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K. G. Sheets, W. C. Gordon, N. G. Bazan; Changes in Photoreceptor Mitochondrial Translocase System Induced by Light Damage Are Prevented by LAU-0901. Invest. Ophthalmol. Vis. Sci. 2007;48(13):636.
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We have shown that photoreceptor mitochondria exhibit early response to intense light and treatment with neuroprotective LAU-0901 induces survival during light damage (Cortina et al, Exp Eye Res, 2005; 81:742). Cell survival signaling recruits anti-apoptotic Bcl-2 family members which are inserted into mitochondrial outer membranes by components of the Translocase Outer Membrane (TOM) complex. Here, we asked if LAU treatment could alter the mitochondrial protein import complex.
Sprague-Dawley rats were given LAU (i.p.) or vehicle and subjected to 5 h fluorescent light (18 kLx) 2 h after injection. After light exposure left retinas were extracted for Western blot; right eyes were collected and prepared for immunohistochemistry. Protein expression of TOM20 and TOM70 was performed by Western blot analysis and immunolocalization was performed.
Western blots revealed a >1.5-fold increase in TOM20 expression of both vehicle and non-treated animals compared to controls, while LAU treatment showed no difference. TOM70 expression showed no significant change throughout. TOM20 immunolocalization in controls showed dense labeling in photoreceptor inner segments and diffuse labeling throughout the ONL. However, after 5 h light damage, untreated animals showed a loss of TOM20 label in inner segments and an increase in ONL. TOM70 immunolocalization in dark controls showed a distribution pattern similar to TOM20, but showed no changes with light damage.
Mitochondrial protein import by the TOM complex is accomplished through two pathways, loop targeting sequences directed by TOM70 and n-terminal targeting sequences directed by TOM20. TOM20 performs the additional role of inserting membrane-anchored proteins (e.g. BAX) directly into mitochondrial outer membrane. We have shown here that TOM20 expression increases with light damage whereas TOM70 does not. This shift in TOM20/ TOM70 balance represents a change in the type of proteins imported, for example, increased insertion of membrane-anchored proteins. Additionally, mitochondria throughout the retina differentially respond to damaging light; TOM20 levels in ellipsoid mitochondria decrease while those in photoreceptor perinuclear (ONL) mitochondria increase. We suggest that changes in TOM20 are coupled to apoptosis because LAU prevents alterations in TOM20 and photoreceptor death. Thus light-induced oxidative stress initiates changes within mitochondria that rapidly alter the mechanism of the TOM complex, implying a close link between mitochondrial protein import and photoreceptor apoptosis.
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