Impairment of Mitochondrial Redox Status in Peripheral Lymphocytes of Multiple Sclerosis Patients

Abstract

Literature suggests that oxidative stress (OS) may be involved in the pathogenesis of multiple sclerosis (MS), in which the immune system is known to play a key role. However, to date, the OS in peripheral lymphocytes and its contribution to the disease remain unknown. The aim of the present study was to explore the influence of OS in peripheral lymphocytes of MS patients. To that end, a cross-sectional, observational pilot study was conducted [n = 58: 34 MS and 24 healthy subjects (control group)]. We have measured superoxide production and protein mitochondrial complex levels in peripheral blood mononuclear cells (PBMCs) isolated from MS patients and control. Lactate levels and the antioxidant capacity were determined in plasma. We adjusted the comparisons between study groups by age, sex and cell count according to case. Results demonstrated that PBMCs, specifically T cells, from MS patients exhibited significantly increased superoxide anion production compared to control group (p = 0.027 and p = 0.041, respectively). Increased superoxide production in PBMCs was maintained after the adjustment (p = 0.044). Regarding mitochondrial proteins, we observe a significant decrease in the representative protein content of the mitochondrial respiratory chain complexes I-V in PBMCs of MS patients (p = 0.002, p = 0.037, p = 0.03, p = 0.044, and p = 0.051, respectively), which was maintained for complexes I, III, and V after the adjustment (p = 0.026; p = 0.033; p = 0.033, respectively). In MS patients, a trend toward increased plasma lactate concentration was detected [8.04 mg lactate/dL (5.25, 9.49) in the control group, 11.36 mg lactate/dL (5.41, 14.81) in MS patients] that was statistically significant after the adjustment (p = 0.013). This might be indicative of compromised mitochondrial function. Finally, antioxidant capacity was also decreased in plasma from MS patients, both before (p = 0.027) and after adjusting for sex and age (p = 0.006). Our findings demonstrate that PBMCs of MS patients show impaired mitochondrial redox status and deficient antioxidant capacity. These results demonstrate for the first time the existence of mitochondrial alterations in the cells immune cells of MS patients already at the peripheral level.

Changes in mitochondrial function in patients with neuromyelitis optica; correlations with motor and cognitive disabilities

“…between the reduction of mitochondrial complex I activity and increased time of 9-HPT. One recent study indicated a decreased protein level of mitochondrial complexes in PBMCs isolated from MS patients [47]. It seems that decrease in available energy in cells can affect the pro-inflammatory activity of lymphocytes.…”

Mitochondria, Oxidative Stress, cAMP Signalling and Apoptosis: A Crossroads in Lymphocytes of Multiple Sclerosis, a Possible Role of Nutraceutics

“…Nowadays, decreased complex I and complex IV activities have been reported in lymphocytes of subjects affected by RR-MS with respect to those of control subjects associated with a decrease of their constituent subunits [ 40 ]. The reduced activity and protein expression of constituent subunits is also reported for complexes III and V of oxidative phosphorylation system (OXPHOS) in PBMC of RR-MS patients [ 24 ]. Also, a reduction of mitochondrial membrane potential, according to decrease of respiratory electron flux, has been found in lymphocytes of a cohort of 65 MS patients [ 41 ].…”

“…Also, a reduction of mitochondrial membrane potential, according to decrease of respiratory electron flux, has been found in lymphocytes of a cohort of 65 MS patients [ 41 ]. Very interesting, the decrease of mitochondrial respiratory chain activity and mitochondrial membrane potential are associated with disease severity [ 24 , 41 ]. Moreover, mitochondrial membrane potential reduction can be ascribed to a mitochondrial decoupling.…”

“…It has been reported that the increase of cAMP level attenuates the T lymphocyte-mediated production of pro-inflammatory cytokines such as IFN-γ and interleukin (IL)-1b (IL-1b) suggesting that a decrease of cAMP level is required for T cell activation [ 14 , 20 , 21 ]. The activation of immune cells, especially T cells, is also related to OS [ 15 ] and the peripheral blood mononuclear cells (PBMCs) of MS patients show an impaired redox status associated with a metabolic reprogramming that includes mitochondrial alterations [ 22 , 23 , 24 , 25 ].…”

PBMC of Multiple Sclerosis Patients Show Deregulation of OPA1 Processing Associated with Increased ROS and PHB2 Protein Levels

“…The etiopathogenesis and pathophysiology of MS involves different factors, among others mitochondrial dysfunction and oxidative stress (OS) play a key role and have a further modulatory effect on many aspects of the disease. OS plays an important role in activation of immune cells, especially T cells [5][6][7], and recently it has been reported that peripheral blood mononuclear cells (PBMCs) of MS patients show impaired redox status associated with mitochondrial alterations [5]. A number of mechanisms participate in the maintenance of the immune homeostasis avoiding the development of autoimmune diseases.…”