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Billy X. Pan, Fred N. Ross-Cisneros, Kevin R. Tozer, Alfredo A. Sadun; Mitochondrial Strain Index: Mathematically Modeling the Susceptibility of Optic Nerve Axons in Leber’s Hereditary Optic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4880.
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© ARVO (1962-2015); The Authors (2016-present)
Leber’s Hereditary Optic Neuropathy (LHON) presents with subacute visual loss in patients with point mutations of mitochondrial DNA. The classic clinical manifestations of LHON reflect the initial preferential involvement of the papillomacular bundle. We created a mathematical model that determines a "Mitochondrial Strain Index" (MSI) which is inversely related to axon caliber and quantitatively identifies the risk of involvement of nerve fibers. We hypothesize that as the wave of axonal involvement in LHON spreads, it reflects an orderly progression of axons, starting with those of highest MSI.
6 optic nerves (ON) were studied, with 2 age-matched controls and 4 LHON tissues selected to represent a spectrum of disease severity. Tissues were processed for epoxy resin via standard protocol, semi-thin sections were stained with paraphenylenediamine, and photomicrographs were taken via light microscopy at 1000x oil immersion. Approximately 40,000 axons were hand measured in 32 sectors of each control ON, generating a nerve fiber layer spectrum. The MSI was calculated on the basis of axonal energy requirements (based on membrane cable properties) divided by available mitochondria.
Axonal diameters in the two control ONs ranged from 0.15µm to 7.80µm (SD = 0.68). The axon calibers were much smaller in the temporal half compared to nasal (Generalized Estimating Equations, P ≤ 0.006), and slightly larger in the superior half compared to inferior (P ≤ 0.002). Arrangement of the grids into 6 vertical columns across the ON showed a progressive increase in the axonal diameters temporally to nasally (P ≤ .002, r2 = 0.76). Similar arrangement of the grids into 6 rows showed a larger axonal caliber of the peripheral most fibers superiorly and inferiorly (P ≤ 0.001). The LHON ONs were selected to reflect four stages of disease severity. Analysis of the 32 sectors from these 4 LHON ONs revealed a step-wise loss of fibers starting from those with the highest MSI (Spearman Rank Correlation, P ≤ .001, r2 = 1.00).
The data shows that mitochondrial diseases such as LHON affect axons in an extremely precise order as predicted by the MSI. The smallest axons have the least energetically favorable MSI and are thus the first to become involved.
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