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bioRxiv · 10.64898/2026.05.18.725821

Copper modulates iron-dependent survival through distinct TORC1 and AMPK signaling pathways

Naaz, A.·Cheng, T. Y. N.·Lin, J. J.·Gao, M.·Dorajoo, R.·Kennedy, B. K.·Alfatah, M.
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Abstract

Copper and iron are redox-active micronutrients with tightly coupled homeostasis, yet how copper modulates iron-dependent stress responses remains unclear. Using Saccharomyces cerevisiae under nutrient-limited conditions, we uncoupled proliferative growth from long-term survival to dissect metal-dependent adaptation. Copper selectively preserved survival without affecting growth, whereas iron showed similar effects. Iron chelation impaired growth and suppressed electron transport chain gene expression; copper partially rescued these defects but required iron for its pro-survival activity. Despite this interdependence, copper and iron engaged distinct signaling programs. Iron-dependent survival required a Target of Rapamycin complex 1 (TORC1)-permissive state and was attenuated by rapamycin, whereas copper remained active under TORC1 inhibition. In contrast, copper promoted survival through AMP-activated protein kinase (AMPK) and antioxidant pathways, while iron exhibited context-dependent AMPK reliance. Together, these findings identify copper and iron as state-dependent regulators of cellular survival.

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Naaz, A., Cheng, T. Y. N., Lin, J. J., Gao, M., Dorajoo, R., Kennedy, B. K., Alfatah, M.. 2026-05-20. Copper modulates iron-dependent survival through distinct TORC1 and AMPK signaling pathways. https://doi.org/10.64898/2026.05.18.725821

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