Elevated levels of branched chain amino acids (BCAAs) and branched-chain α-ketoacids are associated with cardiovascular and metabolic disease, but the molecular mechanisms underlying a putative causal relationship remain unclear. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid) is often used in preclinical models to increase BCAA oxidation and restore steady-state BCAA and branched-chain α-ketoacid levels. BT2 administration is protective in various rodent models of heart failure and metabolic disease, but confoundingly, targeted ablation of Bckdk in specific tissues does not reproduce the beneficial effects conferred by pharmacologic inhibition.
View Article and Find Full Text PDFElevated levels of branched chain amino acids (BCAAs) and branched-chain α-ketoacids (BCKAs) are associated with cardiovascular and metabolic disease, but the molecular mechanisms underlying a putative causal relationship remain unclear. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 is often used in preclinical models to increase BCAA oxidation and restore steady-state BCAA and BCKA levels. BT2 administration is protective in various rodent models of heart failure and metabolic disease, but confoundingly, targeted ablation of in specific tissues does not reproduce the beneficial effects conferred by pharmacologic inhibition.
View Article and Find Full Text PDFIn human spermatozoa, the electrochemical potentials across the mitochondrial and plasma membranes are related to sperm functionality and fertility, but the exact role of each potential has yet to be clarified. Impairing sperm mitochondrial function has been considered as an approach to creating male or unisex contraceptives, but it has yet to be shown whether this approach would ultimately block the ability of sperm to reach or fertilize an egg. To investigate whether the mitochondrial and plasma membrane potentials are necessary for sperm fertility, human sperm were treated with two small-molecule mitochondrial uncouplers (niclosamide ethanolamine and BAM15) that depolarize membranes by inducing passive proton flow, and evaluated the effects on a variety of sperm physiological processes.
View Article and Find Full Text PDFCoenzyme Q (CoQ, aka ubiquinone) is a key component of the mitochondrial electron transport chain (ETC) and membrane-incorporated antioxidant. CoQ10 deficiencies encompass a heterogeneous spectrum of clinical phenotypes and can be caused by hereditary mutations in the biosynthesis pathway or result from pharmacological interventions such as HMG-CoA Reductase inhibitors, and statins, which are widely used to treat hypercholesterolemia and prevent cardiovascular disease. How CoQ deficiency affects individual tissues and cell types, particularly mitochondrial-rich ones such as brown adipose tissue (BAT), has remained poorly understood.
View Article and Find Full Text PDFMitochondria generate heat due to H leak (I) across their inner membrane. I results from the action of long-chain fatty acids on uncoupling protein 1 (UCP1) in brown fat and ADP/ATP carrier (AAC) in other tissues, but the underlying mechanism is poorly understood. As evidence of pharmacological activators of I through UCP1 and AAC is lacking, I is induced by protonophores such as 2,4-dinitrophenol (DNP) and cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP).
View Article and Find Full Text PDFMitochondria of all tissues convert various metabolic substrates into two forms of energy: ATP and heat. Historically, the primary focus of research in mitochondrial bioenergetics was on the mechanisms of ATP production, while mitochondrial thermogenesis received significantly less attention. Nevertheless, mitochondrial heat production is crucial for the maintenance of body temperature, regulation of the pace of metabolism, and prevention of oxidative damage to mitochondria and the cell.
View Article and Find Full Text PDFMitochondrial thermogenesis (also known as mitochondrial uncoupling) is one of the most promising targets for increasing energy expenditure to combat metabolic syndrome. Thermogenic tissues such as brown and beige fats develop highly specialized mitochondria for heat production. Mitochondria of other tissues, which primarily produce ATP, also convert up to 25% of the total mitochondrial energy production into heat and can, therefore, have a considerable impact on the physiology of the whole body.
