MitoNEET (CISD1) Knockout Mice Show Signs of Striatal Mitochondrial Dysfunction and a Parkinson's Disease Phenotype

Werner J. Geldenhuys, Stanley A. Benkovic, Li Lin, Heather M. Yonutas, Samuel D. Crish, Patrick G. Sullivan, Altaf S. Darvesh, Candice M. Brown, Jason R. Richardson

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Mitochondrial dysfunction is thought to play a significant role in neurodegeneration observed in Parkinson's disease (PD), yet the mechanisms underlying this pathology remain unclear. Here, we demonstrate that loss of mitoNEET (CISD1), an iron-sulfur containing protein that regulates mitochondrial bioenergetics, results in mitochondrial dysfunction and loss of striatal dopamine and tyrosine hydroxylase. Mitochondria isolated from mice lacking mitoNEET were dysfunctional as revealed by elevated reactive oxygen species (ROS) and reduced capacity to produce ATP. Gait analysis revealed a shortened stride length and decreased rotarod performance in knockout mice, consistent with the loss of striatal dopamine. Together, these data suggest that mitoNEET KO mice exhibit many of the characteristics of early neurodegeneration in PD and may provide a novel drug discovery platform to evaluate compounds for enhancing mitochondrial function in neurodegenerative disorders.

Original languageEnglish
Pages (from-to)2759-2765
Number of pages7
JournalACS Chemical Neuroscience
Volume8
Issue number12
DOIs
StatePublished - Dec 20 2017

Bibliographical note

Funding Information:
*Mailing address: One Medical Center Drive, Morgantown, WV 26506. Tel: +1-304-293-7401. E-mail: werner. geldenhuys@hsc.wvu.edu. ORCID Werner J. Geldenhuys: 0000-0002-2405-376X Author Contributions W.J.G, S.A.B., L.L., H.M.Y., and A.S.D. designed and performed the research; W.J.G. and S.A.B. analyzed the data; W.J.G., S.D.C., P.G.S., C.M.B., and J.R.R. wrote the paper. Funding This study was funded in part by the Richard Nicely and Glenn and Karen Leppo Parkinson’s Disease Research Funds, the Stark Community Foundation Canton, Ohio, USA, and a grant from the Michael J. Fox Foundation (W.J.G.). The project was also supported by NIH Grants U54GM104942 and P20 GM109098 (W.J.G. and C.M.B.), K01NS081014 (C.M.B.), and R01ES021800 (J.R.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or any other funder. Notes The authors declare no competing financial interest.

Publisher Copyright:
© 2017 American Chemical Society.

Keywords

  • aging
  • drug discovery
  • mitoNEET
  • mitochondrial dysfunction

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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