Mitochondrial and redox modifications in early stages of Huntington disease

Lopes, C.; Ferreira, I. L.; Maranga, C.; Beatriz, M.; Mota, S.; Sereno, J.; Castelhano, J.; Abrunhosa, A.; Oliveira, F.; De Rosa, M.; Hayden, M. R.; Laco, M.; Januario, C.; Castelo Branco, M.; Rego, A. C.

doi:10.1101/2022.01.14.476381

bioRxiv · 10.1101/2022.01.14.476381

Mitochondrial and redox modifications in early stages of Huntington disease

Lopes, C.·Ferreira, I. L.·Maranga, C.·Beatriz, M.·Mota, S.·Sereno, J.·Castelhano, J.·Abrunhosa, A.·Oliveira, F.·De Rosa, M.·Hayden, M. R.·Laco, M.·Januario, C.·Castelo Branco, M.·Rego, A. C.

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Abstract

Defects in mitochondrial function and mitochondrial-related redox deregulation have been attributed to Huntingtons disease (HD), a genetic neurodegenerative disorder largely affecting the striatum. However, whether these changes occur in early stages of the disease and can be detected in vivo is still unclear. Thus, in the present study, we analyzed changes in mitochondrial function and overreduced states associated with production of reactive oxygen species (ROS) at early stages and along disease progression. Studies were performed in vivo in human brain using positron emission tomography (PET) using [64Cu]-ATSM and ex vivo in human skin fibroblasts of premanifest and prodromal (Pre-M) and manifest HD patients; in vivo brain [64Cu]-ATSM PET and isolated mitochondria derived from striatum and cortex were also analyzed in YAC128 transgenic mouse at pre-symptomatic (3 month-old, mo) and symptomatic (6 to 12 mo) stages. Oxygen consumption rates were assessed by Seahorse analysis, hydrogen peroxide levels were determined using fluorescent probes and mitochondrial morphology by transmission electron microscopy in human skin fibroblasts and mouse striatal and cortical isolated mitochondria. Pre-M HD carriers exhibited enhanced whole-brain (with exception of caudate) [64Cu]-ATSM labelling, correlating with CAG repeat number. Fibroblasts from Pre-M showed enhanced basal and maximal respiration, proton (H+) leak and increased hydrogen peroxide levels, the later progressing to manifest HD; mitochondria from fibroblasts of Pre-M HD carriers also showed reduced roundness, while higher number of mitochondrial DNA copies correlated with maximal respiratory capacity. In vivo animal PET analysis showed increased accumulation of [64Cu]-ATSM in YAC128 mouse striatum. Pre-symptomatic YAC128 mouse striatal isolated mitochondria exhibited a rise in basal and maximal mitochondrial respiration and in ATP production, along with increased complex II and III activities; mouse HD mitochondria also showed enhanced mitochondrial hydrogen peroxide levels and roundness, as revealed by brain ultrastructure analysis, and defects in Ca2+ handling, supporting increased striatal susceptibility in YAC128 mouse brain. Data demonstrate both human and mouse mitochondrial overactivity and altered morphology at early HD stages, facilitating redox unbalance, the latter extending over manifest disease stages.

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Lopes, C., Ferreira, I. L., Maranga, C., Beatriz, M., Mota, S., Sereno, J., Castelhano, J., Abrunhosa, A., Oliveira, F., De Rosa, M., Hayden, M. R., Laco, M., Januario, C., Castelo Branco, M., Rego, A. C.. 2022-01-15. Mitochondrial and redox modifications in early stages of Huntington disease. https://doi.org/10.1101/2022.01.14.476381

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