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

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

doi:10.1016/j.expneurol.2021.113597

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

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

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

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.

Original language	English
Article number	113597
Journal	Experimental Neurology
Volume	337
DOIs	https://doi.org/10.1016/j.expneurol.2021.113597
State	Published - Mar 2021

Bibliographical note

Funding Information:
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 . Additional thanks are given to the University of Kentucky's interdepartmental Applied Statistics Laboratory for statistical support.

Funding Information:
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. Additional thanks are given to the University of Kentucky's interdepartmental Applied Statistics Laboratory for statistical support.

Publisher Copyright:
© 2021 The Author(s)

Keywords

Bioenergetics
Metabolism
Mitochondrial Uncouplers
Mitochondrial oxidative damage
Neuroprotection
Secondary injury

ASJC Scopus subject areas

Neurology
Developmental Neuroscience

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10.1016/j.expneurol.2021.113597

Cite this

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title = "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.",

keywords = "Bioenergetics, Metabolism, Mitochondrial Uncouplers, Mitochondrial oxidative damage, Neuroprotection, Secondary injury",

author = "Stewart, {Andrew N.} and McFarlane, {Katelyn E.} and Vekaria, {Hemendra J.} and Bailey, {William M.} and Slone, {Stacey A.} and Tranthem, {Lauren A.} and Bei Zhang and Patel, {Samir P.} and Sullivan, {Patrick G.} and Gensel, {John C.}",

note = "Funding Information: 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 . Additional thanks are given to the University of Kentucky's interdepartmental Applied Statistics Laboratory for statistical support. Funding Information: 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. Additional thanks are given to the University of Kentucky's interdepartmental Applied Statistics Laboratory for statistical support. Publisher Copyright: {\textcopyright} 2021 The Author(s)",

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doi = "10.1016/j.expneurol.2021.113597",

language = "English",

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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 - Funding Information: 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 . Additional thanks are given to the University of Kentucky's interdepartmental Applied Statistics Laboratory for statistical support. Funding Information: 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. Additional thanks are given to the University of Kentucky's interdepartmental Applied Statistics Laboratory for statistical support. Publisher Copyright: © 2021 The Author(s)

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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.

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KW - Metabolism

KW - Mitochondrial Uncouplers

KW - Mitochondrial oxidative damage

KW - Neuroprotection

KW - Secondary injury

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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