Tags

Type your tag names separated by a space and hit enter

Mitochondrial Uncoupling Protein 2 Knock-out Promotes Mitophagy to Decrease Retinal Ganglion Cell Death in a Mouse Model of Glaucoma.
J Neurosci. 2019 05 01; 39(18):3582-3596.JN

Abstract

Glaucoma is a neurodegenerative disorder characterized by mitochondrial dysfunction and an increase in oxidative damage, leading to retinal ganglion cell (RGC) death. The oxidative status of RGCs is regulated intrinsically and also extrinsically by retinal glia. The mitochondrial uncoupling protein 2 (UCP2) relieves oxidative and neuronal damage in a variety of neurodegenerative disease models. We hypothesized that deletion of Ucp2 in either RGCs or retinal glia would increase retinal damage and RGC death in a mouse model of glaucoma. Paradoxically, we found the reverse, and deletion of mitochondrial Ucp2 decreased oxidative protein modification and reduced RGC death in male and female mice. This paradox was resolved after finding that Ucp2 deletion also increased levels of mitophagy in cell culture and retinal tissue. Our data suggest that Ucp2 deletion facilitates increased mitochondrial function by improving quality control. An increase in mitochondrial function explains the resistance of Ucp2-deleted retinas to glaucoma and may provide a therapeutic avenue for other chronic neurodegenerative conditions.SIGNIFICANCE STATEMENT Many unsolved neurodegenerative conditions result from defects in mitochondrial function. Molecular tools that can manipulate mitochondria will therefore be central to developing neuroprotective therapies. Among the most potent regulators of mitochondrial function are the uncoupling proteins, particularly UCP2. In this manuscript, we show that, while loss of Ucp2 does increase mitochondrial membrane potential and the production of reactive oxygen species, it also initiates an increase in mitophagy that is ultimately neuroprotective. This novel protective consequence of uncoupling protein inhibition may lead to new therapeutic approaches to combat neurodegenerative disease, particularly because pharmacological compounds do exist that can selectively inhibit UCP2.

Authors+Show Affiliations

Department of Neural and Behavioral Sciences, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033.Department of Neural and Behavioral Sciences, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033 cbarnstable@psu.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30814312

Citation

Hass, Daniel T., and Colin J. Barnstable. "Mitochondrial Uncoupling Protein 2 Knock-out Promotes Mitophagy to Decrease Retinal Ganglion Cell Death in a Mouse Model of Glaucoma." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 39, no. 18, 2019, pp. 3582-3596.
Hass DT, Barnstable CJ. Mitochondrial Uncoupling Protein 2 Knock-out Promotes Mitophagy to Decrease Retinal Ganglion Cell Death in a Mouse Model of Glaucoma. J Neurosci. 2019;39(18):3582-3596.
Hass, D. T., & Barnstable, C. J. (2019). Mitochondrial Uncoupling Protein 2 Knock-out Promotes Mitophagy to Decrease Retinal Ganglion Cell Death in a Mouse Model of Glaucoma. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 39(18), 3582-3596. https://doi.org/10.1523/JNEUROSCI.2702-18.2019
Hass DT, Barnstable CJ. Mitochondrial Uncoupling Protein 2 Knock-out Promotes Mitophagy to Decrease Retinal Ganglion Cell Death in a Mouse Model of Glaucoma. J Neurosci. 2019 05 1;39(18):3582-3596. PubMed PMID: 30814312.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial Uncoupling Protein 2 Knock-out Promotes Mitophagy to Decrease Retinal Ganglion Cell Death in a Mouse Model of Glaucoma. AU - Hass,Daniel T, AU - Barnstable,Colin J, Y1 - 2019/02/27/ PY - 2018/11/06/received PY - 2019/02/14/revised PY - 2019/02/15/accepted PY - 2019/3/1/pubmed PY - 2020/6/9/medline PY - 2019/3/1/entrez KW - glaucoma KW - mitochondria KW - mitophagy KW - oxidative stress KW - retina KW - uncoupling protein SP - 3582 EP - 3596 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 39 IS - 18 N2 - Glaucoma is a neurodegenerative disorder characterized by mitochondrial dysfunction and an increase in oxidative damage, leading to retinal ganglion cell (RGC) death. The oxidative status of RGCs is regulated intrinsically and also extrinsically by retinal glia. The mitochondrial uncoupling protein 2 (UCP2) relieves oxidative and neuronal damage in a variety of neurodegenerative disease models. We hypothesized that deletion of Ucp2 in either RGCs or retinal glia would increase retinal damage and RGC death in a mouse model of glaucoma. Paradoxically, we found the reverse, and deletion of mitochondrial Ucp2 decreased oxidative protein modification and reduced RGC death in male and female mice. This paradox was resolved after finding that Ucp2 deletion also increased levels of mitophagy in cell culture and retinal tissue. Our data suggest that Ucp2 deletion facilitates increased mitochondrial function by improving quality control. An increase in mitochondrial function explains the resistance of Ucp2-deleted retinas to glaucoma and may provide a therapeutic avenue for other chronic neurodegenerative conditions.SIGNIFICANCE STATEMENT Many unsolved neurodegenerative conditions result from defects in mitochondrial function. Molecular tools that can manipulate mitochondria will therefore be central to developing neuroprotective therapies. Among the most potent regulators of mitochondrial function are the uncoupling proteins, particularly UCP2. In this manuscript, we show that, while loss of Ucp2 does increase mitochondrial membrane potential and the production of reactive oxygen species, it also initiates an increase in mitophagy that is ultimately neuroprotective. This novel protective consequence of uncoupling protein inhibition may lead to new therapeutic approaches to combat neurodegenerative disease, particularly because pharmacological compounds do exist that can selectively inhibit UCP2. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/30814312/Mitochondrial_Uncoupling_Protein_2_Knock_out_Promotes_Mitophagy_to_Decrease_Retinal_Ganglion_Cell_Death_in_a_Mouse_Model_of_Glaucoma_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=30814312 DB - PRIME DP - Unbound Medicine ER -