Purpose: Mitochondrial dysfunction is central to breaking the barrier integrity of retinal endothelial cells (RECs) in various blinding eye diseases such as diabetic retinopathy and retinopathy of prematurity. Therefore, we aimed to investigate the role of different mitochondrial constituents, specifically those of oxidative phosphorylation (OxPhos), in maintaining the barrier function of RECs. Methods: Electric cell-substrate impedance sensing (ECIS) technology was used to assess in real time the role of different mitochondrial components in the total impedance (Z) of human RECs (HRECs) and its components: capacitance (C) and the total resistance (R). HRECs were treated with specific mitochondrial inhibitors that target different steps in OxPhos: rotenone for complex I, oligomycin for complex V (ATP synthase), and FCCP for uncoupling OxPhos. Furthermore, data were modeled to investigate the effects of these inhibitors on the three parameters that govern the total resistance of cells: Cell–cell interactions (Rb), cell–matrix interactions (α), and cell membrane permeability (Cm). Results: Rotenone (1 µM) produced the greatest reduction in Z, followed by FCCP (1 µM), whereas no reduction in Z was observed after oligomycin (1 µM) treatment. We then further deconvoluted the effects of these inhibitors on the Rb, α, and Cm parameters. Rotenone (1 µM) completely abolished the resistance contribution of Rb, as the Rb became zero immediately after the treatment. Secondly, FCCP (1 µM) eliminated the resistance contribution of Rb only after 2.5 h and increased Cm without a significant effect on α. Lastly, of all the inhibitors used, oligomycin had the lowest impact on Rb, as evidenced by the fact that this value became similar to that of the control group at the end of the experiment without noticeable effects on Cm or α. Conclusion: Our study demonstrates the differential roles of complex I, complex V, and OxPhos coupling in maintaining the barrier functionality of HRECs. We specifically showed that complex I is the most important component in regulating HREC barrier integrity. These observed differences are significant since they could serve as the basis for future pharmacological and gene expression studies aiming to improve the activity of complex I and thereby provide avenues for therapeutic modalities in endothelial-associated retinal diseases.
Monoclonal gammopathy of clinical significance (MGCS) represents a new clinical entity referring to a myriad of pathological conditions associated with the monoclonal gammopathy of undetermined significance (MGUS). The establishment of MGCS expands our current understanding of the pathophysiology of a range of diseases, in which the M protein is often found. Aside from the kidney, the three main organ systems most affected by monoclonal gammopathy include the peripheral nervous system, skin, and eye. The optimal management of these MGUS-related conditions is not known yet due to the paucity of clinical data, the rarity of some syndromes, and limited awareness among healthcare professionals. Currently, two main treatment approaches exist. The first one resembles the now-established therapeutic strategy for monoclonal gammopathy of renal significance (MGRS), in which chemotherapy with anti-myeloma agents is used to target clonal lesion that is thought to be the culprit of the complex clinical presentation. The second approach includes various systemic immunomodulatory or immunosuppressive options, including intravenous immunoglobulins, corticosteroids, or biological agents. Although some conditions of the MGCS spectrum can be effectively managed with therapies aiming at the etiology or pathogenesis of the disease, evidence regarding other pathologies is severely limited to individual patient data from case reports or series. Future research should pursue filling the gap in knowledge and finding the optimal treatment for this novel clinical category.
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