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Redox Biology Oct 2020The mitochondrial electron transport chain utilizes a series of electron transfer reactions to generate cellular ATP through oxidative phosphorylation. A consequence of... (Review)
Review
The mitochondrial electron transport chain utilizes a series of electron transfer reactions to generate cellular ATP through oxidative phosphorylation. A consequence of electron transfer is the generation of reactive oxygen species (ROS), which contributes to both homeostatic signaling as well as oxidative stress during pathology. In this graphical review we provide an overview of oxidative phosphorylation and its inter-relationship with ROS production by the electron transport chain. We also outline traditional and novel translational methodology for assessing mitochondrial energetics in health and disease.
Topics: Electron Transport; Mitochondrial Membranes; Oxidants; Oxidative Phosphorylation; Oxidative Stress; Reactive Oxygen Species
PubMed: 32811789
DOI: 10.1016/j.redox.2020.101674 -
Ageing Research Reviews Mar 2021Osteoarthritis (OA) is a degenerative joint disease characterized by low-grade inflammation and high levels of clinical heterogeneity. Aberrant chondrocyte metabolism is... (Review)
Review
Osteoarthritis (OA) is a degenerative joint disease characterized by low-grade inflammation and high levels of clinical heterogeneity. Aberrant chondrocyte metabolism is a response to changes in the inflammatory microenvironment and may play a key role in cartilage degeneration and OA progression. Under conditions of environmental stress, chondrocytes tend to adapt their metabolism to microenvironmental changes by shifting from one metabolic pathway to another, for example from oxidative phosphorylation to glycolysis. Similar changes occur in other joint cells, including synoviocytes. Switching between these pathways is implicated in metabolic alterations that involve mitochondrial dysfunction, enhanced anaerobic glycolysis, and altered lipid and amino acid metabolism. The shift between oxidative phosphorylation and glycolysis is mainly regulated by the AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) pathways. Chondrocyte metabolic changes are likely to be a feature of different OA phenotypes. Determining the role of chondrocyte metabolism in OA has revealed key features of disease pathogenesis. Future research should place greater emphasis on immunometabolism and altered metabolic pathways as a means to understand the pathophysiology of age-related OA. This knowledge will advance the development of new drugs against therapeutic targets of metabolic significance.
Topics: Cartilage, Articular; Chondrocytes; Humans; Osteoarthritis; Oxidative Phosphorylation; Oxidative Stress
PubMed: 33383189
DOI: 10.1016/j.arr.2020.101249 -
Cell Metabolism Dec 2014Metformin is currently the first-line drug treatment for type 2 diabetes. Besides its glucose-lowering effect, there is interest in actions of the drug of potential... (Review)
Review
Metformin is currently the first-line drug treatment for type 2 diabetes. Besides its glucose-lowering effect, there is interest in actions of the drug of potential relevance to cardiovascular diseases and cancer. However, the underlying mechanisms of action remain elusive. Convincing data place energy metabolism at the center of metformin's mechanism of action in diabetes and may also be of importance in cardiovascular diseases and cancer. Metformin-induced activation of the energy-sensor AMPK is well documented, but may not account for all actions of the drug. Here, we summarize current knowledge about the different AMPK-dependent and AMPK-independent mechanisms underlying metformin action.
Topics: AMP-Activated Protein Kinases; Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Hypoglycemic Agents; Metformin; Oxidative Phosphorylation
PubMed: 25456737
DOI: 10.1016/j.cmet.2014.09.018 -
Trends in Pharmacological Sciences Jun 2012Mitochondria are being recognized as key factors in many unexpected areas of biomedical science. In addition to their well-known roles in oxidative phosphorylation and... (Review)
Review
Mitochondria are being recognized as key factors in many unexpected areas of biomedical science. In addition to their well-known roles in oxidative phosphorylation and metabolism, it is now clear that mitochondria are also central to cell death, neoplasia, cell differentiation, the innate immune system, oxygen and hypoxia sensing, and calcium metabolism. Disruption to these processes contributes to a range of human pathologies, making mitochondria a potentially important, but currently seemingly neglected, therapeutic target. Mitochondrial dysfunction is often associated with oxidative damage, calcium dyshomeostasis, defective ATP synthesis, or induction of the permeability transition pore. Consequently, therapies designed to prevent these types of damage are beneficial and can be used to treat many diverse and apparently unrelated indications. Here we outline the biological properties that make mitochondria important determinants of health and disease, and describe the pharmacological strategies being developed to address mitochondrial dysfunction.
