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Show Letters to the Editor ROS-induced apoptosis over bioenergetics. But let us remember that ROS are necessary, and most likely, it is only when the ROS are out of balance within the signaling systems and cross a critical threshold, that they induce apoptosis of the RGC. Alfredo A. Sadun, MD, PhD Rustum Karanjia, MD, PhD Department of Ophthalmology, David Geffen School of Medicine, Doheny Eye Centers, UCLA, Los Angeles, California Billy X. Pan, MD Fred N. Ross-Cisneros, BSc Doheny Eye Institute, Los Angeles, California Valerio Carelli, MD, PhD Department of Neurological Sciences, University of Bologna, Bologna, Italy The authors report no conflicts of interest. Reactive Oxygen Species in Mitochondrial Optic Neuropathies: Response I am grateful for the kind words of Dr. Sadun and colleagues agreeing with the suggestions made in my article with respect to Leber hereditary optic neuropathy (LHON). They make a seminal point with respect to the spread of injury in LHON, and the critical need to understand how it could occur. We are currently attempting to model this mathematically and try to explain why the injury in some optic nerve diseases spreads differently than in others. We look forward to further work in this area. With respect to the role of ATP deficiency vs superoxide signaling, the confusion probably arose because in their 2012 article (1), they explain the preferential involvement of the papillomacular bundle in LHON using the nerve fiber layer stress index, an energy-related measure. Specifically, they wrote: "The NFL-SI equation described by Sadun et al condenses down to the ratio of demand vs supply, . . .whereby the numerator reflects all the factors that require high-energy supply by the axon and the denominator, the source of that energy." It was 1 year later, in their excellent 2013 review (2) (not their reference 3) that they include the role of reactive 446 REFERENCES 1. Levin LA. Superoxide generation explains common features of optic neuropathies associated with cecocentral scotomas. J Neuroophthalmol. 2015;35:152-160. 2. Pan BX, Ross-Cisneros FN, Carelli V, Rue KS, Salomao SR, MoraesFilho MN, Moraes MN, Berezovsky A, Belfort R, Sadun AA. Mathematically modeling the involvement of axons in Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2012;53:7608-7617. 3. Sadun AA, La Morgia C, Carelli V. Mitochondrial optic neuropathies: additional facts and concepts-response. Clin Ophthalmol Exp. 2014;42:207-208. 4. Sadun AA, Win PH, Ross-Cisneros FN, Walker SO, Carelli V. Leber's hereditary optic neuropathy differentially affects smaller axons in the optic nerve. Trans Am Ophthalmol Soc. 2000;98:223-232; discussion 32-5. 5. Cortopassi G, Wang E. Modelling the effects of age-related mtDNA mutation accumulation; complex I deficiency, superoxide and cell death. Biochim Biophys Acta. 1995;1271:171-176. 6. Miller NR. Developing a human clinical trial from a scientific hypothesis. J Neuroophthalmol. 2015;35:160-161. 7. Lin CS, Sharpley MS, Fan W, Waymire KG, Sadun AA, Carelli V, Ross-Cisneros FN, Bacin P, Sung E, McManes MJ, Bx Pan, Gil DW, Macgregor GR, Wallace DC. Mouse mtDNA mutant model of Leber hereditary optic neuropathy. Proc Natl Acad Sci U S A. 2012;109:20065-20070. oxygen species signaling. I obviously agree with their more recent article, which matches our hypothesis first stated in 2007 (3). That said, the overwhelming impact of Dr. Sadun and colleagues' contributions in LHON far outweighs any small historical differences, and the most important issue is that we are converging on an exciting mechanism for LHON and possibly other optic neuropathies. Leonard A. Levin, MD, PhD McGill University, Montreal, Canada University of Wisconsin, Madison, WI The author reports no conflicts of interest. REFERENCES 1. Pan BX, Ross-Cisneros FN, Carelli V, Rue KS, Salomao SR, Moraes-Filho MN, Moraes MN, Berezovsky A, Belfort R, Sadun AA. Mathematically modeling the involvement of axons in Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2012;53:7608-7617. 2. Sadun AA, La Morgia C, Carelli V. Mitochondrial optic neuropathies: our travels from bench to bedside and back again. Clin Exp Ophthalmol. 2013;41:702-712. 3. Levin LA. Mechanisms of retinal ganglion specific-cell death in Leber hereditary optic neuropathy. Trans Am Ophthalmol Soc. 2007;105:379-391. Letters to the Editor: J Neuro-Ophthalmol 2015; 35: 444-446 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |