TY - JOUR
T1 - Activity-based sensing reveals elevated labile copper promotes liver aging via hepatic ALDH1A1 depletion
AU - Zhao, Zhenxiang
AU - Lucero, Melissa Y.
AU - Su, Shengzhang
AU - Chaney, Eric J.
AU - Xu, Jiajie Jessica
AU - Myszka, Michael
AU - Chan, Jefferson
N1 - This work was supported in part by the NSF (1752879). M.Y.L. thanks the Alfred P. Sloan Foundation and the Pines Graduate Fellowship for financial support. J.C. thanks the Helen Corley Petit Scholar Program and the Camille and Henry Dreyfus Foundation. Major funding for the 500 MHz Bruker CryoProbeTM was provided by the Roy J. Carver Charitable Trust (Muscatine, Iowa; Grant No. 15-4521) to the School of Chemical Sciences NMR Lab. The Q-Tof Ultima mass spectrometer was purchased in part with a grant from the National Science Foundation, Division of Biological Infrastructure (DBI-0100085). We also acknowledge the Core Facilities at the Carl R. Woese Institute for Genomic Biology for access to the Zeiss LSM 700 confocal microscope and corresponding software, Prof. Peter M Yau of the Roy J. Carver Biotechnology Center (UIUC) for assistance with mass spectrometric experiments.
This work was supported in part by the NSF (1752879). M.Y.L. thanks the Alfred P. Sloan Foundation and the Pines Graduate Fellowship for financial support. J.C. thanks the Helen Corley Petit Scholar Program and the Camille and Henry Dreyfus Foundation. Major funding for the 500\u2009MHz Bruker CryoProbeTM was provided by the Roy J. Carver Charitable Trust (Muscatine, Iowa; Grant No. 15-4521) to the School of Chemical Sciences NMR Lab. The Q-Tof Ultima mass spectrometer was purchased in part with a grant from the National Science Foundation, Division of Biological Infrastructure (DBI-0100085). We also acknowledge the Core Facilities at the Carl R. Woese Institute for Genomic Biology for access to the Zeiss LSM 700 confocal microscope and corresponding software, Prof. Peter M Yau of the Roy J. Carver Biotechnology Center (UIUC) for assistance with mass spectrometric experiments.
PY - 2025/12
Y1 - 2025/12
N2 - Oxidative stress plays a key role in aging and related diseases, including neurodegeneration, cancer, and organ failure. Copper (Cu), a redox-active metal ion, generates reactive oxygen species (ROS), and its dysregulation contributes to aging. Here, we develop activity-based imaging probes for the sensitive detection of Cu(I) and show that labile hepatic Cu activity increases with age, paralleling a decline in ALDH1A1 activity, a protective hepatic enzyme. We also observe an age-related decrease in hepatic glutathione (GSH) activity through noninvasive photoacoustic imaging. Using these probes, we perform longitudinal studies in aged mice treated with ATN-224, a Cu chelator, and demonstrate that this treatment improves Cu homeostasis and preserves ALDH1A1 activity. Our findings uncover a direct link between Cu dysregulation and aging, providing insights into its role and offering a therapeutic strategy to mitigate its effects.
AB - Oxidative stress plays a key role in aging and related diseases, including neurodegeneration, cancer, and organ failure. Copper (Cu), a redox-active metal ion, generates reactive oxygen species (ROS), and its dysregulation contributes to aging. Here, we develop activity-based imaging probes for the sensitive detection of Cu(I) and show that labile hepatic Cu activity increases with age, paralleling a decline in ALDH1A1 activity, a protective hepatic enzyme. We also observe an age-related decrease in hepatic glutathione (GSH) activity through noninvasive photoacoustic imaging. Using these probes, we perform longitudinal studies in aged mice treated with ATN-224, a Cu chelator, and demonstrate that this treatment improves Cu homeostasis and preserves ALDH1A1 activity. Our findings uncover a direct link between Cu dysregulation and aging, providing insights into its role and offering a therapeutic strategy to mitigate its effects.
UR - https://www.scopus.com/pages/publications/85218492107
UR - https://www.scopus.com/pages/publications/85218492107#tab=citedBy
U2 - 10.1038/s41467-025-56585-4
DO - 10.1038/s41467-025-56585-4
M3 - Article
C2 - 39979263
AN - SCOPUS:85218492107
SN - 2041-1723
VL - 16
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1794
ER -