hyperglycemia, heart mitochondrial O 2 consumption and oxidative phosphorylation efficiency are decreased, and H 2 O 2 and NO productions are increased, leading to a cardiac compromise against a work overload. This mitochondrial impairment was detected in the absence of heart hypertrophy and of resting cardiac performance changes, suggesting that mitochondrial dysfunction could precede the onset of diabetic cardiac failure, being H 2 O 2 , NO and ATP the molecules probably involved in mitochondrion-cytosol signalling.