The Significance of Lipids for the Absorption and Release of Oxygen in Biological Organisms.

A critically important step for the uptake and transport of oxygen (O2) in living organisms is the crossing of the phase boundary between gas (or water) and lipid/proteins in the cell. Classically, this transport across the phase boundary is explained as a transport by proteins or protein-based structures. In our contribution here, we want to show the significance of passive transport of O2 also (and in some cases probably predominantly) through lipids in many if not all aerobic organisms. In plants, the significance of lipids for gas exchange (absorption of CO2 and release of O2) is well recognized. The leaves of plants have a cuticle layer as the last film on both sides formed by polyesters and lipids. In animals, the skin has sebum as its last layer consisting of a mixture of neutral fatty esters, cholesterol and waxes which are also at the border between the cells of the body and the air. The last cellular layers of skin are not vascularized therefore their metabolism totally depends on this extravasal O2 absorption, which cannot be replenished by the bloodstream. The human body absorbs about 0.5% of O2 through the skin. In the brain, myelin, surrounding nerve cell axons and being formed by oligodendrocytes, is most probably also responsible for enabling O2 transport from the extracellular space to the cells (neurons). Myelin, being not vascularized and consisting of water, lipids and proteins, seems to absorb O2 in order to transport it to the nerve cell axon as well as to perform extramitochondrial oxidative phosphorylation inside the myelin structure around the axons (i.e., myelin synthesizes ATP) - similarly to the metabolic process occurring in concentric multilamellar structures of cyanobacteria. Another example is the gas transport in the lung where lipids play a crucial role in the surfactant ensuring incorporation of O2 in the alveoli where there are lamellar body and tubular myelin which form multilayered surface films at the air-membrane border of the alveolus. According to our view, the role played by lipids in the physical absorption of gases appears to be crucial to the existence of many, if not all, of the living aerobic species.

Efficient extra-mitochondrial aerobic ATP synthesis in neuronal membrane systems.

The nervous system displays high energy consumption, apparently not fulfilled by mitochondria, which are underrepresented therein. The oxidative phosphorylation (OxPhos) activity, a mitochondrial process that aerobically provides ATP, has also been reported also in the myelin sheath and the rod outer segment (OS) disks. Thus, commonalities and differences between the extra-mitochondrial and mitochondrial aerobic metabolism were evaluated in bovine isolated myelin (IM), rod OS, and mitochondria-enriched fractions (MIT). The subcellular fraction quality and the absence of contamination fractions have been estimated by western blot analysis. Oxygen consumption and ATP synthesis were stimulated by conventional (pyruvate + malate or succinate) and unconventional (NADH) substrates, observing that oxygen consumption and ATP synthesis by IM and rod OS are more efficient than by MIT, in the presence of both kinds of respiratory substrates. Mitochondria did not utilize NADH as a respiring substrate. When ATP synthesis by either sample was assayed in the presence of 10-100 µM ATP in the assay medium, only in IM and OS it was not inhibited, suggesting that the ATP exportation by the mitochondria is limited by extravesicular ATP concentration. Interestingly, IM and OS but not mitochondria appear able to synthesize ATP at a later time with respect to exposure to respiratory substrates, supporting the hypothesis that the proton gradient produced by the electron transport chain is buffered by membrane phospholipids. The putative transfer mode of the OxPhos molecular machinery from mitochondria to the extra-mitochondrial structures is also discussed, opening new perspectives in the field of neurophysiology.

Extramitochondrial energy production in platelets.

