Mitochondrial Cytochrome C Oxidase Expression in the Central Nervous System Is Elevated at Sites of Pressure Gradient Elevation but Not Absolute Pressure Increase Chandrakumar Balaratnasingam, 1 Duy Pham, 1 William H. Morgan, 1 Louise Bass, 2 Stephen J. Cringle, 1 and Dao-Yi Yu 1 * 1 Centre for Ophthalmology and Visual Science and the ARC Centre of Excellence in Vision Science, The University of Western Australia, Perth, Western Australia, Australia 2 Department of Anesthesia, Murdoch University Veterinary Hospital, Perth, Western Australia, Australia The paucity of suitable experimental models has made it difficult to isolate the pathogenic role of mitochondria in central nervous system diseases associated with absolute pressure elevation and increased pressure gradients. Experimental models of traumatic brain injury (TBI) and hydrocephalus have been useful for examin- ing the mitochondrial response following pressure increase in the central nervous system; however, the presence of multiple pathogenic factors acting on the brain in these previous studies has made it difficult to determine whether the induced changes were a result of mechanical damage, intracranial pressure elevation, or other pathogenic factors. By direct monitoring and control of pressures in the intraocular, intracranial, and vascular compartments, we use the pig optic nerve, a typical central white matter tract, to compare the tem- poral sequence of cytochrome c oxidase (CcO) levels between regions of absolute pressure elevation and pressure gradient increase. We demonstrate that a rise in pressure gradient without traumatic injury up-regu- lates CcO levels across the site of the gradient, in a manner similar to what has been previously reported for hydrocephalus. We also demonstrate that CcO changes do not occur following an absolute pressure rise. These findings taken together with our recent reports suggest that mitochondria initiate an early compensatory response to axonal damage following pressure gradient increase. Extrapolation of our results also suggests that decreased CcO levels in TBI may be secondary to mechanical damage. This study emphasises the importance of pressure gradients in regulating mitochondrial function in the central nervous system. V V C 2009 Wiley-Liss, Inc. Key words: axon; CNS; cytochrome c oxidase; mito- chondria; optic nerve; pressure The optic nerve is a compact central white matter tract that is contained within a meningeal sheath and in this regard shares a similarity to neuronal pathways in the brain (Anderson, 1969b). The optic nerve head is exposed to two distinct pressure compartments: the in- traocular pressure compartment and the cerebrospinal fluid (CSF) pressure compartment. We have previously shown that neural tissue pressure in the portion of optic nerve exposed to the intraocular compartment (the prela- minar region) is determined by intraocular pressure (IOP), whereas neural tissue pressure in the portion of optic nerve exposed to the CSF pressure compartment (post laminar region) is determined largely by CSF pres- sure (Morgan et al., 1995, 1998). The pressure difference between prelaminar and postlaminar regions falls across the lamina cribrosa, which is the site where the pressure gradient acting on axonal structures is greatest (Morgan et al., 1995; see Fig. 1). The optic nerve head is therefore an excellent model for simultaneously comparing and sep- arating the effects of absolute pressure increase and pres- sure gradient elevation on CNS structure and function. This study uses cytochrome c oxidase (CcO) as a marker of mitochondrial activity and examines changes Contract grant sponsor: National Health and Medical Research Council of Australia; Contract grant sponsor: Australian Research Council Centre of Excellence in Vision Science. *Correspondence to: Professor Dao-Yi Yu, Centre for Ophthalmology and Visual Science and the ARC Centre of Excellence in Vision Science, The University of Western Australia, Perth, Western Australia, Australia, 6009. E-mail: dyyu–cyllene.uwa.edu.au Received 15 February 2009; Revised 23 March 2009; Accepted 3 April 2009 Published online 12 May 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/jnr.22120 Journal of Neuroscience Research 87:2973–2982 (2009) ' 2009 Wiley-Liss, Inc.