TY - JOUR
T1 - Mitochondria exert age-divergent effects on recovery from spinal cord injury
AU - Stewart, Andrew N.
AU - McFarlane, Katelyn E.
AU - Vekaria, Hemendra J.
AU - Bailey, William M.
AU - Slone, Stacey A.
AU - Tranthem, Lauren A.
AU - Zhang, Bei
AU - Patel, Samir P.
AU - Sullivan, Patrick G.
AU - Gensel, John C.
N1 - Publisher Copyright:
© 2021 The Author(s)
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - Bioenergetics
KW - Metabolism
KW - Mitochondrial Uncouplers
KW - Mitochondrial oxidative damage
KW - Neuroprotection
KW - Secondary injury
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UR - http://www.scopus.com/inward/citedby.url?scp=85099263534&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2021.113597
DO - 10.1016/j.expneurol.2021.113597
M3 - Article
C2 - 33422552
AN - SCOPUS:85099263534
SN - 0014-4886
VL - 337
JO - Experimental Neurology
JF - Experimental Neurology
M1 - 113597
ER -