Mitochondria exert age-divergent effects on recovery from spinal cord injury.

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.

• Authors: Andrew N Stewart, Katelyn E McFarlane, Hemendra J Vekaria, William M Bailey, Stacey A Slone, Lauren A Tranthem, Bei Zhang, Samir P Patel, Patrick G Sullivan, John C Gensel
• Journal: Experimental neurology (Exp Neurol) Vol. 337 Pg. 113597 (03 2021) ISSN: 1090-2430 [Electronic] United States
• PMID: 33422552 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Reactive Oxygen Species
• Uncoupling Agents
• 3-nitrotyrosine
• Tyrosine
• 2,4-Dinitrophenol

Topics

• 2,4-Dinitrophenol (pharmacology)
• Aging
• Animals
• Cell Survival
• Disease Progression
• Female
• Mice
• Mice, Inbred C57BL
• Mitochondria (metabolism)
• Neurodegenerative Diseases (etiology, pathology)
• Neurons (pathology)
• Oxidative Stress
• Oxygen Consumption
• Reactive Oxygen Species (metabolism)
• Recovery of Function
• Spinal Cord Injuries (complications, pathology)
• Tyrosine (analogs & derivatives, metabolism)
• Uncoupling Agents (pharmacology)