Abstract
Multiple sclerosis (MS) is an autoimmune disease in which activated lymphocytes affect the central nervous system. Increase of reactive oxygen species (ROS), impairment of mitochondria-mediated apoptosis and mitochondrial alterations have been reported in peripheral lymphocytes of MS patients. Mitochondria-mediated apoptosis is regulated by several mechanisms and proteins. Among others, optic atrophy 1 (OPA1) protein plays a key role in the regulating mitochondrial dynamics, cristae architecture and release of pro-apoptotic factors. Very interesting, mutations in OPA1 gene, have been associated with multiple sclerosis-like disorder. We have analyzed OPA1 and some factors involved in its regulation. Fifteen patients with MS and fifteen healthy control subjects (HC) were enrolled into the study and peripheral blood mononuclear cells (PBMCs) were isolated. H2O2 level was measured spectrofluorimetrically, OPA1, PHB2, SIRT3, and OMA1 were analyzed by western blotting. Statistical analysis was performed using Student’s t-test. The results showed that PBMC of MS patients were characterized by a deregulation of OPA1 processing associated with increased H2O2 production, inactivation of OMA1 and increase of PHB2 protein level. The presented data suggest that the alteration of PHB2, OMA1, and OPA1 processing could be involved in resistance towards apoptosis. These molecular parameters could also be useful to assess disease activity.
Highlights
Multiple sclerosis (MS) is a complex neurodegenerative disease that involves immune and central nervous system (CNS) [1,2]
Our results showed the same level of optic atrophy 1 (OPA1) total protein (L+S) in healthy control subjects (HC) and SM samples and no differences were observed in the balance between L and S forms of OPA1 in peripheral blood mononuclear cells (PBMCs) of HC and MS
In PBMCs of MS patients, oxidative stress is associated with increased level of prohibitin 2 (PHB2) and stabilization of OMA1
Summary
Multiple sclerosis (MS) is a complex neurodegenerative disease that involves immune and central nervous system (CNS) [1,2]. Mitochondria are responsive to OS and are critical in modulating apoptosis in response themselves to a variety of stress signals Several mitochondria parameters such as mitochondrial respiratory chain activity, ROS production, dynamics (fusion and fission), and mitochondria cristae architecture are involved in mitochondria-mediated apoptosis [14,15,16]. Among mitochondrial proteins involved in apoptosis mechanism, optic atrophy 1 (OPA1) is a mitochondrial dynamin like GTPase that has attracted great attention for its role in the regulating mitochondrial fusion and fission, the stability of the mitochondrial respiratory chain complexes, pro-apoptotic cytochrome c release and the maintenance of mitochondrial cristae architecture [17]. OPA1 processing is modulated by its acetylation status mediated by SIRT3 enzyme, a mitochondrial deacetylase that plays an important role in apoptosis [20]. In this work we have analyzed the protein level, and proteolytic processing of OPA1 and its stress-associated regulators, OMA1, SIRT3, and PHB2 in PBMCs of MS patients
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