N‐acetyl‐l‐tyrosine is an intrinsic triggering factor of mitohormesis in stressed animals

Abstract

Under stress conditions, mitochondria release low levels of reactive oxygen species (ROS), which triggers a cytoprotective response, called "mitohormesis". It still remains unclear how mitochondria respond to stress-derived stimuli and release a low level of ROS. Here, we show that N-acetyl-L-tyrosine (NAT) functions as a plausible intrinsic factor responsible for these tasks in stressed animals. NAT is present in the blood or hemolymph of healthy animals, and its concentrations increase in response to heat stress. Pretreatment with NAT significantly increases the stress tolerance of tested insects and mice. Analyses using Drosophila larvae and cultured cells demonstrate that the hormetic effects are triggered by transient NAT-induced perturbation of mitochondria, which causes a small increase in ROS production and leads to sequential retrograde responses: NAT-dependent FoxO activation increases in the gene expression of antioxidant enzymes and Keap1. Moreover, we find that NAT represses tumor growth, possibly via the activation of Keap1. In sum, we propose that NAT is a vital endogenous molecule that could serve as a triggering factor for mitohormesis.

Hallmarks of Health

“…Similarly, the endogenous metabolite N-acetyl-L-tyrosine (NAT) triggers mitohormetic responses that do not only involve mitochondrial ROS production but also activate FoxO, which in turn transactivates antioxidant genes and KEAP1 to elicit cytoprotective responses. NAT also represses tumor growth, likely through KEAP1 activation (Matsumura et al, 2020). The future elucidation of mitohormesis-stimulatory pathways may lead to the development of strategies to extend healthspan and lifespan (Table 1).…”

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

“…For instance, metformin, a well-known anti-diabetic drug, extends the life-span of worms through the production of low levels of mitochondrial ROS and Prxs PRDX-2 (De Haes et al, 2014). Low levels of H 2 O 2 extends the life-span of yeast in a Prxdependent manner (Goulev et al, 2017) and an endogenous amino-acid metabolite, namely N-acetyl-L-tyrosine (NAT), was recently shown to reduce tumor growth in mice via mitohormesis (Matsumura et al, 2020). Sestrins could be functionally similar to Prx by fine-tuning a pleitropic level of ROS, which might be beneficial for human health, but the underlying mechanism needs further interrogation.…”

The oxidative stress and metabolic response of Acinetobacter baumannii for aPDT multiple photosensitization

“…It is worth to mentioning that the increased concentration of some amino acids and their derivatives may fulfill the antioxidant functions inside the cells. The levels of tryptophan, tyrosine and long-chain acylated tyrosine (Table 3 ) increased and it cannot be excluded that this phenomenon was related to the inhibition of lipid peroxidation by these amino acids 34 , 35 . Sulfur-containing amino acid—methionine may also be accumulated in response to oxidative stress after ten expositions of A.baumannii cells to the sub-lethal doses of laser light (Table 3 ).…”