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

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 UPRmt 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 UPRmt activator and, more importantly, provides a gate for extending healthy lifespan. Methods: UPRmt 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 UPRmt 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 UPRmt and exerting protective effects in mammalian cells. Conclusions: The results reveal beneficial effects of Co₃O₄ NPs on mitochondrial metabolic control, thus presenting their potential efficacy in anti-aging care.