Topics: Apoptosis; Calcium; Drug Discovery; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Molecular Targeted Therapy; Oxidative Phosphorylation; Protective Agents; Reactive Oxygen Species
PubMed: 22521106
DOI: 10.1016/j.tips.2012.03.010 -
Oncogene Nov 2022Metabolism must be tightly regulated to fulfil the dynamic requirements of cancer cells during proliferation, migration, stemness and differentiation. Src is a node of... (Review)
Review
Metabolism must be tightly regulated to fulfil the dynamic requirements of cancer cells during proliferation, migration, stemness and differentiation. Src is a node of several signals involved in many of these biological processes, and it is also an important regulator of cell metabolism. Glucose uptake, glycolysis, the pentose-phosphate pathway and oxidative phosphorylation are among the metabolic pathways that can be regulated by Src. Therefore, this oncoprotein is in an excellent position to coordinate and finely tune cell metabolism to fuel the different cancer cell activities. Here, we provide an up-to-date summary of recent progress made in determining the role of Src in glucose metabolism as well as the link of this role with cancer cell metabolic plasticity and tumour progression. We also discuss the opportunities and challenges facing this field.
Topics: Humans; Pentose Phosphate Pathway; Glycolysis; Oxidative Phosphorylation; Neoplasms; Glucose
PubMed: 36217026
DOI: 10.1038/s41388-022-02487-4 -
The Journal of Physiology Dec 2017Oxidative phosphorylation provides most of the ATP that higher animals and plants use to support life and is responsible for setting and maintaining metabolic... (Review)
Review
Oxidative phosphorylation provides most of the ATP that higher animals and plants use to support life and is responsible for setting and maintaining metabolic homeostasis. The pathway incorporates three consecutive near equilibrium steps for moving reducing equivalents between the intramitochondrial [NAD ]/[NADH] pool to molecular oxygen, with irreversible reduction of oxygen to bound peroxide at cytochrome c oxidase determining the net flux. Net flux (oxygen consumption rate) is determined by demand for ATP, with feedback by the energy state ([ATP]/[ADP][P ]) regulating the pathway. This feedback affects the reversible steps equally and independently, resulting in the rate being coupled to ([ATP]/[ADP][P ]) . With increasing energy state, oxygen consumption decreases rapidly until a threshold is reached, above which there is little further decrease. In most cells, [ATP] and [P ] are much higher than [ADP] and change in [ADP] is primarily responsible for the change in energy state. As a result, the rate of ATP synthesis, plotted against [ADP], remains low until [ADP] reaches about 30 μm and then increases rapidly with further increase in [ADP]. The dependencies on energy state and [ADP] near the threshold can be fitted by the Hill equation with a Hill coefficients of about -2.6 and 4.2, respectively. The homeostatic set point for metabolism is determined by the threshold, which can be modulated by the PO2 and intramitochondrial [NAD ]/[NADH]. The ability of oxidative phosphorylation to precisely set and maintain metabolic homeostasis is consistent with it being permissive of, and essential to, development of higher plants and animals.
Topics: Animals; Homeostasis; Humans; Mitochondria; Oxidative Phosphorylation
PubMed: 29023737
DOI: 10.1113/JP273839 -
Aging Jun 2019The metabolite α-ketoglutarate is membrane-impermeable, meaning that it is usually added to cells in the form of esters such as dimethyl -ketoglutarate (DMKG),...
