MitoNEET (CISD1) Knockout Mice Show Signs of Striatal Mitochondrial Dysfunction and a Parkinson's Disease Phenotype.
*aging; *Disease Models; *drug discovery; *mitochondrial dysfunction; *mitoNEET; Animal; Animals; Corpus Striatum/*metabolism/*pathology; Inbred C57BL; Iron-Binding Proteins/genetics/*metabolism; Knockout; Male; Membrane Proteins/genetics/*metabolism; Mice; Mitochondria/*metabolism/*pathology; Parkinson Disease/*metabolism/pathology
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.
Geldenhuys Werner J; Benkovic Stanley A; Lin Li; Yonutas Heather M; Crish Samuel D; Sullivan Patrick G; Darvesh Altaf S; Brown Candice M; Richardson Jason R
ACS chemical neuroscience
2017
2017-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1021/acschemneuro.7b00287" target="_blank" rel="noreferrer noopener">10.1021/acschemneuro.7b00287</a>
Identification of small molecules that bind to the mitochondrial protein mitoNEET.
*Bioenergetics; *Glitazones; *Mitochondria; *Small Molecule Libraries; *Type II diabetes; Hypoglycemic Agents/chemistry/metabolism; Ligands; Mitochondrial Proteins/*metabolism; Protein Binding; Thiazolidinediones/chemistry/metabolism
MitoNEET (CISD1) is a 2Fe-2S iron-sulfur cluster protein belonging to the zinc-finger protein family. Recently mitoNEET has been shown to be a major role player in the mitochondrial function associated with metabolic type diseases such as obesity and cancers. The anti-diabetic drug pioglitazone and rosiglitazone were the first identified ligands to mitoNEET. Since little is known about structural requirements for ligand binding to mitoNEET, we screened a small set of compounds to gain insight into these requirements. We found that the thiazolidinedione (TZD) warhead as seen in rosiglitazone was not an absolutely necessity for binding to mitoNEET. These results will aid in the development of novel compounds that can be used to treat mitochondrial dysfunction seen in several diseases.
Geldenhuys Werner J; Yonutas Heather M; Morris Daniel L; Sullivan Patrick G; Darvesh Altaf S; Leeper Thomas C
Bioorganic & medicinal chemistry letters
2016
2016-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2016.09.009" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2016.09.009</a>