MiR 208a Regulates Mitochondrial Biogenesis in Metabolically Challenged Cardiomyocytes.

Metabolic syndrome increases the risk for cardiovascular disease including metabolic cardiomyopathy that may progress to heart failure. The decline in mitochondrial metabolism is considered a critical pathogenic mechanism that drives this progression. Considering its cardiac specificity, we hypothesized that miR 208a regulates the bioenergetic metabolism in human cardiomyocytes exposed to metabolic challenges.

Mitochondria in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end stage renal disease (ESRD) in the USA. The pathogenesis of DKD is multifactorial and involves activation of multiple signaling pathways with merging outcomes including thickening of the basement membrane, podocyte loss, mesangial expansion, tubular atrophy, and interstitial inflammation and fibrosis. The glomerulo-tubular balance and tubule-glomerular feedback support an increased glomerular filtration and tubular reabsorption, with the latter relying heavily on ATP and increasing the energy demand.

Diabetic Retinopathy: The Role of Mitochondria in the Neural Retina and Microvascular Disease.

Diabetic retinopathy (DR), a common chronic complication of diabetes mellitus and the leading cause of vision loss in the working-age population, is clinically defined as a microvascular disease that involves damage of the retinal capillaries with secondary visual impairment. While its clinical diagnosis is based on vascular pathology, DR is associated with early abnormalities in the electroretinogram, indicating alterations of the neural retina and impaired visual signaling. The pathogenesis of DR is complex and likely involves the simultaneous dysregulation of multiple metabolic and signaling pathways through the retinal neurovascular unit.

Type 2 Diabetes and Chronic Conditions Disparities in Medicare Beneficiaries in the State of Michigan.

Background: This study aimed to describe the prevalence of type 2 diabetes and combinations of multiple chronic conditions (MCCs) that are leading causes of death (LCD) and confirm that disparities exist between groups based on race and sex.

Materials And Methods: We conducted a retrospective cohort study using 2012 Medicare claims data from beneficiaries with type 2 diabetes over the age of 65 in the state of Michigan.

Results: Female beneficiaries have type 2 diabetes and 1 or more MCCs that are LCD more often than males.

Liraglutide improves insulin sensitivity in high fat diet induced diabetic mice through multiple pathways.

Glucagon like peptide-1 (GLP-1) promotes postprandial insulin secretion. Liraglutide, a full agonist of the GLP-1 receptor, reduces body weight, improve insulin sensitivity, and alleviate Non Alcoholic Fatty Liver Disease (NAFLD). However, the underlying mechanisms remain unclear.

Berberine hydrochloride protects against cytokine-induced inflammation through multiple pathways in undifferentiated C2C12 myoblast cells.

Obesity is associated with skeletal muscle insulin resistance and the development of metabolic syndrome. Undifferentiated skeletal muscle cells are sensitive to oxidative stress. Berberine hydrochloride (BBR) improves insulin resistance and exhibits anti-inflammatory properties.

Apoptosis inducing factor deficiency causes retinal photoreceptor degeneration. The protective role of the redox compound methylene blue.

Dysfunction in mitochondrial oxidative phosphorylation (OXPHOS) underlies a wide spectrum of human ailments known as mitochondrial diseases. Deficiencies in complex I of the electron transport chain (ETC) contribute to 30-40% of all cases of mitochondrial diseases, and leads to eye disease including optic nerve atrophy and retinal degeneration. The mechanisms responsible for organ damage in mitochondrial defects may include energy deficit, oxidative stress, and an increase in the NADH/NAD redox ratio due to decreased NAD regeneration.

Isolation of mitochondrial subpopulations from skeletal muscle: Optimizing recovery and preserving integrity.

Aim: The subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria in skeletal muscle appear to have distinct biochemical properties affecting metabolism in health and disease. The isolation of mitochondrial subpopulations has been a long-time challenge while the presence of a continuous mitochondrial reticulum challenges the view of distinctive SSM and IFM bioenergetics. Here, a comprehensive approach is developed to identify the best conditions to separate mitochondrial fractions.

