Oxidative stress in myelin sheath: The other face of the extramitochondrial oxidative phosphorylation ability

Abstract

Oxidative phosphorylation (OXPHOS) is not only the main source of ATP for the cell, but also a major source of reactive oxygen species (ROS), which lead to oxidative stress. At present, mitochondria are considered the organelles responsible for the OXPHOS, but in the last years we have demonstrated that it can also occur outside the mitochondrion. Myelin sheath is able to conduct an aerobic metabolism, producing ATP that we have hypothesized is transferred to the axon, to support its energetic demand.

In this work, spectrophotometric, cytofluorimetric, and luminometric analyses were employed to investigate the oxidative stress production in isolated myelin, as far as its respiratory activity is concerned. We have evaluated the levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), markers of lipid peroxidation, as well as of hydrogen peroxide (H₂O₂), marker of ROS production. To assess the presence of endogenous antioxidant systems, superoxide dismutase, catalase, and glutathione peroxidase activities were assayed. The effect of certain uncoupling or antioxidant molecules on oxidative stress in myelin was also investigated.

We report that isolated myelin produces high levels of MDA, 4-HNE, and H₂O₂, likely through the pathway composed by Complex I–III–IV, but it also contains active superoxide dismutase, catalase, and glutathione peroxidase, as antioxidant defense. Uncoupling compounds or Complex I inhibitors increase oxidative stress, while antioxidant compounds limit ROS generation.

Data may shed new light on the role of myelin sheath in physiology and pathology. In particular, it can be presumed that the axonal degeneration associated with myelin loss in demyelinating diseases is related to oxidative stress caused by impaired OXPHOS.

Keywords::

• antioxidants
• malondialdehyde
• myelin energetic metabolism
• OXPHOS
• ROS production

Declaration of interest

All authors have no conflicts of interest.This study was supported by a Grant from the “Fondazione Giuseppe Levi–Accademia Nazionale dei Lincei” for the research project entitled: “Produzione extramitocondriale di ATP in mielina: localizzazione dei complessi della catena respiratoria e possible ruolo nella degenerazione assonale in Sclerosi Multipla” and a Grant from the “Compagnia di San Paolo”–Neuroscience Program 2008, for the research project entitled: “Energetic metabolism in myelinated axon: a new trophic role of myelin sheath.”

Supplementary material available online

Supplementary materials and method, Table I, and Figure 1 to be found online at http://informahealthcare.com/doi/abs/10.3109/10715762.2015.1050962.