BACKGROUND INFORMATION: Energy demand in human platelets is very high, to carry out their functions. As for most human cells, the aerobic metabolism represents the primary energy source in platelets, even though mitochondria are negligibly represented. Following the hypothesis that other structures could be involved in chemical energy production, in this work, we have investigated the functional expression of an extramitochondrial aerobic metabolism in platelets. RESULTS: Oximetric and luminometric analyses showed that platelets consume large amounts of oxygen and produce ATP in the presence of common respiring substrates, such as pyruvate + malate or succinate, although morphological electron microscopy analysis showed that these contain few mitochondria. However, evaluation of the anaerobic glycolytic metabolism showed that only 13% of consumed glucose was converted to lactate. Interestingly, the highest OXPHOS activity was observed in the presence of NADH, not a readily permeant respiring substrate for mitochondria. Also, oxygen consumption and ATP synthesis fuelled by NADH were not affected by atractyloside, an inhibitor of the adenine nucleotide translocase, suggesting that these processes may not be ascribed to mitochondria. Functional data were confirmed by immunofluorescence microscopy and Western blot analyses, showing a consistent expression of the ß subunit of F1 Fo -ATP synthase and COXII, a subunit of Complex IV, but a low signal of translocase of the inner mitochondrial membrane (a protein not involved in OXPHOS metabolism). Interestingly, the NADH-stimulated oxygen consumption and ATP synthesis increased in the presence of the physiological platelets agonists, thrombin or collagen. CONCLUSIONS: Data suggest that in platelets, aerobic energy production is mainly driven by an extramitochondrial OXPHOS machinery, originated inside the megakaryocyte, and that this metabolism plays a pivotal role in platelet activation. SIGNIFICANCE: This work represents a further example of the existence of an extramitochondrial aerobic metabolism, which can contribute to the cellular energy balance.

Tracking protons from respiratory chain complexes to ATP synthase c-subunit: The critical role of serine and threonine residues.

F1Fo-ATP synthase is a multisubunit enzyme responsible for the synthesis of ATP. Among its multiple subunits (8 in E. coli, 17 in yeast S. cerevisiae, 16 in vertebrates), two subunits a and c are known to play a central role controlling the H+ flow through the inner mitochondrial membrane which allows the subsequent synthesis of ATP, but the pathway followed by H+ within the two proteins is still a matter of debate. In fact, even though the structure of ATP synthase is now well defined, the molecular mechanisms determining the function of both F1 and FO domains are still largely unknown. In this study, we propose a pathway for proton migration along the ATP synthase by hydrogen-bonded chain mechanism, with a key role of serine and threonine residues, by X-ray diffraction data on the subunit a of E. coli Fo.

Functional Expression of Electron Transport Chain and FoF1-ATP Synthase in Optic Nerve Myelin Sheath.

Our previous studies reported evidence for aerobic ATP synthesis by myelin from both bovine brainstem and rat sciatic nerve. Considering that the optic nerve displays a high oxygen demand, here we evaluated the expression and activity of the five Respiratory Complexes in myelin purified from either bovine or murine optic nerves. Western blot analyses on isolated myelin confirmed the expression of ND4L (subunit of Complex I), COX IV (subunit of Complex IV) and ß subunit of F1Fo-ATP synthase. Moreover, spectrophotometric and in-gel activity assays on isolated myelin, as well as histochemical activity assays on both bovine and murine transversal optic nerve sections showed that the respiratory Complexes are functional in myelin and are organized in a supercomplex. Expression of oxidative phosphorylation proteins was also evaluated on bovine optic nerve sections by confocal and transmission electron microscopy. Having excluded a mitochondrial contamination of isolated myelin and considering the results form in situ analyses, it is proposed that the oxidative phosphorylation machinery is truly resident in optic myelin sheath. Data may shed a new light on the unknown trophic role of myelin sheath. It may be energy supplier for the axon, explaining why in demyelinating diseases and neuropathies, myelin sheath loss is associated with axonal degeneration.

New findings in ATP supply in rod outer segments: insights for retinopathies.

BACKGROUND INFORMATION: The rod outer segment (OS) is the specialised organelle where phototransduction takes place. Our previous proteomic and biochemical analyses on purified rod disks showed the functional expression of the respiratory chain complexes I-IV and F1 Fo -ATP synthase in OS disks, as well as active soluble tricarboxylic acid cycle enzymes. Here, we focussed our study on the whole OS that contains the cytosol and plasma membrane and disks as native flattened saccules, unlike spherical osmotically intact disks. RESULTS: OS were purified from bovine retinas and characterised for purity. Oximetry, ATP synthesis and cytochrome c oxidase (COX) assays were performed. The presence of COX and F1F0-ATP synthase (ATP synthase) was assessed by semi-quantitative Western blotting, immunofluorescence or confocal laser scanning microscopy on whole bovine retinas and bovine retinal sections and by immunogold transmission electron microscopy (TEM) of purified OS or bovine retinal sections. Both ATP synthase and COX are catalytically active in OS. These are able to consume oxygen (O2) in the presence of pyruvate and malate. CLSM analyses showed that rhodopsin autofluorescence and MitoTracker Deep Red 633 fluorescence co-localise on rod OS. Data are confirmed by co-localisation studies of ATP synthase with Rh in rod OS by immunofluorescence and TEM in bovine retinal sections. CONCLUSIONS: Our data confirm the expression and activity of COX and ATP synthase in OS, suggestive of the presence of an extra-mitochondrial oxidative phosphorylation in rod OS, meant to supply ATP for the visual transduction. In this respect, the membrane rich OS environment would be meant to absorb both light and O2. The ability of OS to manipulate O2 may shed light on the pathogenesis of many retinal degenerative diseases ascribed to oxidative stress, as well as on the efficacy of the treatment with dietary supplements, presently utilised as supporting therapies.

