Abstract
Neuronal mitochondria display distinct morphologies across compartments, with dendritic mitochondria being elongated and axonal ones shorter, and their morphologies are dynamically changed via fusion and fission machineries. Mitochondrial structural abnormalities are common in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, yet systematic evaluation of therapeutic targets remains limited. Here, we tested key mitochondrial shape regulators, mitofusin 1/2 for fusion and Mff/Fis1 for fission, in an α-synucleinopathy model. Using MitoVis, a deep learning-based neuronal mitochondrial image analysis tool, we achieved rapid, compartment-specific analysis of mitochondrial morphologies. Among all interventions, Fis1 knockdown most effectively protected mitochondrial structure to control levels without inducing over-elongation of axonal mitochondria, which was linked to abnormal Ca2+ dynamics. While all manipulations preserved dendritic spine loss, Fis1 optimally maintained axonal mitochondrial function. These findings demonstrate a high-throughput screening approach for mitochondrial regulators and highlight Fis1 as a promising preventive/therapeutic target. Our results support targeting mitochondrial morphology as a viable strategy for treating α-synucleinopathy and potentially other mitochondria-related neurodegenerative diseases.
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All data reported in this paper will be shared by the corresponding authors upon request. This paper does not report original code. Any additional information required to reanalyze the data reported in this work paper is available from the corresponding authors upon request.
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Acknowledgements
We also thank all members of the Kwon lab and collaborators for feedback and discussion along the way. This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (2019M3E5D2A0106379412, 2020R1C1C1006386, RS-2022-NR067817, RS-2023-00264980 to S.-K.K.; RS-2021-NR061738 to D.C.J.) and KIST Program (26Z9001 and 26E0131 to S.-K.K.).
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S.Y.K., K.H., S-K.K. conceptualized the study. S.Y.K., J.Y.C., D.C.J., P.L., G.S.H., J.K., W-K.J., K.H., S-K.K. performed the study and S.Y.K., J.Y.C, D.C.J., P.L. analyzed data with a manual way or a software. S.Y.K. and S-K.K. originally wrote the paper, and all authors reviewed and edited it.
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S.Y.K. and S-K.K. are preparing the patent application related to the contents of this article, in which S.Y.K. and S-K.K. are listed as inventors. J.Y.C. and W-K.J. are co-founders of VIENCE Inc. Other authors declare that they have no competing interests.
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Kim, S.Y., Choi, J., Jang, D.C. et al. Systematic evaluation of mitochondrial morphology regulators for amelioration of neuronal α-synucleinopathy. npj Parkinsons Dis. (2026). https://doi.org/10.1038/s41531-026-01277-z
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DOI: https://doi.org/10.1038/s41531-026-01277-z
