Work

Zinc toxicity induces intestinal cell death via inhibiting NAD+ synthesis in mice and IPEC-J2 cells

Year: 2025

Type: article

Abstract: Excessive zinc (Zn) intake can lead to Zn toxicity, causing adverse effects in gastrointestinal system. To date, there remains no definitive consensus on the mechanisms by which Zn overload induces cell death and intestinal injury. This study was to assess the toxicity mechanism of Zn overload in intestine, with a particular concentrate on oxidative stress and energy metabolism. We first explore the effects of short- and long-term Zn imbalances on intestinal health in mice. We found that the Zn imbalances resulted in oxidative damage, and impaired ketoglutarate dehydrogenase (α-KGDH) activity, which collectively contributed to a detrimental impact on the integrity of the intestinal barrier in mice. We next determined the dynamics of oxidative stress and energy metabolism in Zn overload treatment IPEC-J2 cells. Excessive Zn activated reactive oxygen species (ROS) overproduction and the PKC-NOX oxidative stress pathway. Moreover, the increase of mitochondrial Zn2+ caused mitochondrial ROS accumulation and influenced the expressions of α-KGDH andisocitrate dehydrogenase (IDH), two pivotal rate-limiting enzymes in tricarboxylic acid (TCA) cycle. Zn overload also significantly inhibited the expressions of key nicotinamide adenine dinucleotide (NAD+) synthesis enzymes, namely NMNAT1 and NAMPT, leading to a notable decline of NAD+ and ATP. Furthermore, rescue experiments showed supplementation of NAD+ or boosting NAD+ synthesis, but not antioxidants addition, could rescue Zn toxicity. The collective findings suggest NAD+ reduction is the primary factor contributing to intestinal Zn toxicity, although ROS also plays a role. This indicates that the modulation of NAD+ synthesis may prove an effective strategy for the minimization or elimination of Zn toxicity.

Source: Animal Nutriomics

DOI: 10.1017/anr.2025.10008

Authors: Lingjun Chen, Feifei Huang, Leilei Zhu, Xin Tian, Mohan Zhou, Jie Feng

Institution: Zhejiang University

Language: English

Topic: Trace Elements in Health

Subfield: Nutrition and Dietetics

Field: Nursing

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,000