Should the standard model of cellular energy metabolism be reconsidered? Possible coupling between the pentose phosphate pathway, glycolysis and extra-mitochondrial oxidative phosphorylation.

The process of cellular respiration occurs for energy production through catabolic reactions, generally with glucose as the first process step. In the present work, we introduce a novel concept for understanding this process, based on our conclusion that glucose metabolism is coupled to the pentose phosphate pathway (PPP) and extra-mitochondrial oxidative phosphorylation in a closed-loop process. According to the current standard model of glycolysis, glucose is first converted to glucose 6-phosphate (glucose 6-P) and then to fructose 6-phosphate, glyceraldehyde 3-phosphate and pyruvate, which then enters the Krebs cycle in the mitochondria. However, it is more likely that the pyruvate will be converted to lactate. In the PPP, glucose 6-P is branched off from glycolysis and used to produce NADPH and ribulose 5-phosphate (ribulose 5-P). Ribulose 5-P can be converted to fructose 6-P and glyceraldehyde 3-P. In our view, a circular process can take place in which the ribulose 5-P produced by the PPP enters the glycolysis pathway and is then retrogradely converted to glucose 6-P. This process is repeated several times until the complete degradation of glucose 6-P. The role of mitochondria in this process is to degrade lipids by beta-oxidation and produce acetyl-CoA; the function of producing ATP appears to be only secondary. This proposed new concept of cellular bioenergetics allows the resolution of some previously unresolved controversies related to cellular respiration and provides a deeper understanding of metabolic processes in the cell, including new insights into the Warburg effect.

Oxydative phosphorylation in sciatic nerve myelin and its impairment in a model of dysmyelinating peripheral neuropathy.

Myelin sheath is the proteolipid membrane wrapping the axons of CNS and PNS. We have shown data suggesting that CNS myelin conducts oxidative phosphorylation (OXPHOS), challenging its role in limiting the axonal energy expenditure. Here, we focused on PNS myelin. Samples were: (i) isolated myelin vesicles (IMV) from sciatic nerves, (ii) mitochondria from primary Schwann cell cultures, and (iii) sciatic nerve sections, from wild type or Charcot-Marie-Tooth type 1A (CMT1A) rats. The latter used as a model of dys-demyelination. O2 consumption and activity of OXPHOS proteins from wild type (Wt) or CMT1A sciatic nerves showed some differences. In particular, O2 consumption by IMV from Wt and CMT1A 1-month-old rats was comparable, while it was severely impaired in IMV from adult affected animals. Mitochondria extracted from CMT1A Schwann cell did not show any dysfunction. Transmission electron microscopy studies demonstrated an increased mitochondrial density in dys-demyelinated axons, as to compensate for the loss of respiration by myelin. Confocal immunohistochemistry showed the expression of OXPHOS proteins in the myelin sheath, both in Wt and dys-demyelinated nerves. These revealed an abnormal morphology. Taken together these results support the idea that also PNS myelin conducts OXPHOS to sustain axonal function.

Are rod outer segment ATP-ase and ATP-synthase activity expression of the same protein?

Vertebrate retinal rod outer segments (OS) consist of a stack of disks surrounded by the plasma membrane, where phototransduction takes place. Energetic metabolism in rod OS remains obscure. Literature described a so-called Mg(2+)-dependent ATPase activity, while our previous results demonstrated the presence of oxidative phosphorylation (OXPHOS) in OS, sustained by an ATP synthetic activity. Here we propose that the OS ATPase and ATP synthase are the expression of the same protein, i.e., of F1Fo-ATP synthase. Imaging on bovine retinal sections showed that some OXPHOS proteins are expressed in the OS. Biochemical data on bovine purified rod OS, characterized for purity, show an ATP synthase activity, inhibited by classical F1Fo-ATP synthase inhibitors. Moreover, OS possess a pH-dependent ATP hydrolysis, inhibited by pH values below 7, suggestive of the functioning of the inhibitor of F1 (IF1) protein. WB confirmed the presence of IF1 in OS, substantiating the expression of F1Fo ATP synthase in OS. Data suggest that the OS F1Fo ATP synthase is able to hydrolyze or synthesize ATP, depending on in vitro or in vivo conditions and that the role of IF1 would be pivotal in the prevention of the reversal of ATP synthase in OS, for example during hypoxia, granting photoreceptor survival.