Methylene blue alleviates endothelial dysfunction and reduces oxidative stress in aortas from diabetic rats.

Endothelial dysfunction and the related increase in reactive oxygen species (ROS) production are important events in the pathophysiology of diabetes mellitus (DM). Methylene blue (MB) has been systematically investigated for its protective effects against refractory hypotension and mitochondrial dysfunction. We have previously demonstrated that MB improved mitochondrial respiration and partially decreased oxidative stress in diabetic rat hearts.

Mitochondrial NAD/NADH Redox State and Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a frequent complication occurring even in well-controlled asymptomatic diabetic patients, and it may advance to heart failure (HF). The diabetic heart is characterized by a state of "metabolic rigidity" involving enhanced rates of fatty acid uptake and mitochondrial oxidation as the predominant energy source, and it exhibits mitochondrial electron transport chain defects. These alterations promote redox state changes evidenced by a decreased NAD/NADH ratio associated with an increase in acetyl-CoA/CoA ratio.

Methylene blue decreases mitochondrial lysine acetylation in the diabetic heart.

Diabetic cardiomyopathy is preceded by mitochondrial alterations, and progresses to heart failure. We studied whether treatment with methylene blue (MB), a compound that was reported to serve as an alternate electron carrier within the mitochondrial electron transport chain (ETC), improves mitochondrial metabolism and cardiac function in type 1 diabetes. MB was administered at 10 mg/kg/day to control and diabetic rats.

Gclc deficiency in mouse CNS causes mitochondrial damage and neurodegeneration.

Gamma glutamyl cysteine ligase (GCL) is the rate-limiting enzyme for intracellular glutathione (GSH) synthesis. The GSH concentration and GCL activity are declining with age in the central nervous system (CNS), and is accompanied by elevated reactive oxygen species (ROS). To study the biological effects of low GSH levels, we disrupted its synthesis both at birth by breeding a Gclc loxP mouse with a thy1-cre mouse (NEGSKO mouse) and at a later age by breeding with a CaMKII-ERT2-Cre (FIGSKO mouse).

Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis.

Mitochondrial homeostasis is critical for tissue health, and mitochondrial dysfunction contributes to numerous diseases, including heart failure. Here, we have shown that the transcription factor Kruppel-like factor 4 (KLF4) governs mitochondrial biogenesis, metabolic function, dynamics, and autophagic clearance. Adult mice with cardiac-specific Klf4 deficiency developed cardiac dysfunction with aging or in response to pressure overload that was characterized by reduced myocardial ATP levels, elevated ROS, and marked alterations in mitochondrial shape, size, ultrastructure, and alignment.

Mitochondrial complex I defect and increased fatty acid oxidation enhance protein lysine acetylation in the diabetic heart.

Aims: Cardiomyopathy is a major complication of diabetes. Our study was aimed to identify the sites of mitochondrial dysfunction and delineate its consequences on mitochondrial metabolism in a model of type 1 diabetes.

Methods And Results: Diabetes was induced by streptozotocin injection to male Lewis rats.

Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism.

The mammalian heart, the body's largest energy consumer, has evolved robust mechanisms to tightly couple fuel supply with energy demand across a wide range of physiologic and pathophysiologic states, yet, when compared with other organs, relatively little is known about the molecular machinery that directly governs metabolic plasticity in the heart. Although previous studies have defined Kruppel-like factor 15 (KLF15) as a transcriptional repressor of pathologic cardiac hypertrophy, a direct role for the KLF family in cardiac metabolism has not been previously established. We show in human heart samples that KLF15 is induced after birth and reduced in heart failure, a myocardial expression pattern that parallels reliance on lipid oxidation.

Multiple muscle cell alterations in a case of encephalomyopathy.

Skeletal muscle from an encephalomyopathy was examined by morphological and biochemical modalities. Mitochondria displayed variability in size, numbers per myocyte, and morphology. Certain organelles had stacks of dense cristae, others contained variable numbers of crystalloids or several lipid droplets.

Aging-dependent changes in rat heart mitochondrial glutaredoxins--Implications for redox regulation.

