Mitochondria “Shackled” by Mutant Huntingtin: Analysis of Morphological Alterations and Disruptions of Intracellular Transport

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Vyacheslav I. Pasko^1#, Aleksandra S. Churkina^2#, Lilia D. Belikova³, Anton S. Shakhov², Svetlana V. Lavrushkina², Anton V. Burakov², Alexandra N. Bogomazova^3,4, Maria A. Lagarkova^3,4, and Irina B. Alieva^2,3,a*

¹Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992 Moscow, Russia

²Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia

³Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, 119435 Moscow, Russia

⁴Center for Genetic Reprogramming and Gene Therapy, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, 119435 Moscow, Russia

^* To whom correspondence should be addressed.

^# These authors contributed equally to the work.

Received: September 1, 2025; Revised: November 25, 2025; Accepted: December 7, 2025

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Mitochondria are semi-autonomous, multifunctional organelles that supply cells with energy. They are highly dynamic structures, capable of moving, fusing, dividing, and forming branched networks. The number, density, and complexity of mitochondrial network are unique to each cell type and reflect cellular demands for ATP and other mitochondria-dependent metabolites. Mitochondrial dysfunction is a hallmark of many neurodegenerative diseases; however, the relationships between neurodegeneration and mitochondrial morphogenesis, intracellular localization, and dynamics remain incompletely understood. Interpretation and comparison of published data are complicated by the diversity of analytical approaches used to study mitochondrial behavior. In this research, we investigated the effects of a pathogenic mutation in the huntingtin protein (HTT), which causes Huntington’s disease (HD), on mitochondrial morphology and motility, with particular emphasis on associated disruptions in the cytoskeletal organization. We performed a systematic evaluation of automated mitochondrial analysis tools and selected MiNA, TrackMate, and JACoP as the optimal platforms for quantitative assessment of the effects of mutant HTT (mHTT) on the mitochondrial morphology, motility, and interaction with cytoskeletal components and identification of specific disruptions directly related to HD pathogenesis. Our analysis revealed that mitochondria in mHTT-expressing cells are significantly shorter, more branched, and less motile than in control cells. Moreover, their interactions with microtubules and vimentin intermediate filaments are markedly altered. Together, these findings establish a link between HD and specific defects in the mitochondrial network, thus contributing to understanding cellular mechanisms of HD development, and suggest that mHTT disrupts the interaction of mitochondria with cytoskeletal components responsible for their movement and distribution in the cell, thereby negatively affecting mitochondrial motility and morphology.

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KEY WORDS: Huntington’s disease, huntingtin, neurodegenerative diseases, mitochondrial dynamics

DOI: 10.1134/S0006297925602850

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