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Dusp26 phosphatase regulates mitochondrial respiration and oxidative stress and protects neuronal cell death

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Abstract

The dual specificity protein phosphatases (Dusps) control dephosphorylation of mitogen-activated protein kinases (MAPKs) as well as other substrates. Here, we report that Dusp26, which is highly expressed in neuroblastoma cells and primary neurons is targeted to the mitochondrial outer membrane via its NH2-terminal mitochondrial targeting sequence. Loss of Dusp26 has a significant impact on mitochondrial function that is associated with increased levels of reactive oxygen species (ROS), reduction in ATP generation, reduction in mitochondria motility and release of mitochondrial HtrA2 protease into the cytoplasm. The mitochondrial dysregulation in dusp26-deficient neuroblastoma cells leads to the inhibition of cell proliferation and cell death. In vivo, Dusp26 is highly expressed in neurons in different brain regions, including cortex and midbrain (MB). Ablation of Dusp26 in mouse model leads to dopaminergic (DA) neuronal cell loss in the substantia nigra par compacta (SNpc), inflammatory response in MB and striatum, and phenotypes that are normally associated with Neurodegenerative diseases. Consistent with the data from our mouse model, Dusp26 expressing cells are significantly reduced in the SNpc of Parkinson’s Disease patients. The underlying mechanism of DA neuronal death is that loss of Dusp26 in neurons increases mitochondrial ROS and concurrent activation of MAPK/p38 signaling pathway and inflammatory response. Our results suggest that regulation of mitochondrial-associated protein phosphorylation is essential for the maintenance of mitochondrial homeostasis and dysregulation of this process may contribute to the initiation and development of neurodegenerative diseases.

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Acknowledgements

Authors wish to thank Erin Eroglu for technical assistance. We also thank Drs. B. Lokeshwar and A. Terry and S. Naughton for providing valuable materials.

Funding

Research was supported by grants from NIHCA062130 and NIHCA132640 and in part by VA Merit Award 1I01BX000161 (NFM).

Author information

Author notes

  1. Sadiki Deane

    Present address: Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA

  2. Bahadır Öztürk

    Present address: Medical Biochemistry Department, Selcuk University Medical Faculty, Konya, Turkey

  3. Binnur Eroglu and **ongjie ** contributed equally to this work.

Authors and Affiliations

  1. Molecular Chaperone Biology, Georgia Cancer Center, Medical College of Georgia at Augusta University, 1120 15th St., CN3153, Augusta, GA, 30912, USA

    Binnur Eroglu, **ongjie **, Sadiki Deane, Bahadır Öztürk, Demetrius Moskophidis & Nahid F. Mivechi

  2. Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL, 32224, USA

    Owen A. Ross

  3. Department of Medicine, Medical College of Georgia at Augusta University, 1120 15th St., CN3153, Augusta, GA, 30912, USA

    Demetrius Moskophidis

  4. Departments of Radiation Oncology, Medical College of Georgia at Augusta University, 1120 15th St., CN3153, Augusta, GA, 30912, USA

    Nahid F. Mivechi

  5. Charlie Norwood VAMC, One Freedom Way, Augusta, GA, 30904, USA

    Nahid F. Mivechi

Authors
  1. Binnur Eroglu
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  2. **ongjie **
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  3. Sadiki Deane
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  4. Bahadır Öztürk
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  5. Owen A. Ross
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  6. Demetrius Moskophidis
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  7. Nahid F. Mivechi
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Contributions

BE performed experiments and analyzed data. XJ generated the mouse model and performed experiments and analyzed data and wrote the manuscript. SD, BO performed initial experiments. OAR analyzed data, DM and NFM, discuss results, designed experiments and wrote the manuscript.

Corresponding authors

Correspondence to Demetrius Moskophidis or Nahid F. Mivechi.

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Conflict of interest

Authors declare no financial or non-financial interest.

Ethical approval

All experiments involving mice were approved by Augusta University Institutional Animal Care and Use Committee (IACUC) in compliance with National Institutes of Health (NIH) guidelines.

Human subject

Tissue specimens were generously provided by the NIH NeuroBank and Brain Tissue Repository. The materials were deidentified bio-specimens.

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Not applicable.

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Eroglu, B., **, X., Deane, S. et al. Dusp26 phosphatase regulates mitochondrial respiration and oxidative stress and protects neuronal cell death. Cell. Mol. Life Sci. 79, 198 (2022). https://doi.org/10.1007/s00018-022-04162-z

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  • DOI: https://doi.org/10.1007/s00018-022-04162-z

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