The metabolite α-ketoglutarate is membrane-impermeable, meaning that it is usually added to cells in the form of esters such as dimethyl -ketoglutarate (DMKG), trifluoromethylbenzyl α-ketoglutarate (TFMKG) and octyl α-ketoglutarate (O-KG). Once these compounds cross the plasma membrane, they are hydrolyzed by esterases to generate α-ketoglutarate, which remains trapped within cells. Here, we systematically compared DMKG, TFMKG and O-KG for their metabolic and functional effects. All three compounds similarly increased the intracellular levels of α-ketoglutarate, yet each of them had multiple effects on other metabolites that were not shared among the three agents, as determined by mass spectrometric metabolomics. While all three compounds reduced autophagy induced by culture in nutrient-free conditions, TFMKG and O-KG (but not DMKG) caused an increase in baseline autophagy in cells cultured in complete medium. O-KG (but neither DMKG nor TFMK) inhibited oxidative phosphorylation and exhibited cellular toxicity. Altogether, these results support the idea that intracellular α-ketoglutarate inhibits starvation-induced autophagy and that it has no direct respiration-inhibitory effect.
Topics: Autophagy; Cell Line, Tumor; Humans; Ketoglutaric Acids; Mass Spectrometry; Oxidative Phosphorylation
PubMed: 31173576
DOI: 10.18632/aging.102001 -
Cells Oct 2021The developing and adult brain is a target organ for the vast majority of hormones produced by the body, which are able to cross the blood-brain barrier and bind to... (Review)
Review
The developing and adult brain is a target organ for the vast majority of hormones produced by the body, which are able to cross the blood-brain barrier and bind to their specific receptors on neurons and glial cells. Hormones ensure proper communication between the brain and the body by activating adaptive mechanisms necessary to withstand and react to changes in internal and external conditions by regulating neuronal and synaptic plasticity, neurogenesis and metabolic activity of the brain. The influence of hormones on energy metabolism and mitochondrial function in the brain has gained much attention since mitochondrial dysfunctions are observed in many different pathological conditions of the central nervous system. Moreover, excess or deficiency of hormones is associated with cell damage and loss of function in mitochondria. This review aims to expound on the impact of hormones (GLP-1, insulin, thyroid hormones, glucocorticoids) on metabolic processes in the brain with special emphasis on oxidative phosphorylation dysregulation, which may contribute to the formation of pathological changes. Since the brain concentrations of sex hormones and neurosteroids decrease with age as well as in neurodegenerative diseases, in parallel with the occurrence of mitochondrial dysfunction and the weakening of cognitive functions, their beneficial effects on oxidative phosphorylation and expression of antioxidant enzymes are also discussed.
Topics: Animals; Brain; Brain Diseases; Energy Metabolism; Hormones; Humans; Mitochondria; Oxidative Phosphorylation
PubMed: 34831160
DOI: 10.3390/cells10112937 -
International Journal of Molecular... Apr 2022Oxidative phosphorylation is an efficient way to generate the cellular energy currency ATP in a cascade of redox reactions, which ultimately terminate in the reduction...
Oxidative phosphorylation is an efficient way to generate the cellular energy currency ATP in a cascade of redox reactions, which ultimately terminate in the reduction of molecular oxygen to water [...].
Topics: Homeostasis; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen; Oxygen Consumption; Reactive Oxygen Species
PubMed: 35562895
DOI: 10.3390/ijms23094505 -
Viruses Dec 2023Mitochondria have been identified as the "powerhouse" of the cell, generating the cellular energy, ATP, for almost seven decades. Research over time has uncovered a... (Review)
Review
Mitochondria have been identified as the "powerhouse" of the cell, generating the cellular energy, ATP, for almost seven decades. Research over time has uncovered a multifaceted role of the mitochondrion in processes such as cellular stress signaling, generating precursor molecules, immune response, and apoptosis to name a few. Dysfunctional mitochondria resulting from a departure in homeostasis results in cellular degeneration. Viruses hijack host cell machinery to facilitate their own replication in the absence of a bonafide replication machinery. Replication being an energy intensive process necessitates regulation of the host cell oxidative phosphorylation occurring at the electron transport chain in the mitochondria to generate energy. Mitochondria, therefore, can be an attractive therapeutic target by limiting energy for viral replication. In this review we focus on the physiology of oxidative phosphorylation and on the limited studies highlighting the regulatory effects viruses induce on the electron transport chain.
Topics: Humans; Oxidative Phosphorylation; Mitochondria; Apoptosis; Signal Transduction; Virus Diseases; Phosphorylation; Oxidative Stress
PubMed: 38140621
DOI: 10.3390/v15122380