Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (8): 3512-3514.doi: 10.4103/NRR.NRR-D-25-00167

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TDP-43 loss-of-function triggers mitochondrial dysfunction and metabolic imbalance

Miriam Ceron-Codorniu, Anna Fernàndez-Bernal, Reinald Pamplona, Manuel Portero-Otín*   

  1. Metabolic Pathophysiology Research Group, Universitat de Lleida-IRBLleida, Lleida, Spain
  • Online:2026-08-18 Published:2026-04-25
  • Contact: Manuel Portero-Otín, PhD, manuel.portero@udl.cat.
  • Supported by:
    This work was funded by the “Instituto de Salud Carlos III” (PI 17–000134, PI 20–0155, PI23/00176) and the “Diputació de Lleida” (PP10601—PIRS2021) to MPO; Also from the “Diputació de Lleida” (PP10605—PIRS2021) and the “Generalitat de Catalunya”: Agency for Management of University and Research Grants (2021SGR00990) to RP; Support was also received in the form of a FUNDELA Grant, “RedELA-Plataforma Investigación” and the “Fundació Miquel Valls” (Jack Van den Hoek donation) (to MPO); MCC is a “University of Lleida” PhD fellow. AFB is a “Fundació LaCaixa” postdoctoral fellow. These funding bodies had no roles in the design of the study, collection, analysis, interpretation of data, and in writing the manuscript.

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Abstract: Neurodegenerative diseases are chronic, agerelated disorders characterized by a relentless, irreversible, and selective loss of neurons in motor, sensory, or cognitive systems (Gao et al., 2019). Despite their heterogeneity, a common pathological feature across many of these diseases is the accumulation of aggregate-prone proteins. Particularly, the cytoplasmic aggregation in neurons of the Transactive response DNAbinding protein 43 (TDP-43), referred to as“TDP-43 proteinopathy,” is observed in most cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (Vanden Broeck et al., 2014). These inclusions are accompanied by the loss of TDP-43 nuclear localization, which leads to a loss of its main function regulating RNA metabolism. Besides, cytoplasmic inclusions have also been described to further contribute to this dysfunction by toxic gain of function mechanisms. Pathologically, both loss of function (LoF) and toxic gain of function disrupt many cellular processes including energy metabolism, mitochondria and endoplasmic reticulum function, autophagy, and protein-clearance systems (Gao et al., 2019). We have recently shown the effects of TDP-43 LoF on cellular metabolism and viability using human-induced pluripotent stem cellderived motor neurons (hIPSC-MNs) and HeLa cells (Ceron-Codorniu et al., 2024). TARDBP loss decreased metabolic activity, impaired adenosine triphosphate (ATP) production, and enhanced superoxide production, suggesting that TDP-43 plays a crucial role in maintaining cellular bioenergetics. Furthermore, TARDBP depletion triggered a metabolic shift leading to lipid droplet accumulation and increased Long-chain-fattyacid—CoA ligase 4 expression, while enhancing ferroptosis resistance.