Clinical and animal studies have documented that hearts of the elderly are more susceptible to ischemia/reperfusion damage compared to young adults. Recently we found that aging-dependent increase in susceptibility of cardiomyocytes to apoptosis was attributable to decrease in cytosolic glutaredoxin 1 (Grx1) and concomitant decrease in NF-κB-mediated expression of anti-apoptotic proteins. Besides primary localization in the cytosol, Grx1 also exists in the mitochondrial intermembrane space (IMS).

Mitochondria in cardiac hypertrophy and heart failure.

Heart failure (HF) frequently is the unfavorable outcome of pathological heart hypertrophy. In contrast to physiological cardiac hypertrophy, which occurs in response to exercise and leads to full adaptation of contractility to the increased wall stress, pathological hypertrophy occurs in response to volume or pressure overload, ultimately leading to contractile dysfunction and HF. Because cardiac hypertrophy impairs the relationship between ATP demand and production, mitochondrial bioenergetics must keep up with the cardiac hypertrophic phenotype.

Mitochondrial dysfunction in heart failure.

Heart failure (HF) is a complex chronic clinical syndrome. Energy deficit is considered to be a key contributor to the development of both cardiac and skeletal myopathy. In HF, several components of cardiac and skeletal muscle bioenergetics are altered, such as oxygen availability, substrate oxidation, mitochondrial ATP production, and ATP transfer to the contractile apparatus via the creatine kinase shuttle.

Oxidation of fatty acids is the source of increased mitochondrial reactive oxygen species production in kidney cortical tubules in early diabetes.

Mitochondrial reactive oxygen species (ROS) cause kidney damage in diabetes. We investigated the source and site of ROS production by kidney cortical tubule mitochondria in streptozotocin-induced type 1 diabetes in rats. In diabetic mitochondria, the increased amounts and activities of selective fatty acid oxidation enzymes is associated with increased oxidative phosphorylation and net ROS production with fatty acid substrates (by 40% and 30%, respectively), whereas pyruvate oxidation is decreased and pyruvate-supported ROS production is unchanged.

Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation.

The ability of skeletal muscle to enhance lipid utilization during exercise is a form of metabolic plasticity essential for survival. Conversely, metabolic inflexibility in muscle can cause organ dysfunction and disease. Although the transcription factor Kruppel-like factor 15 (KLF15) is an important regulator of glucose and amino acid metabolism, its endogenous role in lipid homeostasis and muscle physiology is unknown.

Cardiac mitochondria in heart failure: normal cardiolipin profile and increased threonine phosphorylation of complex IV.

Mitochondrial dysfunction is a major contributor in heart failure (HF). We investigated whether the decrease in respirasome organization reported by us previously in cardiac mitochondria in HF is due to changes in the phospholipids of the mitochondrial inner membrane or modifications of the subunits of the electron transport chain (ETC) complexes. The contents of the main phospholipid species, including cardiolipin, as well as the molecular species of cardiolipin were unchanged in cardiac mitochondria in HF.

Mitochondria in heart failure.

This review focuses on the evidence accumulated in humans and animal models to the effect that mitochondria are key players in the progression of heart failure (HF). Mitochondria are the primary source of energy in the form of adenosine triphosphate that fuels the contractile apparatus, and are thus essential for the pumping activity of the heart. We evaluate changes in mitochondrial morphology and alterations in the main components of mitochondrial energetics, such as substrate utilization and oxidative phosphorylation coupled with the level of respirasomes, in the context of their contribution to the chronic energy deficit and mechanical dysfunction in HF.

Mitochondria in the elderly: Is acetylcarnitine a rejuvenator?

Endogenous acetylcarnitine is an indicator of acetyl-CoA synthesized by multiple metabolic pathways involving carbohydrates, amino acids, fatty acids, sterols, and ketone bodies, and utilized mainly by the tricarboxylic acid cycle. Acetylcarnitine supplementation has beneficial effects in elderly animals and humans, including restoration of mitochondrial content and function. These effects appear to be dose-dependent and occur even after short-term therapy.