Proteomics unravels the exportability of mitochondrial respiratory chains.

Expression of F1Fo-ATP synthase, which generates the majority of cellular ATP and is believed to be strictly confined to mitochondria, has recently been identified in ectopic locations, together with the four complexes of oxidative phosphorylation (OXPHOS) or enzymes from the Krebs cycle. Identification of these proteins has mostly been accomplished by proteomic methods and mass spectrometry - techniques that hold great promise in increasing our understanding of the proteome. The ectopic presence of ATP synthase has variably been attributed to contamination of the sample or to its action as a cell-surface receptor for apparently unrelated ligands, but OXPHOS proteins have sometimes been found to be catalytically active in oxidative phosphorylation, as they were true components of the system under investigation. The present article focuses on how mass spectrometry can increase our understanding of the proteome of subcellular membranes. We review the recent evidence for an extra-mitochondrial expression of OXPHOS by proteomics studies, highlighting what we can learn by combining these data.

Evidence for ectopic aerobic ATP production on C6 glioma cell plasma membrane.

Extracellular ATP plays a pivotal role as a signaling molecule in physiological and pathological conditions in the CNS. In several glioma cell lines, ATP is a positive factor for one or more characteristics important for the abnormal growth and survival of these cells. This work presents immunofluorescence and biochemical analyses suggesting that an aerobic metabolism, besides mitochondria, is located also on the plasma membrane of C6 glioma cells. An ATP synthesis coupled to oxygen consumption was measured in plasma membrane isolated from C6 cells, sensitive to common inhibitors of respiratory chain complexes, suggesting the involvement of a putative surface ATP synthase complex. Immunofluorescence imaging showed that Cytochrome c oxydase colocalized with WGA, a typical plasma membrane protein, on the plasma membrane of glioma cells. Cytochrome c oxydase staining pattern appeared punctuate, suggesting the intriguing possibility that the redox chains may be expressed in discrete sites on C6 glioma cell membrane. Data suggest that the whole respiratory chain is localized on C6 glioma cell surface. Moreover, when resveratrol, an ATP synthase inhibitor, was added to culture medium, a cytostatic effect was observed, suggesting a correlation among the ectopic ATP synthesis and the tumor growth. So, a potential direction for the design of new targets for future therapies may arise.

A novel hypothesis about mechanisms affecting conduction velocity of central myelinated fibers.

The hypothesis that gap junctions are implicated in facilitating axonal conduction has not yet been experimentally demonstrated at the electrophysiological level. We found that block of gap junctions with oleammide slows down axonal conduction velocity in the hippocampal Schaffer collaterals, a central myelinated pathway. Moreover, we explored the possibility that support by the oligodendrocyte to the axon involves energy metabolism, a hypothesis that has been recently proposed by some of us. In agreement with this hypothesis, we found that the effect of oleammide was reversed by pretreatment with creatine, a compound that is known to increase the energy charge of the tissue. Moreover, conduction velocity was also slowed down by anoxia, a treatment that obviously decreases the energy charge of the tissue, and by ouabain, a compound that blocks plasma membrane Na/K-ATPase, the main user of ATP in the brain. We hypothesize that block of gap junctions slows down conduction velocity in central myelinated pathways because oligodendrocytes synthesize ATP and transfer it to the axon through gap junctions.

Catalytic properties of the retinal rod outer segment disk ADP-ribosyl cyclase.

