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Nicotinamide counteracts Rotenone-induced mitochondrial and neuronal dysfunction in a translational early-life model
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  • Published: 04 February 2026

Nicotinamide counteracts Rotenone-induced mitochondrial and neuronal dysfunction in a translational early-life model

  • Amanda Siena1,
  • E Silva Luiz Felipe Souza1,
  • Vitória Cristina Araujo1,
  • Martina Raissa Ribeiro1,
  • Larissa de Sá Lima1,
  • Diana Zukas Andreotti1,2,
  • Ana Maria Orellana1,2,
  • Elisa Mitiko Kawamoto2,
  • Silva Junior Pedro Ismael3,
  • Cristoforo Scavone1 &
  • …
  • Tatiana Rosado Rosenstock1,4 

Scientific Reports , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Developmental biology
  • Neuroscience

Abstract

Mitochondrial function is essential for key neurodevelopmental processes, including cellular proliferation, differentiation, migration, synaptogenesis, and synaptic pruning. Previous research from our group demonstrated that neonatal administration of Rotenone (Rot), a mitochondrial complex I inhibitor, led to mitochondrial dysfunction and schizophrenia-like behavioral phenotypes. In this study, we aimed to identify possible cellular pathways disrupted by Rot exposure that may underlie these behavioral alterations. Thus, primary cortical neurons were treated with 1.325 nM Rot for 24 h, a concentration extrapolated from cortical levels observed in the neonatal Rot model. This treatment impaired mitochondrial complex I activity, decreased superoxide production, disrupted mitochondrial respiration and dynamics, reduced dendritic branching, and decreased synapse formation. Notably, pretreatment with Nicotinamide (NAM), a NAD precursor, improved mitochondrial function, reversing these effects. Altogether, our findings underscore the critical role of mitochondrial integrity in neurodevelopment and its potential contribution to neurodevelopmental disorders such as schizophrenia.

Data availability

The datasets utilized or analyzed in this study can be obtained from the corresponding author upon request.

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Acknowledgements

We gratefully acknowledge Dr. Pedro Ismael da Silva Júnior from the LETA Laboratory at the Butantan Institute for his valuable assistance with the HPLC analysis. We also thank animal facilities personnel for the animal care. Additionally, we acknowledge Dr. Fernando Delgado Pretel from the Biomedical Sciences Institute III – CEFAP Facilities at the University of São Paulo for his support in obtaining confocal microscopy images, and Dr. Mario Costa Cruz from the Biomedical Sciences Institute IV – CEFAP Facilities at the University of São Paulo for his assistance in developing the synaptic analysis pipeline. We also thank Professor Alicia Kowaltowski and Camille Caldeira, from the Laboratory of Bioenergetics, Mitochondrial Ion Transport and Redox State at the Institute of Chemistry – University of São Paulo, for their valuable support with the Seahorse analysis.

Funding

This work was funded by: (i) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP): 2015/02041–1 to TRR; 2016/07427-8, 2021/06009-6 to CS, 2016/22996-9 and 2019/12974-6 to EMK; 2021/03021-5 and 2023/14145-2 to AS; 2023-01789-9 to VCA; 2018/13814–0 to LFSS; 2021/12906-0 to MRR. (ii) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq): 403646/2021-9; 472744/2012-7 to PISJ. (iii) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES): CAPES – STINT program 88887.125409/2016-00 (Joint Brazilian-Swedish Research Collaboration and USP Neuroscience Research Support Centers); (iv) University of São Paulo grants (to DZA and LSL).

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Authors and Affiliations

  1. Laboratory of Molecular Neuropharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

    Amanda Siena, E Silva Luiz Felipe Souza, Vitória Cristina Araujo, Martina Raissa Ribeiro, Larissa de Sá Lima, Diana Zukas Andreotti, Ana Maria Orellana, Cristoforo Scavone & Tatiana Rosado Rosenstock

  2. Laboratory of Molecular and Functional Neurobiology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil

    Diana Zukas Andreotti, Ana Maria Orellana & Elisa Mitiko Kawamoto

  3. Laboratory of Applied Toxinology - Butantan Institute, São Paulo, SP, Brazil

    Silva Junior Pedro Ismael

  4. Dept. of Bioscience, In-vitro Neuroscience, Sygnature Discovery, Nottingham, UK

    Tatiana Rosado Rosenstock

Authors
  1. Amanda Siena
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  2. E Silva Luiz Felipe Souza
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  3. Vitória Cristina Araujo
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  9. Silva Junior Pedro Ismael
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  10. Cristoforo Scavone
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Contributions

AS, TRR and CS conceived and designed the experiments. AS, DZA, AMMO, MRR, VCA, LFSS, LSL and PISJ performed the experiments. AS, MRR, LFSS, EMK, PISJ, TRR and CS analyzed the data. AS, LFSS, TRR and CS wrote the paper. All authors reviewed the manuscript.

Corresponding author

Correspondence to Cristoforo Scavone.

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Competing interests

The authors declare no competing interests.

Ethical approval

All animal experiments were performed according to the ARRIVE (Animal Research: Reporting of In vivo Experiments) guidelines. This study was also carried out in accordance with (i) Guidance on the operation of the Animals (Scientific Procedures) Act 1986 and associated guidelines; (ii) EU Directive 2010/63 for the protection of animals used for scientific purposes; (iii) Brazilian Society for Laboratory Animal Science (SBCAL); (iv) the National Council for the Control of Animal Experimentation (CONCEA) law 11794/2008. The methodology was approved by the Ethics Committee from University of São Paulo Biomedical Sciences Institute protocol registered under no. 4482061120 (ID 001756), approved on 01/19/2021, and extended on 01/29/2025 (Of. CEUA. 4482061120 - ID 036313) until January 31, 2027.

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Siena, A., Luiz Felipe Souza, E., Araujo, V.C. et al. Nicotinamide counteracts Rotenone-induced mitochondrial and neuronal dysfunction in a translational early-life model. Sci Rep (2026). https://doi.org/10.1038/s41598-026-36651-7

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  • Received: 20 October 2025

  • Accepted: 14 January 2026

  • Published: 04 February 2026

  • DOI: https://doi.org/10.1038/s41598-026-36651-7

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Keywords

  • Mitochondrial dynamics
  • Cell respiration
  • Dendritic spines
  • Neurodevelopmental disorders
  • Schizophrenia
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