Identification of Cysl-2 as a Compensatory Factor in Vitamin B12-Mediated Protection in a Mitochondrial Aβ Toxicity Model

Abstract

Alzheimer’s disease (AD) is a highly sophisticated disease associated with mitochondrial deterioration, which potentiates proteotoxic stress and accelerates neuronal decline. Vitamin B12 (B12), an essential cofactor in one-carbon metabolism and cellular homeostasis, plays a pivotal role in modulating neurodegenerative pathology. Here, we established a mitochondrial-associated AD model by using Caenorhabditis elegans (C. elegans) expressing Aβ combining with the mtDNA deletion uaDf5, and evaluated the effect of B12 as a metabolic modulator of neurodegenerative stress. We observed that mitochondrial dysfunction markedly exacerbated Aβ phenotypes, while B12 mitigated paralysis and cellular deficits. Integrated transcriptomics and proteomics revealed a compensatory mechanism activated by B12 under mitochondrial stress, predominantly engaging one-carbon and transsulfuration pathways. Functional analyses uncovered that metr-1 and cysl-2 are required for B12-mediated protection, and multiomics corroborated this rescue axis. This study indicates that cysl-2 is an essential mediator and reveals a B12-driven adaptive response, which provides mechanistic insight into nutrition-based neuroprotection in AD.