Nrf2 modulates cytosolic and mitochondrial calcium signal

TY - JOUR

T1 - Nrf2 modulates cytosolic and mitochondrial calcium signal

AU - Preziuso, Alessandra

AU - Baev, Artyom Y.

AU - Rustamova, Fozila R.

AU - Naidu, Sharadha Dayalan

AU - Millichap, Lauren

AU - Angelova, Plamena R.

AU - Lariccia, Vincenzo

AU - Dinkova-Kostova, Albena T.

AU - Abramov, Andrey Y.

N1 - Copyright: © 2026 The Authors. Published by Elsevier B.V.

PY - 2026/5/17

Y1 - 2026/5/17

N2 - Nrf2 is a transcription factor which regulates ∼1% of the mammalian genome and is responsible for orchestrating the cellular defense against oxidative, inflammatory and metabolic stress. Calcium (Ca2+) is a ubiquitous intracellular messenger which controls most cellular processes, from fertilization to cell death. Nrf2 and Ca2+ are involved in a large number of similar physiological processes, but it is not clear if they can regulate each other. Here, using primary co-cultures of neurons and astrocytes we asked if Nrf2 activation or deficiency alters physiological Ca2+ signaling and mitochondrial Ca2+ handling in brain cells. We found that activation of Nrf2 leads to an increase in the amplitude of Ca2+ peak and a faster Ca2+efflux in response to glutamate and ATP in neurons and astrocytes. Interestingly, Nrf2-deficient neurons and astrocytes also had higher Ca2+ peaks in response to glutamate and ATP, but the recovery in neurons was significantly delayed. Genetic (Keap1-knockdown) or pharmacological (ovameloxolone, RTA-408) activation of Nrf2 increases mitochondrial Ca2+ uptake and mitochondrial Ca2+ capacity, and this correlates with increased activity of the Na+/Ca2+/Li+ exchanger (NCLX) and inhibition of the mitochondrial permeability transition pore (mPTP). Conversely, mitochondria in neurons and astrocytes from Nrf2-knockout mice had a lower Ca2+ uptake, lower mitochondrial Ca2+ capacity and lower mitochondrial Ca2+efflux, making these cell vulnerable to Ca2+-induced cell death. Thus, Nrf2 modulates cytosolic calcium signaling and activates the mitochondrial NCLX, increasing the mitochondrial Ca2+ capacity, which adds another critical aspect to the multifaceted nature of Nrf2-mediated cytoprotection.

AB - Nrf2 is a transcription factor which regulates ∼1% of the mammalian genome and is responsible for orchestrating the cellular defense against oxidative, inflammatory and metabolic stress. Calcium (Ca2+) is a ubiquitous intracellular messenger which controls most cellular processes, from fertilization to cell death. Nrf2 and Ca2+ are involved in a large number of similar physiological processes, but it is not clear if they can regulate each other. Here, using primary co-cultures of neurons and astrocytes we asked if Nrf2 activation or deficiency alters physiological Ca2+ signaling and mitochondrial Ca2+ handling in brain cells. We found that activation of Nrf2 leads to an increase in the amplitude of Ca2+ peak and a faster Ca2+efflux in response to glutamate and ATP in neurons and astrocytes. Interestingly, Nrf2-deficient neurons and astrocytes also had higher Ca2+ peaks in response to glutamate and ATP, but the recovery in neurons was significantly delayed. Genetic (Keap1-knockdown) or pharmacological (ovameloxolone, RTA-408) activation of Nrf2 increases mitochondrial Ca2+ uptake and mitochondrial Ca2+ capacity, and this correlates with increased activity of the Na+/Ca2+/Li+ exchanger (NCLX) and inhibition of the mitochondrial permeability transition pore (mPTP). Conversely, mitochondria in neurons and astrocytes from Nrf2-knockout mice had a lower Ca2+ uptake, lower mitochondrial Ca2+ capacity and lower mitochondrial Ca2+efflux, making these cell vulnerable to Ca2+-induced cell death. Thus, Nrf2 modulates cytosolic calcium signaling and activates the mitochondrial NCLX, increasing the mitochondrial Ca2+ capacity, which adds another critical aspect to the multifaceted nature of Nrf2-mediated cytoprotection.

KW - Astrocyte

KW - Calcium signal

KW - Keap1

KW - Mitochondria

KW - Neuron

KW - Nrf2

U2 - 10.1016/j.redox.2026.104213

DO - 10.1016/j.redox.2026.104213

M3 - Article

C2 - 42142419

SN - 2213-2317

VL - 94

JO - Redox Biology

JF - Redox Biology

M1 - 104213

ER -