Mitochondria Exert Age-Divergent Effects on Recovery from Spinal Cord Injury

Authors

Andrew N. Stewart, University of KentuckyFollow
Katelyn E. McFarlane, University of Kentucky
Hemendra J. Vekaria, University of KentuckyFollow
William M. Bailey, University of KentuckyFollow
Stacey A. Slone, University of KentuckyFollow
Lauren A. Tranthem, University of KentuckyFollow
Bei Zhang, Weill Cornell Medicine
Samir P. Patel, University of KentuckyFollow
Patrick G. Sullivan, University of KentuckyFollow
John C. Gensel, University of KentuckyFollow

Abstract

The extent that age-dependent mitochondrial dysfunction drives neurodegeneration is not well understood. This study tested the hypothesis that mitochondria contribute to spinal cord injury (SCI)-induced neurodegeneration in an age-dependent manner by using 2,4-dinitrophenol (DNP) to uncouple electron transport, thereby increasing cellular respiration and reducing reactive oxygen species (ROS) production. We directly compared the effects of graded DNP doses in 4- and 14-month-old (MO) SCI-mice and found DNP to have increased efficacy in mitochondria isolated from 14-MO animals. In vivo, all DNP doses significantly exacerbated 4-MO SCI neurodegeneration coincident with worsened recovery. In contrast, low DNP doses (1.0-mg/kg/day) improved tissue sparing, reduced ROS-associated 3-nitrotyrosine (3-NT) accumulation, and improved anatomical and functional recovery in 14-MO SCI-mice. By directly comparing the effects of DNP between ages we demonstrate that mitochondrial contributions to neurodegeneration diverge with age after SCI. Collectively, our data indicate an essential role of mitochondria in age-associated neurodegeneration.

Document Type

Article

Publication Date

1-7-2021

Notes/Citation Information

Published in Experimental Neurology, v. 337, 113597.

© 2021 The Author(s)

This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.expneurol.2021.113597

Funding Information

Funding support provided by: The Craig H. Neilsen Foundation, USA under award #465079, and the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health, USA (NIH) under Awards: RO1NS091582 and F32NS111241.

Repository Citation

Stewart, Andrew N.; McFarlane, Katelyn E.; Vekaria, Hemendra J.; Bailey, William M.; Slone, Stacey A.; Tranthem, Lauren A.; Zhang, Bei; Patel, Samir P.; Sullivan, Patrick G.; and Gensel, John C., "Mitochondria Exert Age-Divergent Effects on Recovery from Spinal Cord Injury" (2021). Physiology Faculty Publications. 168.
https://uknowledge.uky.edu/physiology_facpub/168