HMN 2026: How Mitochondria reveal new TDP-43 signaling route tied to ALS and dementia

A new study published in Nature Communications has uncovered a communication pathway between mitochondria and RNA granules that may help scientists understand how the toxic buildup of the TDP-43 protein leads to the development of certain neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Yvette Wong, Ph.D., assistant professor in the Ken and Ruth Davee Department of Neurology’s Division of Movement Disorders, was senior author of the study.

Mitochondria, the cell’s energy powerhouse, form inter-organelle contact sites to support bidirectional crosstalk, the exchange of essential signals and information between organelles.

RNA granules are membrane-less cellular compartments formed by proteins and RNA, but how they interact at inter-organelle contact sites and crosstalk with mitochondrial oxidative phosphorylation—the process by which cells convert nutrients to energy—has remained poorly understood.

To better understand how RNA granules interact at these contact sites, the scientists used super-resolution live microscopy and added drugs to regulate mitochondrial oxidative phosphorylation conditions.

“We treated cells with different mitochondrial drugs to better understand what TDP-43 is doing in the cell in real time,” said Hannah Ball, a Ph.D. student in the Driskill Graduate Program in Life Sciences (DGP), who was lead author of the study.

In these cells, they found that reactive oxygen species generated by mitochondrial oxidative phosphorylation (OXPHOS) promote the localization of the TDP-43 protein to RNA granules in the cell’s cytoplasm over time. This pathway was further dependent on the oxidation of TDP-43 at cysteine residues and disrupted by ALS-associated mutant TDP-43.

Under normal conditions, TDP-43 regulates RNA processing. The accumulation of TDP-43 in the cytoplasm, however, is a hallmark of many neurodegenerative diseases, including ALS and FTD, in which accumulated TDP-43 forms toxic clumps and causes loss of neuronal function.

Furthermore, the scientists found that RNA granule-mitochondria contact sites dynamically formed under mitochondrial OXPHOS conditions. These contacts were tethered together by TDP-43 on RNA granules binding to the GADD34 protein on mitochondria, while the untethering of this contact site was regulated by TDP-43 oxidation.

“TDP-43 can regulate how long an RNA granule tethers to mitochondria, just by changing the oxidation state of TDP-43,” Wong said.

Lastly, the scientists discovered that ALS-associated mutant TDP-43 disrupts the regulation of this pathway and promotes the phase separation of protein phosphatase 1 (PP1) into cytosolic granules lacking TDP-43. These findings may help shed light on recent ALS clinical trials that have aimed to therapeutically target PP1 and its binding partner GADD34 but have been unsuccessful, Wong said.

“Some of these clinical trials have been unsuccessful, we think, because they’re potentially modulating the proteins the wrong way,” Wong said. “But now that we know that proteins such as GADD34 and PP1 are highly dynamic, it might actually matter when and where you target them in the cell. Just because drugs target the same protein doesn’t mean that all drugs work the same way—they might make PP1 form granules faster or slower or alter its localization or activity in different ways.”

This previously unknown dynamic crosstalk between TDP-43 and PP1 may help improve understanding of TDP-43-associated diseases, including ALS and FTD, and inform future treatment strategies, Wong said.

“We know that oxidation is important for the activity of both PP1 and TDP, and so trying to figure out how to modulate that interaction is what we’re trying to look at right now. What are the functions of PP1 granules? Are we happy that they’re forming or do we not want them to form? These are some of the exciting future questions that we are studying,” Ball said.

The investigators also plan to investigate how TDP-43 mutations linked to ALS and FTD that cause this defect in PP1 granules may affect other organelles, Wong said.

“Are there other cellular pathways downstream of this that might converge, in which PP1 is the converging point? If we could show that multiple different genes linked to FTD disrupt PP1 dynamics, could targeting PP1 somehow be helpful for specific forms of dementia?” Wong said.

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