PolyQ-expanded ataxin-3 is associated with mitochondrial alterations in Machado-Joseph disease.

Spinocerebellar ataxia type 3, also known as Machado-Joseph disease (MJD), is a fatal neurodegenerative disease caused by an expanded CAG repeat in ataxin-3 (ATXN3). Here, we investigated mitochondrial alterations across complementary MJD models, including transgenic zebrafish, CMVMJD135 mice and primary neuronal cultures. Proteomic profiling of brain lysates from male and female wild-type and CMVMJD135 mice identified mitochondrial alterations and altered oxidative phosphorylation-associated protein abundance as major shared features in both male and female MJD mice. Primary neuron cultures derived from CMVMJD135 mice were examined, validating the proteomic findings and revealing alterations in mitochondrial morphology. We further examined a transgenic zebrafish model of MJD that expresses EGFP-fused human ataxin-3 containing 84 glutamines in neurons (driven by the pan-neuronal elavl3/HuC promoter). The MJD zebrafish model also exhibited altered levels of mitochondrial electron transport chain complex proteins and enhanced sensitivity to rotenone. Notably, complex II-associated alterations featured across most assays, supporting complex II-linked dysregulation as a convergent, potentially targetable component of MJD. These phenotypes provide a robust platform for evaluating potential mitochondrial-targeted therapies and support growing evidence that disrupted mitochondrial homeostasis contributes to MJD pathogenesis.