Dietary cobalt oxide nanoparticles alleviate aging through activation of mitochondrial UPR in Caenorhabditis elegans

This is the authors' abstract. We don't add key points for this paper.

Mitochondrial unfolded protein response (UPR mt ), which is a mitochondrial proteostasis pathway, orchestrates an adaptive reprogramming for metabolism homeostasis and organismal longevity. Similar to other defense systems, compromised UPR mt is a feature of several age-related diseases. Here we report that dimercapto succinic acid (DMSA)-modified cobalt oxide nanoparticles (Co3O4 NPs), which have received wide-spread attention in biomedical fields, is a promising UPR mt activator and, more importantly, provides a gate for extending healthy lifespan. Methods: UPR mt activation by Co3O4 NPs was tested in transgenetic Caenorhabditis elegans (C. elegans) specifically expressing UPR mt reporter Phsp-6::GFP, and the underlying mechanism was further validated by mitochondrial morphology, mtDNA/nDNA, metabolism-related genes' expression, mitonuclear protein imbalance, oyxgen assumption and ATP level in C. elegans. Then therapeutic response aganist senescence was monitored by lifespan analysis, lipofusin contents, MDA contents, Fe accumulation, pharyngeal locomotion performance as well as athletic ability (head thrashes and body bends) at different developmental stages of C. elegans. RNAi towards ubl-5 or atfs-1 in UPR mt pathway was applied to clarify the role of UPR mt in Co3O4 NPs -mediated anti-aging effects. Finally, the effect of Co3O4 NPs on mitochondrial homeostasis and D-galactose-induced cell viability decline in mammalian cells were studied. Results: Co3O4 NPs was revealed as a bona fide activator of the UPR mt signaling pathway, through fine-tuning mitochondrial dynamics and inducing a stoichiometric imbalance between OXPHOS subunits encoded by mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) at early life stage of C. elegans. Phenotypically, Co3O4 NPs treatment protect C. elegans from external stresses. More importantly, dietary low level of Co3O4 NPs effectively extend lifespan and alleviate aging-related physiological and functional decline of worms, demonstrating its potential roles in delaying aging. While the protective effect exerted by Co3O4 NPs was compromised in line with atfs-1 or ubl-5 RNAi treatment. Further studies verified the conservation of Co3O4 NPs in activating UPR mt and exerting protective effects in mammalian cells.