  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.
