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Enhanced Endocytosis, Mitochondrial Stress and NK/NKT Cells Mediated Immune Response Underlie Severe Retinitis Pigmentosa with RHO P347L Mutants

ABSTRACT: Abstract Purpose: Rhodopsin (RHO) is the initiator of phototransduction and the most frequent cause of autosomal dominant retinitis pigmentosa (adRP). While Class 1 RHO mutations cause a more severe phenotype than Class 2, the underlying pathogenesis remains poorly defined. This study investigates the mechanistic basis for this disparity using cell models and humanized mouse models of Class 1 (P347L) and Class 2 (L125R) mutations. Methods: We first analyzed the localization, degradation and downstream pathway of wild-type (WT) and mutant rhodopsin in 293T cells overexpressing the corresponding plasmids. Then we used humanized mouse models to conduct a side-by-side comparison of mitochondrial dysfunction, photoreceptor death, and neuroinflammation in vivo. Results: Unlike WT rhodopsin, the P347L mutant exhibited plasma membrane localization in a non-polarized manner, whereas the L125R mutant showed partial trafficking to the membrane. Correspondingly, the degradation of P347L was primarily mediated by the lysosomal pathway, while L125R was processed through both proteasomal and lysosomal pathways. The P347L mutant demonstrated a propensity to bind visual arrestin, potentially explaining its observed higher rate of endocytosis. In vivo, the P347L model displayed more severe mitochondrial dysfunction. However, both mutants induced a comparable level of neuroinflammation, characterized by the activation of microglia, natural killer (NK) cells, and natural killer T (NKT) cells. Conclusions: We propose a pathogenic model in which elevated endocytosis and mitochondrial impairment directly underlie the severe RP in P347L mutants, with neuroinflammation serving to amplify the initial insult.

ORGANISM(S): Mus musculus

PROVIDER: GSE313062 | GEO | 2026/07/22

REPOSITORIES: GEO

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Project description:Mitochondrial abnormalities are commonly associated with aging-related degenerative disease and the atrophy of tissues including muscle and brain. Whether bioenergetic defect is the sole pathogenic factor has been long questioned. Lysosomal damage is another hallmark of degenerative disease. However, it is unknown whether these two pathogenic pathways affect tissue homeostasis independently, convergently or epistatically. Here, we show that mitochondrial protein import stress, which can be induced by many forms of mitochondrial injuries, causes structural and functional damage to the yeast vacuole and its mouse counterpart, the lysosome. This effect is independent of bioenergetic defects and the production of reactive oxygen species. We found that unimported mitochondrial proteins are targeted to the vacuole for degradation in yeast. Overloading by these proteins causes V-ATPase disassembly, and vacuolar deacidification, fragmentation and membrane permeabilization. In a mouse model of mitochondrial protein import stress and muscle atrophy induced by overloading of the mitochondrial protein ANT1, genes involved in amino acid uptake/biosynthesis, one-carbon metabolism, nucleotide biosynthesis, lysosomal biogenesis and iron homeostasis are activated. These signatures are recapitulated in yeast mutants of severe vacuolar damage. Supporting lysosomal dysfunction, the Ant1-transgenic muscles accumulate glycogens, lipofuscins and poorly processed multiple vesicle bodies. Multiple lysosomal repair and lysophagic pathways are activated. Luminal proteolytic enzymes including cathepsins are released into the cytosol, which likely contributes to imbalanced cellular proteostasis, reduced myofiber size and progressive muscle atrophy. In summary, we show an evolutionarily conserved pathway wherein mitochondrial defect can epistatically cause proteostatic damage to the lysosome thereby leading to tissue atrophy. This finding could help the better understanding of how the mitochondrial and lysosomal pathways of pathogenesis interact to cause degenerative disease.

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Enhanced Endocytosis, Mitochondrial Stress and NK/NKT Cells Mediated Immune Response Underlie Severe Retinitis Pigmentosa with RHO P347L Mutants

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