Cyclic ADP-ribose (cADPR) is a second messenger modulating intracellular calcium levels. We have previously described a cADPR-dependent calcium signaling pathway in bovine rod outer segments (ROS), where calcium ions play a pivotal role. ROS ADP-ribosyl cyclase (ADPR-cyclase) was localized in the membrane fraction. In the present work, we examined the properties of the disk ADPR-cyclase through the production of cyclic GDP-ribose from the NAD(+) analogue NGD(+). The enzyme displayed an estimated K(m) for NGD(+) of 12.5 ± 0.3 µM, a V(max) of 26.50 ± 0.70 pmol cyclic GDP-ribose synthesized/min/mg, and optimal pH of 6.5. The effect of divalent cations (Zn(2+), Cu(2+), and Ca(2+)) was also tested. Micromolar Zn(2+) and Cu(2+) inhibited the disk ADPR-cyclase activity (half maximal inhibitory concentration, IC50=1.1 and 3.6 µM, respectively). By contrast, Ca(2+) ions had no effect. Interestingly, the properties of the intracellular membrane-associated ROS disk ADPR-cyclase are more similar to those of the ADPR-cyclase found in CD38-deficient mouse brain, than to those of CD38 or CD157. The novel intracellular mammalian ADPR-cyclase would elicit Ca(2+) release from the disks at various rates in response to change in free Ca(2+) concentrations, caused by light versus dark adaptation, in fact there was no difference in disk ADPR-cyclase activity in light or dark conditions. Data suggest that disk ADPR-cyclase may be a potential target of retinal toxicity of Zn(2+) and may shed light to the role of Cu(2+) and Zn(2+) deficiency in retina.

Inactivation of Crotalus atrox venom hemorrhagic activity by direct current exposure using hens' egg assay.

The hemotoxic venoms of Viperidae and Crotalidae are responsible for most of the evenomations in the United States, West Africa, India, South-East Asia, New Guinea, and Latin America. We previously reported that a short exposure of Crotalus atrox venom to direct electric current (dc) from a low-voltage generator, in solution, causes consistent and irreversible inactivation of venom phospholipase A(2) and metalloproteases. Here we report by in vivo assay on chicken embryos at stage 18 of development according to Hamburger and Hamilton that the hemorrhagic activity of C. atrox venom is lost after exposure to dc (from low voltage). Venom was exposed to dc ranging between 0 and 1 mA. dc values above 0.7 mA abolished hemorrhage. Such in vivo data, showing that dc neutralizes C. atrox venom hemorrhagic activity suggest that a deeper knowledge is needed to understand the relationship among dc and biological matter.

Extremely low-frequency electromagnetic fields affect lipid-linked carbonic anhydrase.

In the last years, the effect of extremely low-frequency electromagnetic fields (ELF-EMF) on the activity of different enzymes were investigated. Only the membrane-anchored enzymes did decrease their activity, up to 50%. In this work, the effect of ELF-EMF on bovine lung membrane carbonic anhydrase (CA) were studied. Carbonic anhydrases are a family of 14 zinc-containing isozymes catalyzing the reversible reaction: CO(2)+H(2)O = HCO(3)(- )+H(+). CA differ in catalytic activity and subcellular localization. CA IV, IX, XII, XIV, and XV are membrane bound. In particular, CA IV, which is expressed in the lung, is glycosyl phosphatidyl inositol-linked to the membrane, therefore it was a candidate to inhibition by ELF-EMF. Exposure to the membranes to a field of 75 Hz frequency and different amplitudes caused CA activity to a reproducible decrease in enzymatic activity by 17% with a threshold of about 0.74 mT. The decrease in enzymatic activity was independent of the time of permanence in the field and was completely reversible. When the source of enzyme was solubilized with Triton, the field lost its effect on CA enzymatic activity, suggesting a crucial role of the membrane, as well as of the particular linkage of the enzyme to it, in determining the conditions for CA inactivation. Results are discussed in terms of the possible physiologic effects of CA inhibition in target organs.

Myelin sheath and cyanobacterial thylakoids as concentric multilamellar structures with similar bioenergetic properties.

There is a surprisingly high morphological similarity between multilamellar concentric thylakoids in cyanobacteria and the myelin sheath that wraps the nerve axons. Thylakoids are multilamellar structures, which express photosystems I and II, cytochromes and ATP synthase necessary for the light-dependent reaction of photosynthesis. Myelin is a multilamellar structure that surrounds many axons in the nervous system and has long been believed to act simply as an insulator. However, it has been shown that myelin has a trophic role, conveying nutrients to the axons and producing ATP through oxidative phosphorylation. Therefore, it is tempting to presume that both membranous structures, although distant in the evolution tree, share not only a morphological but also a functional similarity, acting in feeding ATP synthesized by the ATP synthase to the centre of the multilamellar structure. Therefore, both molecular structures may represent a convergent evolution of life on Earth to fulfill fundamentally similar functions.

