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.
Highlights
Metabolic processes shift throughout a lifespan as an inevitable consequence of aging (a thorough review of how aging affects brain metabolism can be found in Mattson and Arumugam (2018))
By directly comparing the effects of DNP between ages we demonstrate that mitochondrial contributions to neurodegeneration diverge with age after spinal cord injury (SCI)
We first set out to determine if age and SCI affect mitochondrial function
Summary
Metabolic processes shift throughout a lifespan as an inevitable consequence of aging (a thorough review of how aging affects brain metabolism can be found in Mattson and Arumugam (2018)). Mitochondria are the primary producers of energy and play vital roles in maintaining health and homeostasis of cellular functions. It is, not surprising that mitochondrial dysfunction significantly contributes to aging and disease progression (Gruber et al, 2008; Sri vastava, 2017). In excess how ever, increases in ROS drive pathophysiological processes such as pro tein and lipid oxidation that can induce senescence and accelerate disease pathology (Birla et al, 2020; Cherubini et al, 2020; Hall et al, 2015; Ricke et al, 2020; Saxena et al, 2019; Zhang et al, 2019)
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