Olanzapine induces Mdivi-1-resistant disruption of insulin signaling in skeletal muscle cells
10 affiliations
- 1Laboratorio de Fisiología y Bioenergética Celular (LABFBE), Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile
- 2Laboratorio de Investigación en Nutrición y Actividad Física (LABINAF), Instituto de Nutrición y Tecnología de Los Alimentos (INTA), Universidad de Chile
- 3Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile (USACH)
- 4Centro de Biotecnología Acuícola, Universidad de Santiago de Chile (USACH)
- 5Chemical Biology & Drug Discovery Lab, Escuela de Química y Farmacia, Facultad de Ciencias, Universidad San Sebastián
- 6Centro Basal Ciencia & Vida, Fundación Ciencia & Vida
- 7Laboratorio de Obesidad y Metabolismo (OMEGA), Instituto de Nutrición y Tecnología de Los Alimentos (INTA), Universidad de Chile
- 8Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile & Pontificia Universidad Católica de Chile
- 9Centro Interuniversitario de Envejecimiento Saludable (CIES), Consorcio de Universidades del Estado de Chile (CUECH)
- 10International Research Center for Medical Sciences, Kumamoto University
Abstract
Introduction: Second‐generation antipsychotics such as olanzapine (OLZ) are widely prescribed because they produce fewer extrapyramidal adverse effects than first‐generation agents. However, OLZ is strongly associated with metabolic dysfunction, and alterations in mitochondrial dynamics have been proposed to contribute to these effects. We investigated whether OLZ‐induced mitochondrial dysfunction is linked to impaired insulin signaling in skeletal muscle cells and explored a potential interaction with the mitochondrial fission regulator dynamin‐related protein 1 (DRP1).
Methods: L6 skeletal myoblasts were treated with OLZ, alone or in combination with the mitochondrial fission inhibitor Mdivi‐1. Insulin signaling, glucose uptake, mitochondrial morphology, and insulin‐stimulated mitochondrial bioenergetics were evaluated. In parallel, molecular dynamics simulations and MM/PBSA calculations were performed using a common DRP1/Mg ² ⁺ receptor model to compare the interactions of protonated OLZ and Mdivi‐1 within the DRP1 GTPase domain.
Results: OLZ reduced insulin‐mediated signaling and glucose uptake, promoted mitochondrial fragmentation, and impaired the insulin‐induced increase in mitochondrial bioenergetic activity. Co-treatment with Mdivi‐1 partially rescued OLZ‐induced mitochondrial fragmentation but did not restore insulin responsiveness. Molecular simulations showed that protonated OLZ and Mdivi‐1 remained within the same hydrophobic region of the DRP1 GTPase domain and shared an anchoring interaction involving Ile252. Their calculated MM/PBSA interaction free energies were similar (–22.26 ± 1.7 and –24.50 ± 0.5 kcal mol ⁻ ¹ , respectively), supporting compatible occupancy of a shared binding region but not demonstrating high‐affinity or GTP‐competitive binding.
Discussion: These findings indicate that OLZ disrupts mitochondrial dynamics and bioenergetics while decreasing insulin sensitivity in skeletal muscle cells. However, the dissociation between recovery of mitochondrial morphology and persistence of insulin resistance suggests that excessive mitochondrial fission alone does not account for OLZ‐induced metabolic dysfunction. The computational results are compatible with an interaction of OLZ with the DRP1 GTPase domain but do not establish DRP1 as its primary pharmacological target. OLZ‐associated insulin resistance therefore likely involves additional, potentially extramitochondrial mechanisms.
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BibTeX
@article{arias2026olanzapine,
title = {{Olanzapine induces Mdivi-1-resistant disruption of insulin signaling in skeletal muscle cells}},
author = {Pablo Arias and Catalina Salamanca and Fernanda Briones-Manriquez and Lucas Oyaneder and Andrea Marimán and Gonzalo Almarza and Edson Yañez and Juan Rodriguez and Rodrigo Troncoso and Leonel E. Rojo and Carlos F. Lagos and Roberto Bravo-Sagua and Andrea del Campo},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1920978},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1920978/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Olanzapine induces Mdivi-1-resistant disruption of insulin signaling in skeletal muscle cells
AU - Pablo Arias
AU - Catalina Salamanca
AU - Fernanda Briones-Manriquez
AU - Lucas Oyaneder
AU - Andrea Marimán
AU - Gonzalo Almarza
AU - Edson Yañez
AU - Juan Rodriguez
AU - Rodrigo Troncoso
AU - Leonel E. Rojo
AU - Carlos F. Lagos
AU - Roberto Bravo-Sagua
AU - Andrea del Campo
PY - 2026
DA - 2026/10/26
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1920978
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1920978/full
AB - Introduction: Second‐generation antipsychotics such as olanzapine (OLZ) are widely prescribed because they produce fewer extrapyramidal adverse effects than first‐generation agents. However, OLZ is strongly associated with metabolic dysfunction, and alterations in mitochondrial dynamics have been proposed to contribute to these effects. We investigated whether OLZ‐induced mitochondrial dysfunction is linked to impaired insulin signaling in skeletal muscle cells and explored a potential interaction with the mitochondrial fission regulator dynamin‐related protein 1 (DRP1). Methods: L6 skeletal myoblasts were treated with OLZ, alone or in combination with the mitochondrial fission inhibitor Mdivi‐1. Insulin signaling, glucose uptake, mitochondrial morphology, and insulin‐stimulated mitochondrial bioenergetics were evaluated. In parallel, molecular dynamics simulations and MM/PBSA calculations were performed using a common DRP1/Mg ² ⁺ receptor model to compare the interactions of protonated OLZ and Mdivi‐1 within the DRP1 GTPase domain. Results: OLZ reduced insulin‐mediated signaling and glucose uptake, promoted mitochondrial fragmentation, and impaired the insulin‐induced increase in mitochondrial bioenergetic activity. Co-treatment with Mdivi‐1 partially rescued OLZ‐induced mitochondrial fragmentation but did not restore insulin responsiveness. Molecular simulations showed that protonated OLZ and Mdivi‐1 remained within the same hydrophobic region of the DRP1 GTPase domain and shared an anchoring interaction involving Ile252. Their calculated MM/PBSA interaction free energies were similar (–22.26 ± 1.7 and –24.50 ± 0.5 kcal mol ⁻ ¹ , respectively), supporting compatible occupancy of a shared binding region but not demonstrating high‐affinity or GTP‐competitive binding. Discussion: These findings indicate that OLZ disrupts mitochondrial dynamics and bioenergetics while decreasing insulin sensitivity in skeletal muscle cells. However, the dissociation between recovery of mitochondrial morphology and persistence of insulin resistance suggests that excessive mitochondrial fission alone does not account for OLZ‐induced metabolic dysfunction. The computational results are compatible with an interaction of OLZ with the DRP1 GTPase domain but do not establish DRP1 as its primary pharmacological target. OLZ‐associated insulin resistance therefore likely involves additional, potentially extramitochondrial mechanisms.
SN - 1663-9812
ER -