TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites

Topic: Brain proteins, microglia and lab models

Inter-organelle contact sites are key hubs for organelle bidirectional crosstalk. However, how mitochondria and RNA granules interact at contact sites and its regulation by mitochondrial oxidative phosphorylation (OXPHOS) remain unclear. Here, using Super-Resolution live microscopy, we identify RNA granule-mitochondria contact site formation in OXPHOS conditions. Reactive oxygen species (ROS) generated by mitochondrial OXPHOS promotes TDP-43 localization to cytoplasmic RNA granules via TDP-43 cysteine oxidation at Cys173/Cys175. Mechanistically, RNA granule-mitochondria contact tethering is mediated by TDP-43 on RNA granules binding to GADD34 on mitochondria, while contact untethering is regulated by TDP-43 oxidation. Functionally, this allows for GADD34 and its binding partner PP1 to regulate TDP-43 RNA granule dynamics, and conversely, for TDP-43 oxidation to regulate the ability of the phosphatase PP1 to form granules. Finally, disease-associated mutant TDP-43 misregulates this pathway, ultimately leading to PP1 granules lacking TDP-43. This dynamic crosstalk between TDP-43 oxidation and PP1 has significant consequences for TDP-43-associated diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).

@article{ball2026-42248860,
  author  = {Ball, Hannah E. and Woods, Abby C. and Wong, Yvette C.},
  title   = {{TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites}},
  journal = {Nature Communications},
  year    = {2026},
  doi     = {10.1038/s41467-026-74009-9},
  pmid    = {42248860},
  url     = {https://doi.org/10.1038/s41467-026-74009-9}
}

Key findings

• This dynamic crosstalk between TDP-43 oxidation and PP1 has significant consequences for TDP-43-associated diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).

Why it matters

This study identified that reactive oxygen species promote TDP-43 localization to RNA granules via oxidation at specific cysteine sites, and that this dynamic crosstalk has consequences for ALS and FTD. These findings are from super-resolution live microscopy and describe a mechanism, not a treatment.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s41467-026-74009-9
• PubMed: 42248860
• Original source →
• Free full text: Nature Communications →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

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