The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to the cytosol and nucleus. Superoxide (O2•−) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2•− production within the matrix of mammalian mitochondria. The flux of O2•− is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2•− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Δp (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Δp and NADH/NAD+ ratio, the extent of O2•− production is far lower. The generation of O2•− within the mitochondrial matrix depends critically on Δp, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2•− generation by mitochondria in vivo from O2•−-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2•− and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.

/pdf/how-mitochondria-produce-reactive-oxygen-species-4spvs9r9mw.pdf

How mitochondria produce reactive oxygen species.

If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.

Why do cancers have high aerobic glycolysis

The ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The cloning of cDNAs encoding glutamate receptor subunits, which occurred mainly between 1989 and 1992 ([Hollmann and Heinemann, 1994][1]), stimulated this

/pdf/the-glutamate-receptor-ion-channels-560mntczdb.pdf

The glutamate receptor ion channels

This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...

Ischemic Cell Death in Brain Neurons

Anatomic and physiologic data are used to analyze the energy expenditure on different components of excitatory signaling in the grey matter of rodent brain. Action potentials and postsynaptic effects of glutamate are predicted to consume much of the energy (47% and 34%, respectively), with the resting potential consuming a smaller amount (13%), and glutamate recycling using only 3%. Energy usage depends strongly on action potential rate--an increase in activity of 1 action potential/cortical neuron/s will raise oxygen consumption by 145 mL/100 g grey matter/h. The energy expended on signaling is a large fraction of the total energy used by the brain; this favors the use of energy efficient neural codes and wiring patterns. Our estimates of energy usage predict the use of distributed codes, with <or=15% of neurons simultaneously active, to reduce energy consumption and allow greater computing power from a fixed number of neurons. Functional magnetic resonance imaging signals are likely to be dominated by changes in energy usage associated with synaptic currents and action potential propagation.

https://journals.sagepub.com/doi/pdf/10.1097/00004647-200110000-00001

An Energy Budget for Signaling in the Grey Matter of the Brain

The importance of A TP as the main source of chemical energy in living matter and its involve­ ment in cellular processes has long been recog­ nized. The primary mechanism whereby higher or­ ganisms, including humans, generate ATP is through mitochondrial oxidative phosphorylation. For the majority of organs, the main metabolic fuel is glucose, which in the presence of oxygen under­ goes complete combustion to CO2 and H20: C6H1206 + 602 � 602 + 6H20 + energy ( 1) The free energy (.:lG) liberated in this exergonic re­ action is partially trapped as ATP in two consecu­ tive processes: glycolysis (cytosol) and oxidative phosphorylation (mitochondria). The first produces 2 mol of ATP per mol of glucose, and the second 36 mol of ATP per mol of glucose. In the latter case, 6 mol of ATP are contributed from the oxidation of 2 mol of NADH generated in the cytosol during gly­ colysis and transferred into the mitochondria indi­ rectly through various \"shuttle\" systems. (In the a-glycerophosphate shuttle, the yield of ATP per NADH is reduced from 3 to 2 because the relevant mitochondrial dehydrogenase is a flavoprotein­ linked enzyme). Thus, oxidative phosphorylation yields 1718 times as much useful energy in the form of ATP as can be obtained from the same amount of glucose by glycolysis alone. It is there­ fore not surprising that limitation of O2 supply pro­ duces very damaging effects on cellular function. The brain is one of the organs that is particularly sensitive to lack of oxygen and in humans at rest is responsible for 20% of total O2 consumption al­ though it accounts for only 2% of the body weight. The role of energy in the maintenance of central

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1989.2

ATP and brain function

Metabolism and role of glutamate in mammalian brain.

Tissue oxygen tension and brain sensitivity to hypoxia

Ions and energy in mammalian brain.

This review analyzes, in some depth, results of studies on the effect of lowered temperatures on cerebral energy metabolism in animals under normal conditions and in some selected pathologic situations. In sedated and paralyzed mammals, acute uncomplicated 0.5- to 3-h hypothermia decreases the global cerebral metabolic rate for glucose (CMR(glc)) and oxygen (CMRo(2)) but maintains a slightly better energy level, which indicates that ATP breakdown is reduced more than its synthesis. Intracellular alkalinization stimulates glycolysis and independently enhances energy generation. Lowering of temperature during hypoxia-ischemia slows the rate of glucose, phosphocreatine, and ATP breakdown and lactate and inorganic phosphate formation, and improves recovery of energetic parameters during reperfusion. Mild hypothermia of 12 to 24-h duration after normothermic hypoxic-ischemic insults seems to prevent or ameliorate secondary failures in energy parameters. The authors conclude that lowered head temperatures help to protect and maintain normal CNS function by preserving brain ATP supply and level. Hypothermia may thus prove a promising avenue in the treatment of stroke and trauma and, in particular, of perinatal brain injury.

Ian A. Silver

Papers

ATP and brain function

Metabolism and role of glutamate in mammalian brain.

Tissue oxygen tension and brain sensitivity to hypoxia

Ions and energy in mammalian brain.

Effects of hypothermia on energy metabolism in Mammalian central nervous system.