Biology subjects

Fry, M. Y.

Publications and source records attributed to Fry, M. Y..

3 recordsLinked to original sources

bioRxiv2024

Loss of SARM1 protects against retinal ganglion cell degeneration in Autosomal Dominant Optic Atrophy

Autosomal Dominant Optic Atrophy (ADOA), the most prevalent inherited optic neuropathy, leads to retinal ganglion cell (RGC) degeneration and vision loss. ADOA is primarily caused by mutations in the 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. Here, we present a novel mouse model carrying the pathogenic Opa1R290Q/+ allele that recapitulates key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC functions. We identify SARM1, a neurodegeneration switch, as a key driver of RGC degeneration in these mice. Sarm1 knockout nearly completely suppresses all the degeneration phenotypes. Additionally, we show that SARM1 is located within the mitochondrial intermembrane space (IMS). These findings indicate that SARM1 is activated downstream of mitochondrial dysfunction in ADOA, highlighting it as a promising therapeutic target.

neuroscience↗

bioRxiv2023

In situ architecture of Opa1-dependent mitochondrial cristae remodeling

Cristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to lack of native three-dimensional views of cristae. We perform in situ cryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe a variety of cristae shapes with distinct trends dependent on s-Opa1:l-Opa1 balance. Increased l-Opa1 levels promote cristae stacking and elongated mitochondria while increased s-Opa1 levels correlated with irregular cristae packing and round mitochondria shape. Functional assays indicate a role for l-Opa1 in wild-type apoptotic and calcium handling responses, and compromised respiratory function under Opa1 imbalance. In summary, we provide three-dimensional visualization of cristae architecture to reveal relationships between mitochondrial ultrastructure and cellular function dependent on Opa1-mediated membrane remodeling. HighlightsO_LIIn situ ultrastructural characterization of mitochondrial cristae with different forms of Opa1. C_LIO_LIMitochondria with predominantly l-Opa1 show crista stacking, longer cristae, reduced globular cristae and an absence of tubular cristae. C_LIO_LIMitochondria with mostly s-Opa1 showed irregular cristae packing with wider cristae junctions and narrower cristae. C_LIO_LIl-Opa1 expressing cells with WT-like cristae junction properties, show wild-type apoptotic response and calcium handling. C_LIO_LIImbalance in Opa1 processing show compromised respiratory function and an increase in amorphous cristae. C_LI

biophysics↗

bioRxiv2019

The client-binding domain of the cochaperone SGTA/Sgt2 has a helical-hand structure that binds a short hydrophobic helix

The targeting and insertion of tail-anchored (TA) integral membrane proteins (IMP) into the correct membrane is critical for cellular homeostasis. The fungal protein Sgt2, and its human homolog SGTA, binds hydrophobic clients and is the entry point for targeting of ER-bound TA IMPs. Here we reveal molecular details that underlie the mechanism of Sgt2 binding to TA IMP clients. We establish that the Sgt2 C-terminal region is flexible but conserved and sufficient for client binding. A molecular model for this domain reveals a helical hand forming a hydrophobic groove, consistent with a higher affinity for TA IMP clients with hydrophobic faces and a minimal length of 11 residues. This work places Sgt2 into a broader family of TPR-containing co-chaperone proteins.

biochemistry↗