Mitochondria from huntington´s disease striatal astrocytes are hypermetabolic and compromise neuronal branching

作者：Laura López-Molina, Alba Pereda-Velarde, Nadia Di Franco, Inne Aerts, E. Mena Sebastiá, Laura Valls‐Roca, Mariona Guitart‐Mampel, Glòria Garrabou, Sílvia Ginés · 发表于：Cell Communication and Signaling · 年份：2025 · DOI：10.1186/s12964-025-02341-6 · 被引用次数：12 · 研究领域：Mitochondrial Function and Pathology、Amyotrophic Lateral Sclerosis Research、Neurological diseases and metabolism

BACKGROUND: Deficits in mitochondrial bioenergetics and dynamics are strongly implicated in the selective vulnerability of striatal neurons in Huntington´s disease. Beyond these neuron-intrinsic factor, increasing evidence suggest that non-neuronal mechanisms, particularly astrocytic dysfunction involving disrupted homeostasis and metabolic support also contribute to disease progression. These findings underscore the critical role of metabolic crosstalk between neurons and astrocytes in maintaining striatal integrity. However, it remains unclear whether this impaired communication affects the transfer of mitochondria from astrocytes to striatal neurons, a potential metabolic support mechanism that may be compromised in Huntington´s Disease. METHODS: Primary striatal astrocytes were obtained from wild-type and R6/1 mice to investigate mitochondrial dynamics. Expression levels of key mitochondrial fusion and fission proteins were quantified by Western blotting and RT-PCR. Mitochondria morphology, oxidative stress and membrane potential were assessed using confocal microscopy following staining with mitochondria-specific dyes. Mitochondrial respiration was measured using the Oxygraph-2k respirometer system (Oroboros Instruments). Transmitophagy was evaluated by confocal imaging after labeling astrocytic mitochondria with Mitotracker dyes. To assess the functional impact of mitochondrial transfer on neurons, Sholl analysis, neuronal death and oxidative stress levels were quantifi...