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.
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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.
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.