Disruption of the mitochondrial network in a mouse model of Huntington's disease visualized by in tissue multiscale 3D electron microscopy

TL;DR

This study uses advanced 3D electron microscopy to reveal mitochondrial network disruption and fragmentation in a mouse model of Huntington's disease, providing detailed structural insights into mitochondrial alterations in affected neurons.

Contribution

It introduces a novel multiscale 3D imaging approach to analyze mitochondrial structural changes in brain tissue in situ, advancing understanding of HD pathology.

Findings

Mitochondrial network becomes fragmented in HD

Mitochondria show swelling, cristae disorganization, and abnormal matrix granules

3D imaging reveals detailed mitochondrial structural alterations in affected neurons

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the coding sequence of the huntingtin protein. Initially, it predominantly affects medium-sized spiny neurons (MSSNs) of the corpus striatum. No effective treatment is available, thus urging the identification of potential therapeutic targets. While evidence of mitochondrial structural alterations in HD exists, previous studies mainly employed 2D approaches and were performed outside the strictly native brain context. In this study, we adopted a novel multiscale approach to conduct a comprehensive 3D in situ structural analysis of mitochondrial disturbances in a mouse model of HD. We investigated MSSNs within brain tissue under optimal structural conditions utilizing state-of-the-art 3D imaging technologies, specifically FIB/SEM for the complete imaging of neuronal somas and Electron Tomography for detailed morphological examination and image processing-based quantitative analysis. Our findings suggest a disruption of the mitochondrial network towards fragmentation in HD. The network of interlaced, slim, and long mitochondria observed in healthy conditions transforms into isolated, swollen, and short entities, with internal cristae disorganization, cavities, and abnormally large matrix granules.