Nogueras 2017 MiPschool Obergurgl

Mitochondrial dysfunction in peripheral blood mononuclear cells from multiple sclerosis patients.

Link: MitoEAGLE

Nogueras L, Gil A, Hervas JV, Gonzalez C, Martin-Gari M, Canudes M, Peralta S, Moga MJ, Boada J, Pamplona R, Portero M, Brieva L, Gonzalo H (2017)

Event: MiPschool Obergurgl 2017

Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease of the central nervous system (CNS). Its etiology is still unknown; nevertheless, the abundance of immune cells in CNS lesions of MS patients supports the notion that MS is an immune-mediated disorder[1,2]. On the other hand mitochondrial dysfunction might have a central role in the pathophysiology of MS. Different studies have reported a mitochondrial impairment in the CNS but the results in the immune system are still inconsistent[3].

Cellular immune function depends on energy supply and mitochondrial function that is why this study has investigated mitochondrial respiration (Oroboros O2k; Oroboros Instruments, Innsbruck, Austria) in peripheral blood mononuclear cells (PBMCs), an established model to investigate the mitochondrial impairments. Mitochondrial respiration was assessed in intact PBMCs in 45 individuals with a diagnosis of MS compared with 29 healthy age gender-matched controls using high-resolution respirometry. Furthermore we analyzed superoxide production of lymphocytes (they represent between 70-90% of PBMCs cells) by median fluorescent intensity (MFI) of MitoSoxTM (Red mitocondrial superoxide indicator, Molecular Probes, Invitrogen, Barcelona, Spain) by flow citometry.

Individuals with MS showed a significant increase in ROUTINE respiration (p=0.045), uncoupled respiration (after oligomycin addition p=0.035), as well as in the maximum respiratory capacity (after carbonyl cyanide-p-trifluoromethoxyphenylhydrazone titration p=0.035). Finally Antimycin A was added but not significant differences were founded between groups (Figure 1). In addition, PBMCs of these patients produced more superoxide than those in control group individuals (p=0.021) (Figure 2).

PBMCs cells in MS patients show a significant increase of uncoupled respiration which is consistent with immune system activation and with an autoimmune disease. A higher maximal uncoupled respiration can indicate a higher capacity of mitochondrial respiration and is related to superoxide production which is also higher in MS patients[4]. In conclusion, our results support systemic involvement in MS, and reveal the study of mitochondrial function in blood cells as a source of potential biomarkers of the disease.

• Bioblast editor: Kandolf G • O2k-Network Lab: ES Lleida Boada J

Labels: MiParea: Respiration, Patients  Pathology: Neurodegenerative 

Tissue;cell: Blood cells  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k  Event: C1, Oral  PMBCs 

Affiliations

Nogueras L(2), Gil A(2), Hervás JV(3), Gonzalez C(3), Martin-Gari M(2), Canudes M(2), Peralta S(1), Moga MJ(3), Boada J(2), Pamplona R(2), Portero M(2), Brieva L(3), Gonzalo H(1,3)

1. Fundación Esclerosis Multiple
2. Inst recerca biomèdica de Lleida
3. Arnau Vilanova Hospital

Lleida, Spain. - lara.noguerasp@gmail.com

Figures

Figure 1. Boxplots of group-wise comparison of respiration in PBMCs from MS patients (n = 45) and control subjects (n = 29) characterized by mitochondrial oxygen flux.

Asterisk (*) indicates significant group differences on an alpha level of 0.05 (Student’s independent ttest).

Leak: flux oxygen after oligomycin addition

Uncoupled: flux oxygen after carbonyl cyanide-p-trifluoromethoxyphenylhydrazone titration

Figure 2. Boxplots of group-wise comparison of superoxide production of lymphocytes from MS patients (n = 45) and control subjects (n = 29) characterized by median fluorescent intensity.

Asterisk (*) indicates significant group differences on an alpha level of 0.05 (Student’s independent ttest).

MFI: median fluorescent intensity

References and support

1. Legroux L, Arbour N (2015) Multiple sclerosis and T lymphocytes: an entangled story. J Neuroimmune Pharmacol 10:528-46.
2. Haghikia A, Faissner S, Pappas D, Pula B, Akkad DA, Arning L, Ruhrmann S, Duscha A, Gold R, Baranzini SE, Malhotra S, Montalban X, Comabella M, Chan A (2015) Interferon-beta affects mitochondrial activity in CD4+ lymphocytes: Implications for mechanism of action in multiple sclerosis. Mult Scler 21:1262–70.
3. Petzold A, Nijland PG, Balk LJ, Amorini AM, Lazzarino G, Wattjes MP, Gasperini C, van der Valk P, Tavazzi B, Lazzarino G, van Horssen J (2015) “Visual pathway neurodegeneration winged by mitochondrial dysfunction. Ann Clin Transl Neurol 2:140–50.
4. Karabatsiakis A, Böck C, Salinas-Manrique J, Kolassa S, Calzia E, Dietrich DE, Kolassa IT (2014) Mitochondrial respiration in peripheral blood mononuclear cells correlates with depressive subsymptoms and severity of major depression. Transl Psychiatry 4:e397.

Selected mentor: Jordi Boada