Mitochondrial function of peripheral lymphocytes: role on multiple sclerosis clinical subtypes

Area of Science:

• Neuroimmunology
• Mitochondrial Biology
• Neurodegenerative Diseases

Background:

• Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease with unknown causes.
• Heterogeneous symptoms and limited understanding of disease mechanisms impede effective patient stratification.
• Unmet therapeutic needs persist due to incomplete mechanistic understanding.

Purpose of the Study:

• To investigate peripheral immune responses in established MS clinical subtypes.
• To analyze mitochondrial function differences across MS subtypes (RRMS, SPMS, PPMS) and healthy controls (HC).
• To explore if mitochondrial dysfunction validates MS stratification and clarifies disease etiology.

Main Methods:

• Peripheral blood mononuclear cells (PBMCs) from MS patients and HC were analyzed for mitochondrial activity.
• PBMCs were stimulated with PHA (phytohemagglutinin) to assess immune cell activation and proliferation.
• Mitochondrial respiration, reactive oxygen species (ROS), membrane potential, and GLUT1 expression were measured.

Main Results:

• Unstimulated MS PBMCs showed higher ROS and decreased coupling compared to HC.
• Stimulated RRMS PBMCs exhibited higher activation and proliferation than progressive MS (PMS) subtypes.
• Stimulated PMS PBMCs displayed reduced basal, maximal, and ATP-linked respiration, and lower glycolytic capacity compared to RRMS and HC.

Conclusions:

• Progressive MS patients show impaired mitochondrial respiration and glycolytic capacity, differing from RRMS patients and healthy controls.
• Findings suggest a disease severity gradient in MS, supporting a continuum model over distinct subtypes.
• Mitochondrial dysfunction is central to MS pathogenesis and may offer novel therapeutic strategies.