View Article and Find Full Text PDFNonshivering thermogenesis is essential for mammals to maintain body temperature. According to the canonical view, temperature is sensed by cutaneous thermoreceptors and nerve impulses transmitted to the hypothalamus, which generates sympathetic signals to ß-adrenergic receptors in brown adipocytes. The energy for heat generation is primarily provided by the oxidation of fatty acids derived from triglyceride hydrolysis and cellular uptake.
View Article and Find Full Text PDFMitochondria convert the chemical energy of metabolic substrates into adenosine triphosphate (ATP) and heat. Although ATP production has become a focal point of research in bioenergetics, mitochondrial thermogenesis is also crucial for energy metabolism. Mitochondria generate heat due to H leak across the inner mitochondrial membrane (IMM) which is mediated by mitochondrial uncoupling proteins.
View Article and Find Full Text PDFThe mitochondrial ADP/ATP carrier (AAC) is a major transport protein of the inner mitochondrial membrane. It exchanges mitochondrial ATP for cytosolic ADP and controls cellular production of ATP. In addition, it has been proposed that AAC mediates mitochondrial uncoupling, but it has proven difficult to demonstrate this function or to elucidate its mechanisms.
View Article and Find Full Text PDFUncoupling protein 1 (UCP1) is an integral protein of the inner mitochondrial membrane (IMM) that is expressed specifically in brown and beige fat depots. UCP1 is responsible for the production of heat to control core body temperature, the regulation of fat metabolism, and the energy balance. As an uncoupling protein, UCP1 transports H across the IMM in presence of long-chain fatty acids (FA), which makes brown fat mitochondria produce heat at the expense of ATP.
View Article and Find Full Text PDFCold and other environmental factors induce "browning" of white fat depots-development of beige adipocytes with morphological and functional resemblance to brown fat. Similar to brown fat, beige adipocytes are assumed to express mitochondrial uncoupling protein 1 (UCP1) and are thermogenic due to the UCP1-mediated H leak across the inner mitochondrial membrane. However, this assumption has never been tested directly.
View Article and Find Full Text PDFAdaptive thermogenesis regulates core body temperature, controls fat deposition, and contributes strongly to the overall energy balance. This process occurs in brown fat and requires uncoupling protein 1 (UCP1), an integral protein of the inner mitochondrial membrane. Classic biochemical studies revealed the general principle of adaptive thermogenesis: in the presence of long-chain fatty acids (FA), UCP1 increases the permeability of the inner mitochondrial membrane for H, which makes brown fat mitochondria produce heat rather than ATP.
View Article and Find Full Text PDFObjective: OPA1 mutations cause protein haploinsufficiency leading to dominant optic atrophy (DOA), an incurable retinopathy with variable severity. Up to 20% of patients also develop extraocular neurological complications. The mechanisms that cause this optic atrophy or its syndromic forms are still unknown.
View Article and Find Full Text PDFFor placental mammals, the transition from the in utero maternal environment to postnatal life requires the activation of thermogenesis to maintain their core temperature. This is primarily accomplished by induction of uncoupling protein 1 (UCP1) in brown and beige adipocytes, the principal sites for uncoupled respiration. Despite its importance, how placental mammals license their thermogenic adipocytes to participate in postnatal uncoupled respiration is not known.
View Article and Find Full Text PDFMitochondrial dynamics control the organelle's morphology, with fusion leading to the formation of elongated tubules and fission leading to isolated puncta, as well as mitochondrial functions. Recent reports have shown that disruptions of mitochondrial dynamics contribute to neurodegenerative diseases. Mutations of the inner membrane GTPase OPA1 are responsible for type 1 dominant optic atrophy, by mechanisms not fully understood.
View Article and Find Full Text PDFThis paper evaluates the involvement of hippocampal ATP-sensitive potassium channels (K(ATP)) in learning and memory. After confirming expression of the Kir6.2 subunit in the CA3 region of C57BL/6J mice, we performed intra-hippocampal pharmacological injections of specific openers and blockers of K(ATP) channels.
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