TRIM16 attenuates TDP43-mediated oxidative injury by coordinating Nrf2 activation and TFR1 autophagic degradation.

Abstract

TAR DNA-binding protein 43 (TDP43) aggregation is a well-established pathological hallmark of amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders, contributing significantly to oxidative stress and neuronal injury. Here, we report that the M337V mutation in TDP43 exacerbates its proteotoxicity relative to the wild-type protein. Concurrently, multi-omics analysis revealed a pronounced downregulation of TRIM16 in motor neuron-like cells expressing either wild-type or M337V mutant TDP43. Functional studies demonstrated that TRIM16 overexpression effectively mitigated oxidative stress, restored mitochondrial integrity, and suppressed ferroptosis. Mechanistically, TRIM16 promoted the ubiquitination and degradation of Keap1, thereby facilitating the activation of Nrf2-mediated antioxidant genes. Furthermore, we identified the iron import receptor TFR1 as a novel ubiquitination substrate of TRIM16. TRIM16 mediated the ubiquitination of TFR1 and targeted it for p62-dependent autophagic degradation, which in turn reduced iron accumulation and lipid peroxidation. Collectively, our findings establish TRIM16 as a pivotal suppressor of TDP43-induced toxicity by orchestrating dual cytoprotective pathways to enhance cellular resilience, highlighting its promising therapeutic potential for TDP43 proteinopathy.

Key Findings

• The M337V mutation in TDP43 increases proteotoxicity compared to the wild-type protein.
• TRIM16 expression is downregulated in motor neuron-like cells expressing TDP43, and its overexpression reduces oxidative stress, restores mitochondrial integrity, and suppresses ferroptosis.
• TRIM16 promotes ubiquitination and degradation of Keap1, activating Nrf2-mediated antioxidant responses, and also targets the iron import receptor TFR1 for autophagic degradation to reduce iron accumulation and lipid peroxidation.

Clinical Significance

Citation

Chen Qiuyu, Zhou Yujun, Peng Yuchenet al.. TRIM16 attenuates TDP43-mediated oxidative injury by coordinating Nrf2 activation and TFR1 autophagic degradation. Free radical biology & medicine. 2026-Aug-16.