Life sciences · 2026
Mitochondrial function of peripheral lymphocytes: role on multiple sclerosis clinical subtypes.
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González-Jiménez Adela, de Heras-Pino Paloma, Moreno-Jerez Alba, Mena-Plaza Estela, Aladro Yolanda, Pilo Belén, Oreja-Guevara Celia, Gómez-Estévez Irene, López-Pastor Andrea R, Gómez-Delgado Irene, Urcelay Elena
Аннотация
AIMS: Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of unknown etiology, resulting in unmet therapeutic needs. Symptoms heterogeneity and incomplete mechanistic understanding hinder effective patient stratification. We aimed to evaluate the integrated peripheral immune response in established MS clinical subtypes, focusing on differences in mitochondrial function that might validate this stratification and further clarify MS etiology.
MATERIALS AND METHODS: Mitochondrial activity of peripheral blood mononuclear cells (PBMCs) upon PHA-stimulation was analysed in MS patients (58 relapsing-remitting (RRMS), 21 secondary progressive (SPMS), and 35 primary progressive (PPMS)) and 35 healthy controls (HC).
KEY FINDINGS: In unstimulated conditions, MS patients presented higher mitochondrial ROS (reactive oxygen species) and decreased coupling than HC. Compared with other progressive MS (PMS) subtypes, PBMCs from RRMS presented significantly higher early/late activation and proliferation after PHA stimulation (P = 0.013/P = 0.002, and P = 0.04, respectively), with increased mitochondrial depolarization (P = 0.017). Compared to HC, PHA-stimulated PBMCs from PMS exhibited marked decreases in basal (P = 0.017), maximal, and ATP-linked respiration, increased coupling (P = 0.009), and lower spare respiratory and glycolytic capacities (basal: P = 0.015, maximal: P = 0.064), with parallel decreased GLUT1 expression (P = 0.025). These changes appeared independent of some treatments.
SIGNIFICANCE: Upon PHA-stimulation, PMS patients displayed decreased basal, maximal, ATP-linked respiration, and reduced spare respiratory and glycolytic capacities, compared to RRMS and HC, mirroring opposed trends in unstimulated conditions. These findings suggest a severity gradient across MS clinical forms, supporting a disease continuum rather than strictly defined subtypes. The central role of unresolved mitochondrial dysfunction in MS warrants further investigation and may guide novel therapeutic strategies.
MATERIALS AND METHODS: Mitochondrial activity of peripheral blood mononuclear cells (PBMCs) upon PHA-stimulation was analysed in MS patients (58 relapsing-remitting (RRMS), 21 secondary progressive (SPMS), and 35 primary progressive (PPMS)) and 35 healthy controls (HC).
KEY FINDINGS: In unstimulated conditions, MS patients presented higher mitochondrial ROS (reactive oxygen species) and decreased coupling than HC. Compared with other progressive MS (PMS) subtypes, PBMCs from RRMS presented significantly higher early/late activation and proliferation after PHA stimulation (P = 0.013/P = 0.002, and P = 0.04, respectively), with increased mitochondrial depolarization (P = 0.017). Compared to HC, PHA-stimulated PBMCs from PMS exhibited marked decreases in basal (P = 0.017), maximal, and ATP-linked respiration, increased coupling (P = 0.009), and lower spare respiratory and glycolytic capacities (basal: P = 0.015, maximal: P = 0.064), with parallel decreased GLUT1 expression (P = 0.025). These changes appeared independent of some treatments.
SIGNIFICANCE: Upon PHA-stimulation, PMS patients displayed decreased basal, maximal, ATP-linked respiration, and reduced spare respiratory and glycolytic capacities, compared to RRMS and HC, mirroring opposed trends in unstimulated conditions. These findings suggest a severity gradient across MS clinical forms, supporting a disease continuum rather than strictly defined subtypes. The central role of unresolved mitochondrial dysfunction in MS warrants further investigation and may guide novel therapeutic strategies.