Cross talk between increased intracellular zinc (Zn²⁺) and accumulation of reactive oxygen species in chemical ischemia

Abstract

Both zinc (Zn) and reactive oxygen species (ROS) have been shown to accumulate during hypoxic-ischemic stress and play important roles in pathological processes. To understand the cross talk between the two of them, here we studied Zn and ROS accumulation by employing fluorescent probes in HeLa cells to further the understanding of the cause and effect relationship of these two important cellular signaling systems during chemical-ischemia, stimulated by oxygen and glucose deprivation (OGD). We observed two Zn rises that were divided into four phases in the course of 30 min of OGD. The first Zn rise was a transient, which was followed by a latent phase during which Zn levels recovered; however, levels remained above a basal level in most cells. The final phase was the second Zn rise, which reached a sustained plateau called Zn overload. Zn rises were not observed when Zn was removed by TPEN (a Zn chelator) or thapsigargin (depleting Zn from intracellular stores) treatment, indicating that Zn was from intracellular storage. Damaging mitochondria with FCCP significantly reduced the second Zn rise, indicating that the mitochondrial Zn accumulation contributes to Zn overload. We also detected two OGD-induced ROS rises. Two Zn rises preceded two ROS rises. Removal of Zn reduced or delayed OGD- and FCCP-induced ROS generation, indicating that Zn contributes to mitochondrial ROS generation. There was a Zn-induced increase in the functional component of NADPH oxidase, p47, thus suggesting that NADPH oxidase may mediate Zn-induced ROS accumulation. We suggest a new mechanism of cross talk between Zn and mitochondrial ROS through positive feedback processes that eventually causes excessive free Zn and ROS accumulations during the course of ischemic stress.

Excitotoxicity: Still Hammering the Ischemic Brain in 2020

“…Further examination revealed that an OGD-induced increase in neuronal [Zn 2+ ] i preceded mitochondrial depolarization, Ca 2+ deregulation and membrane failure, with Zn 2+ likely entering mitochondria and contributing to loss of mitochondrial membrane potential (Medvedeva et al, 2009). This meshed with earlier demonstration that elevated intracellular Zn 2+ , like Ca 2+ , can enter and damage mitochondria, leading to their swelling, loss of membrane potential and, at high levels of Zn 2+ , increased ROS generation (Sensi et al, 2003;Clausen et al, 2013), the last likely a consequence of disturbances in mitochondrial electron transport as well as Zn 2+ induction of p47 PHOX and increased NOX activity (Noh and Koh, 2000;Slepchenko et al, 2017). Downstream ROS/RNS-induced release of Zn 2+ from intracellular stores (Berendji et al, 1997;Cuajungco and Lees, 1998;Aizenman et al, 2000) thus drives further oxidative stress.…”

“Iron free” zinc oxide nanoparticles with ion-leaking properties disrupt intracellular ROS and iron homeostasis to induce ferroptosis

“…The aberrant homeostasis of transition metal ions, e.g., Fe 2+ /Fe 3+ , Zn 2+ , and Ca 2+ , plays important roles in the pathogenesis of various diseases. For instance, a recent study has highlighted the interaction of Zn 2+ homeostasis and ROS signaling suggesting their interdependence 49 . Mitochondria contain dynamic pools of these metal ions that are incorporated into corresponding metalloproteins 50 .…”

Zinc in Wound Healing Modulation

“…Several studies have shown that zinc deficiency increases oxidative stress [ 22 , 116 , 117 ]. It is well accepted that oxidative damage is a major cause of tissue injury and redox regulation plays a prominent role in wound repair [ 118 , 119 , 120 ].…”