Para-Benzoquinone (pBQ) Modifies Human Mitochondrial Phenylalanyl-tRNA Synthetase and Contributes to Mitochondrial Dysfunction

Authors

• Debraj Roy, University of Calcutta
• Soham Bose, University of Calcutta
• Anwesha Das, University of Calcutta
• Riya Manna, University of Calcutta
• Dipanwita Roy, Bose Institute
• Shubhangini Singh Verma, Indian Institute of Technology
• Jagari Bhattacharjee, University of Calcutta
• Surajit Das, University of Calcutta
• Surajit Tudu, University of Calcutta
• Rebecca E. Steiner, Lincoln Memorial University
• Madhusudan Das, University of Calcutta
• Nitin Chaudhary, Indian Institute of Technology
• Anirban Bhunia, Bose Institute
• Alok Ghosh, University of Calcutta
• Michael Ibba, Chapman UniversityFollow
• Rajat Banerjee, University of Calcutta

Document Type

Article

Publication Date

3-11-2026

Abstract

Para-benzoquinone (pBQ) is of growing concern as an emerging redox-active environmental pollutant due to its ubiquitous presence in smoke and combustion byproducts. Recent reports have highlighted its potential role as a redox-driven mitotoxicant, although the involvement of specific mitochondrial protein targets remains unexplored. Here, we investigated the effects of pBQ on human mitochondrial phenylalanyl-tRNA synthetase (hmtPheRS), an essential enzyme required for mitochondrial protein synthesis and linked to severe neurodevelopmental disorders. Our biophysical analyses revealed that pBQ enhanced the formation of covalently modified higher-ordered structures of hmtPheRS by 75% and induced conformational instability, thereby significantly reducing its aminoacylation activity. NMR spectroscopy and molecular docking analyses further supported interactions between pBQ and residues within the catalytic domain of hmtPheRS, indicating the formation of a protein adduct. In parallel, exposure of HEK293 cells to sublethal concentrations of pBQ (20–40 μM) resulted in altered cellular redox homeostasis. It also impaired mitochondrial membrane potential and respiration, disrupted mitochondrial dynamics, and activated mitophagy. Consistent with the broad reactivity of pBQ and its ability to induce oxidative stress, these findings suggest that hmtPheRS is a vulnerable mitochondrial target whose modification may contribute to mitochondrial dysfunction, together with other redox-dependent pathways. Together, this work highlights mitochondrial aminoacyl-tRNA synthetases as an underexplored class of proteins susceptible to redox-active environmental pollutants.

Comments

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Chemical Research in Toxicology, volume 39, issue 4, in 2026 following peer review. This article may not exactly replicate the final published version. The definitive publisher-authenticated version is available online at https://doi.org/10.1021/acs.chemrestox.5c00493.

Recommended Citation

Roy, D. et al. Para-Benzoquinone (pBQ) modifies human mitochondrial phenylalanyl-tRNA synthetase and contributes to mitochondrial dysfunction. Chem. Res. Toxicol 39, 596-613 (2026). https://doi.org/10.1021/acs.chemrestox.5c00493

Copyright

American Chemical Society