The first two authors contributed equally to this study.
Differential effects of the mitochondrial uncoupling agent, 2,4-dinitrophenol, or the nitroxide antioxidant, Tempol, on synaptic or nonsynaptic mitochondria after spinal cord injury
Article first published online: 15 AUG 2008
Copyright © 2008 Wiley-Liss, Inc.
Journal of Neuroscience Research
Volume 87, Issue 1, pages 130–140, January 2009
How to Cite
Patel, S. P., Sullivan, P. G., Pandya, J. D. and Rabchevsky, A. G. (2009), Differential effects of the mitochondrial uncoupling agent, 2,4-dinitrophenol, or the nitroxide antioxidant, Tempol, on synaptic or nonsynaptic mitochondria after spinal cord injury. J. Neurosci. Res., 87: 130–140. doi: 10.1002/jnr.21814
- Issue published online: 16 DEC 2008
- Article first published online: 15 AUG 2008
- Manuscript Accepted: 16 MAY 2008
- Manuscript Revised: 8 MAY 2008
- Manuscript Received: 27 MAR 2008
- Kentucky Spinal Cord and Head Injury Research Trust. Grant Numbers: 3-11, NS 048191
- electron transport system;
- mitochondrial bioenergetics;
- mitochondrial membrane potential (ΔΨ);
- mitochondrial permeability transition;
- oxidative damage
We recently documented the progressive nature of mitochondrial dysfunction over 24 hr after contusion spinal cord injury (SCI), but the underlying mechanism has not been elucidated. We investigated the effects of targeting two distinct possible mechanisms of mitochondrial dysfunction by using the mitochondrial uncoupler 2,4-dinitrophenol (2,4-DNP) or the nitroxide antioxidant Tempol after contusion SCI in rats. A novel aspect of this study was that all assessments were made in both synaptosomal (neuronal)- and nonsynaptosomal (glial and neuronal soma)-derived mitochondria 24 hr after injury. Mitochondrial uncouplers target Ca2+ cycling and subsequent reactive oxygen species production in mitochondria after injury. When 2,4-DNP was injected 15 and 30 min after injury, mitochondrial function was preserved in both populations compared with vehicle-treated rats, whereas 1 hr postinjury treatment was ineffective. Conversely, targeting peroxynitrite with Tempol failed to maintain normal bioenergetics in synaptic mitochondria, but was effective in nonsynaptic mitochondria when administered 15 min after injury. When administered at 15 and 30 min after injury, increased hydroxynonenal, 3-NT, and protein carbonyl levels were significantly reduced by 2,4-DNP, whereas Tempol only reduced 3-NT and protein carbonyls after SCI. Despite such antioxidant effects, only 2,4-DNP was effective in preventing mitochondrial dysfunction, indicating that mitochondrial Ca2+ overload may be the key mechanism involved in acute mitochondrial damage after SCI. Collectively, our observations demonstrate the significant role that mitochondrial dysfunction plays in SCI neuropathology. Moreover, they indicate that combinatorial therapeutic approaches targeting different populations of mitochondria holds great potential in fostering neuroprotection after acute SCI. © 2008 Wiley-Liss, Inc.