Efficient extra‐mitochondrial aerobic ATP synthesis in neuronal membrane systems

Abstract

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.

"Acidic and Basic Proteins from Spider Latrodectus Pallidus Venom that Induce Formation of Non-Bilayer Phase and Increase Proton Capacity in Model Myelin Membranes Feature High Sequence Homology to Isoforms of Myelin Basic Protein: Pharmacological Relevance"

“…Professor Alessandro Morelli of Genoa University proposed that mitochondria, which have their own DNA for respiratory complexes and ATP synthase to drive oxidative phosphorylation, deliver all the protein complexes necessary for ATP synthesis to the myelin sheath with the help of the endoplasmic reticulum (ER) [64], with which mitochondria are closely associated in cytoplasmic space and function [65,66]. It has been determined that mitochondria produce necessary vesicles providing the ER with the necessary oxidative phosphorylation complexes [67,68]. Aerobic ATP synthesis has also been observed in structures devoid of mitochondria such as rod outer segment discs [69][70][71][72], platelets [73], cell plasma membranes [74][75][76][77][78], exosomes, and microvesicles [79], strongly implying that the oxidative phosphorylation machinery is transferred to these extra-mitochondrial sites via the ER [80].…”

Cobra Venom Cytotoxins as a Tool for Probing Mechanisms of Mitochondrial Energetics and Understanding Mitochondrial Membrane Structure

“…These observations assume that mitochondria transfer the OxPhos machinery to the ER, rendering the ER's ability for aerobic ATP synthesis [91,95,97]. In fact, it has recently been demonstrated that mitochondria generate the necessary vesicles that provide the ER with the necessary OxPhos components [98,99]. However, this phenomenon is not ubiquitous and is restricted to a small number of specialized cell types, as supported by the findings in recent years describing extra-mitochondrial OxPhos in cellular districts including rod outer segment discs [100][101][102][103], platelets [104], cell plasma membrane [105][106][107][108][109], exosomes, and microvesicles [110,111].…”

Neuron Protection by EDTA May Explain the Successful Outcomes of Toxic Metal Chelation Therapy in Neurodegenerative Diseases

“…On the other hand, myelination is able to deliver energy via adenosine triphosphate (ATP) to the axons and exert its neurotrophic activity without modifying the mechanism of nerve conduction [ 43 ]. Similarly, the mitochondria, which are the main source of ATP, have been identified as a sensitive target of Pb exposure [ 44 ].…”