PINK1 and PARKIN Deficiency Increases Neuronal Vulnerability to Autoimmune Neuroinflammation Through Mitochondrial Fragmentation in Aged Mice

: PINK1 and Parkin regulate mitochondrial quality control in both neuronal and immune-cell populations, but their roles during autoimmune neuroinflammation in aging remain incompletely understood. We investigated the association of PINK1 or Parkin deficiency with clinical disease, peripheral immune responses, CNS inflammation, and neuronal mitochondrial morphology during experimental autoimmune encephalomyelitis (EAE). EAE was induced in aged PINK1-/- and PARK2-/- mice and age-matched controls. Clinical disease was assessed longitudinally, while independent cohorts were analyzed at peak disease using flow cytometry, spinal cord histology, transmission electron microscopy, and Western blotting of mitochondrial fractions. PINK1-/- and PARK2-/- showed greater cumulative disease burden and incomplete clinical recovery, most prominently in PARK2-/- mice. At peak disease, knockout mice exhibited increased dendritic cells, monocytes, and CD8+ T cells, while aged knockouts showed more IFN-γ-producing CD4+ and CD8+ T cells following ex vivo stimulation. Increased spinal cord inflammation was not accompanied by genotype-dependent differences in myelin staining. Ultrastructural analysis revealed more numerous, smaller mitochondria in substantia nigra pars compacta and motor cortex neurons, accompanied by selective alterations in OPA1 and DRP1, but not MFN2. These findings demonstrate that PINK1 or Parkin deficiency is associated with enhanced inflammation, greater EAE disease burden, and altered neuronal mitochondrial morphology in aging. These results support an association between immune dysregulation and altered mitochondrial homeostasis without establishing impaired mitophagy or a direct causal relationship.