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

doi:10.1021/acschemneuro.7b00287

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 journal › Article › peer-review

73 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 language	English
Pages (from-to)	2759-2765
Number of pages	7
Journal	ACS Chemical Neuroscience
Volume	8
Issue number	12
DOIs	https://doi.org/10.1021/acschemneuro.7b00287
State	Published - Dec 20 2017

Bibliographical note

Publisher Copyright:
© 2017 American Chemical Society.

Funding

*Mailing address: One Medical Center Drive, Morgantown, WV 26506. Tel: +1-304-293-7401. E-mail: werner. [email protected]. 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.

Funders	Funder number
Richard Nicely and Glenn and Karen Leppo Parkinson’s Disease Research Funds
Stark Community Foundation Canton
National Institutes of Health (NIH)	P20 GM109098, R01ES021800, K01NS081014
National Institutes of Health (NIH)
National Institute of General Medical Sciences	U54GM104942
National Institute of General Medical Sciences
The Michael J Fox Foundation for Parkinson's Research

Keywords

aging
drug discovery
mitoNEET
mitochondrial dysfunction

ASJC Scopus subject areas

Biochemistry
Physiology
Cognitive Neuroscience
Cell Biology

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10.1021/acschemneuro.7b00287

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

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.",

keywords = "aging, drug discovery, mitoNEET, mitochondrial dysfunction",

author = "Geldenhuys, \{Werner J.\} and Benkovic, \{Stanley A.\} and Li Lin and Yonutas, \{Heather M.\} and Crish, \{Samuel D.\} and Sullivan, \{Patrick G.\} and Darvesh, \{Altaf S.\} and Brown, \{Candice M.\} and Richardson, \{Jason R.\}",

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doi = "10.1021/acschemneuro.7b00287",

language = "English",

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AU - Geldenhuys, Werner J.

AU - Benkovic, Stanley A.

AU - Lin, Li

AU - Yonutas, Heather M.

AU - Crish, Samuel D.

AU - Sullivan, Patrick G.

AU - Darvesh, Altaf S.

AU - Brown, Candice M.

AU - Richardson, Jason R.

PY - 2017/12/20

Y1 - 2017/12/20

N2 - 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.

AB - 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.

KW - aging

KW - drug discovery

KW - mitoNEET

KW - mitochondrial dysfunction

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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