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bioRxiv · 10.1101/2025.10.24.684183

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

Kumar, V.·Kodam, P.·Kunja, C.·Komal, P.·Sanyal, A.·Maity, S.
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Abstract

Peroxisomal biogenesis factor 11 beta (Pex11{beta}) is a key regulator of peroxisome proliferation, functioning in coordination with mitochondrial fission proteins. Recent human proteome co-regulation mapping has revealed a distinctive co-expression pattern between Pex11{beta} and components of the mitochondrial respiratory chain complex at the peroxisome-mitochondria interface. In neurodegenerative disorders, such as Huntingtons disease (HD) and Alzheimers disease (AD), mitochondrial dysfunction is primarily associated with impairments in the respiratory chain complexes, particularly Complex II. However, the role of Pex11{beta} in maintaining mitochondrial homeostasis in these two disease conditions remains largely unexplored. In this study, using both in vitro and in vivo models, we identify Pex11{beta} as a critical modulator of mitochondrial dynamics, influencing the balance between fission and fusion. Through targeted knockdown and overexpression experiments, we demonstrate a direct link between Pex11{beta} level and mitochondrial dysfunction, mediated by transcriptional dysregulation of nuclear-encoded Complex II and mitochondrial fusion genes. Restoration of Pex11{beta} expression, along with Complex II and fusion gene level in striatal brain via a peroxisome proliferator & chemical chaperone, significantly alleviates motor and cognitive deficits in 3-NP-induced HD mouse model indicating better mitochondrial health in striatal brain. Furthermore, in silico analysis and ChIP-qPCR reveal Yin Yang 1 (YY1) is a critical transcription factor governing the co-expression of Pex11{beta} and Complex II genes. This establishes a novel transcriptional axis that orchestrates inter-organellar communication. Collectively, our findings position Pex11{beta} as a pivotal mediator of mitochondrial fission-fusion dynamics, linking mitochondrial morphology and oxidative phosphorylation (OXPHOS) to behavioural outcomes, and offering mechanistic insights relevant to amyloid-associated neurodegenerative diseases.

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Kumar, V., Kodam, P., Kunja, C., Komal, P., Sanyal, A., Maity, S.. 2025-10-26. PEX11β-mediated improvement of mitochondrial dysfunction restores behavioral defect and cellular viability in neuropathological conditions. https://doi.org/10.1101/2025.10.24.684183

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