PEX11β-mediated improvement of mitochondrial dysfunction restores behavioral defect and cellular viability in neuropathological conditions

Mitochondrial fission and altered Complex II expression and function are hallmarks of Huntington’s (HD) and Alzheimer’s (AD) diseases. Notably, peroxisomal fission protein, PEX11β, works in coordination with mitochondrial fission proteins and exhibits a unique co-expression pattern with respiratory chain complexes. However, whether a PEX11β-mediated shared mechanism drives mitochondrial fragmentation across different neurodegenerative conditions remains unclear. Using patient transcriptomic data and in vitro cellular models, we establish a novel connection between disease-associated downregulation of PEX11β, mitochondrial fragmentation, and impaired expression of fusion and Complex II genes. Restoration of PEX11β alleviates motor and cognitive deficits, and reinstates mitochondrial gene expression in the striatum of 3-NP-induced HD mice. In silico analysis and ChIP-PCR reveal Yin Yang 1 is a critical transcription factor regulating co-expression of PEX11β and Complex II genes. Our findings uncover PEX11β-mediated regulation of mitochondrial fission-fusion dynamics, linking mitochondrial integrity to behavioral outcomes, and offer a novel insight into amyloid-associated neuropathology.