Zinc dyshomeostasis, mitochondrial dysfunction, and their pathological cycle in ischemic stroke pathophysiology: Mechanisms and potential therapeutic targets

Ischemic stroke is a leading cause of global mortality and long-term neurological disability. Zinc, an essential trace element critical for neuronal survival within the central nervous system, becomes a key pathological mediator when its homeostasis is disrupted following ischemia. Mitochondria, which are essential for neuronal energy production and survival, are primary targets of zinc-induced toxicity. Excess zinc disrupts mitochondria through multiple mechanisms, causing significant structural damage (swelling and cristae remodeling), impairing dynamic balance (fission/fusion and mitophagy), disrupting oxidative respiratory chain function, reducing ATP production, inducing loss of membrane potential, and triggering oxidative stress responses. Notably, mitochondrial impairment during cerebral ischemia-reperfusion further promotes intracellular zinc accumulation by disrupting cytosolic zinc pools and calcium homeostasis, as well as impairing the interactions between mitochondria and other organelles including the endoplasmic reticulum and lysosomes, creating a vicious cycle that exacerbate ischemic damage. Due to the critical role of zinc ions, emerging zinc-related technologies such as the AggHX sensor, antioxidant zinc oxide nanoparticles and modern zinc chelation strategies offer promising diagnosing and therapeutic avenues for neurological disorders like cerebral ischemia. Meanwhile, the emergence of mitochondrial DNA editing tools marks a new era of precise mitochondrial therapy. Firstly, this review systematically traces the historical evolution of the understanding of zinc's dual roles in neural physiology and pathology, and subsequently summarizes the pathogenic interplay between zinc dyshomeostasis and mitochondrial dysfunction in ischemic stroke, highlighting the "zinc-mitochondria axis" as a potential therapeutic target. It also provides a comprehensive overview of recent advances in zinc-based technologies for neurological diseases, evaluating their opportunities and challenges in neuroprotection and clinical applications, aiming to provide novel insights for developing advanced therapeutic strategies.