SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy
Chen Ding, … , Michael Tri H. Do, Thomas L. Schwarz
Chen Ding, … , Michael Tri H. Do, Thomas L. Schwarz
Published May 9, 2025
Citation Information: J Clin Invest. 2025;135(12):e191315. https://doi.org/10.1172/JCI191315.
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Research Article Cell biology Neuroscience

SARM1 loss protects retinal ganglion cells in a mouse model of autosomal dominant optic atrophy

Abstract

Autosomal dominant optic atrophy (ADOA), the most prevalent hereditary optic neuropathy, leads to retinal ganglion cell (RGC) degeneration and vision loss. ADOA is primarily caused by mutations in the optic atrophy type 1 (OPA1) gene, which encodes a conserved GTPase important for mitochondrial inner membrane dynamics. To date, the disease mechanism remains unclear, and no therapies are available. We generated a mouse model carrying the pathogenic Opa1R290Q/+ allele that recapitulated key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC functions. We identified sterile alpha and TIR motif containing 1 (SARM1), a neurodegeneration switch, as a key driver of RGC degeneration in these mice. Sarm1 KO nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation. Additionally, we show that a portion of SARM1 localized within the mitochondrial intermembrane space. These findings indicated that SARM1 was activated downstream of mitochondrial dysfunction in ADOA, highlighting it as a promising therapeutic target.

Authors

Chen Ding, Papa S. Ndiaye, Sydney R. Campbell, Michelle Y. Fry, Jincheng Gong, Sophia R. Wienbar, Whitney Gibbs, Philippe Morquette, Luke H. Chao, Michael Tri H. Do, Thomas L. Schwarz

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Figure 1

The Opa1R290Q/+ mutation impairs mitochondrial morphology and cristae structure.

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The Opa1R290Q/+ mutation impairs mitochondrial morphology and cristae st...
(A) Mouse OPA1 domains (90). MTS, mitochondrial targeting sequence; TM, transmembrane domain; B, bundle signaling element. Schematic was created with BioRender. (B) Representative images of mitochondria in cortical neurons, glial cells, and fibroblasts isolated from Opa1R290Q/+ mice and WT littermate controls. Scale bars: 10 μm. (C) Quantification of mitochondrial length in cortical neurons (n = 16 WT neurons and 15 Opa1R290Q/+ neurons from 2 cultures), glia (n = 51 WT glia and 23 Opa1R290Q/+ glia from 1 culture), and fibroblasts (n = 39 WT cells from 2 experiments and 23 Opa1R290Q/+ cells from 3 experiments). (D) Opa1R290Q/+ fibroblasts grew at a slower rate than did the WT control (n = 6 wells per genotype). Data indicate the mean ± SEM. (E) Fibroblasts GSH/GSSG ratios measured by LC-MS/MS. n = 6 samples per genotype from 2 experiments. redox, reduction-oxidation. (F and G) Representative summed projections of the central slices of cryo-electron tomograms of mitochondria (F) and corresponding 3D segmentations of the entire stack (G). In the Opa1R290Q/+ cell, the OMM (purple in G) has fused, while the IMMs (blue and pink in G) remains separate. Scale bars: 100 nm. (H) Percentage of mitochondria with fused OMM but unfused IMM. The numbers of stalled-fusion/total mitochondria are indicated. (I) Percentage of WT mitochondria (n = 50 WT and 64 Opa1R290Q/+) displaying stacked cristae. (J) Classification of cristae morphology (n = 362 WT and n = 337 Opa1R290Q/+ cristae). (K–M) The highest-frequency values for OMM-IMM distance (K), cristae angle relative to the OMM (L), and cristae curvedness (M) (n = 19 WT and 22 Opa1R290Q/+ mitochondria). Box plots denote minimum, first quartile, median, third quartile, and maximum values. *P < 0.05, **P < 0.01, and ****P < 0.0001 by Mann-Whitney U test (C, E, and K–M) and 2-way ANOVA with Šidák’s multiple-comparison test (D). ctrl, control; mito, mitochondria.