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

• Published in: Experimental neurology Vol. 337; p. 113597
• Main Authors: 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., Gensel, John C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2021
• Subjects: Bioenergetics; Metabolism; Mitochondrial oxidative damage; Mitochondrial Uncouplers; Neuroprotection; Secondary injury; Secondary injury; Neuroprotection; Mitochondrial oxidative damage; Bioenergetics; Metabolism; Mitochondrial Uncouplers
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2021.113597

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. •Aging worsens spinal cord lesions by increasing reactive oxygen species damage.•Aging differentially affects mitochondrial response to uncoupling after spinal injury.•Treatment with dinitrophenol exerts age-divergent responses after spinal injury.•Dinitrophenol is toxic to 4-month old mice but protective to 14-month old mice.