Sinusoidal ELF magnetic fields affect acetylcholinesterase activity in cerebellum synaptosomal membranes.

The effects of extremely low frequency magnetic fields (ELF-MF) on acetylcholinesterase (AChE) activity of synaptosomal membranes were investigated. Sinusoidal fields with 50 Hz frequency and different amplitudes caused AChE activity to decrease about 27% with a threshold of about 0.74 mT. The decrease in enzymatic activity was independent of the time of permanence in the field and was completely reversible. Identical results were obtained with exposure to static MF of the same amplitudes. Moreover, the inhibitory effects on enzymatic activity are spread over frequency windows with different maximal values at 60, 200, 350, and 475 Hz. When synaptosomal membranes were solubilized with Triton, ELF-MF did not affect AChE activity, suggesting the crucial role of the membrane, as well as the lipid linkage of the enzyme, in determining the conditions for inactivation. The results are discussed in order to give an interpretation at molecular level of the macroscopic effects produced by ELF-MF on biological systems, in particular the alterations of embryo development in many organisms due to acetylcholine accumulation.

Accelerated removal of deamidated proteins and endogenous electric fields: possible implications.

Changes in protein structure through the spontaneous deamidation of asparaginyl (Asn) and glutaminyl (Gln) residues have been observed in many proteins. Amide residues were supposed to serve as clocks for development and aging. Deamidated proteins are rapidly degraded by as yet unclear molecular mechanisms. Deamidation leads to elevation of the ratio of charged versus polar residues (CH-PO) of a protein and to a decrease in its pI value. We had reported that those enzymes, characterized by a high CH-PO, are prone to inactivation and loss of ordered structure by exposure to direct current from low voltage in solution. Nano-local endogenous electric fields arise within cells. Endogenous currents may cause the unfolding of the products of deamidation at Asn. In turn, these unfolded proteins would be removed, likely by proteolysis.

The aerobic mitochondrial ATP synthesis from a comprehensive point of view.

Most of the ATP to satisfy the energetic demands of the cell is produced by the F1Fo-ATP synthase (ATP synthase) which can also function outside the mitochondria. Active oxidative phosphorylation (OxPhos) was shown to operate in the photoreceptor outer segment, myelin sheath, exosomes, microvesicles, cell plasma membranes and platelets. The mitochondria would possess the exclusive ability to assemble the OxPhos molecular machinery so to share it with the endoplasmic reticulum (ER) and eventually export the ability to aerobically synthesize ATP in true extra-mitochondrial districts. The ER lipid rafts expressing OxPhos components is indicative of the close contact of the two organelles, bearing different evolutionary origins, to maximize the OxPhos efficiency, exiting in molecular transfer from the mitochondria to the ER. This implies that its malfunctioning could trigger a generalized oxidative stress. This is consistent with the most recent interpretations of the evolutionary symbiotic process whose necessary prerequisite appears to be the presence of the internal membrane system inside the eukaryote precursor, of probable archaeal origin allowing the engulfing of the α-proteobacterial precursor of mitochondria. The process of OxPhos in myelin is here studied in depth. A model is provided contemplating the biface arrangement of the nanomotor ATP synthase in the myelin sheath.

Myelination increases chemical energy support to the axon without modifying the basic physicochemical mechanism of nerve conduction.

The existence of different conductive patterns in unmyelinated and myelinated axons is uncertain. It seems that considering exclusively physical electrical phenomena may be an oversimplification. A novel interpretation of the mechanism of nerve conduction in myelinated nerves is proposed, to explain how the basic mechanism of nerve conduction has been adapted to myelinated conditions. The neurilemma would bear the voltage-gated channels and Na+/K+-ATPase in both unmyelinated and myelinated conditions, the only difference being the sheath wrapping it. The dramatic increase in conduction speed of the myelinated axons would essentially depend on an increment in ATP availability within the internode: myelin would be an aerobic ATP supplier to the axoplasm, through connexons. In fact, neurons rely on aerobic metabolism and on trophic support from oligodendrocytes, that do not normally duplicate after infancy in humans. Such comprehensive framework of nerve impulse propagation in axons may shed new light on the pathophysiology of nervous system disease in humans, seemingly strictly dependent on the viability of the pre-existing oligodendrocyte.