The Interplay between Mitochondrial Dysfunction and Ferroptosis during Ischemia-Associated Central Nervous System Diseases

Abstract

Cerebral ischemia, a leading cause of disability and mortality worldwide, triggers a cascade of molecular and cellular pathologies linked to several central nervous system (CNS) disorders. These disorders primarily encompass ischemic stroke, Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, and other CNS conditions. Despite substantial progress in understanding and treating the underlying pathological processes in various neurological diseases, there is still a notable absence of effective therapeutic approaches aimed specifically at mitigating the damage caused by these illnesses. Remarkably, ischemia causes severe damage to cells in ischemia-associated CNS diseases. Cerebral ischemia initiates oxygen and glucose deprivation, which subsequently promotes mitochondrial dysfunction, including mitochondrial permeability transition pore (MPTP) opening, mitophagy dysfunction, and excessive mitochondrial fission, triggering various forms of cell death such as autophagy, apoptosis, as well as ferroptosis. Ferroptosis, a novel type of regulated cell death (RCD), is characterized by iron-dependent accumulation of lethal reactive oxygen species (ROS) and lipid peroxidation. Mitochondrial dysfunction and ferroptosis both play critical roles in the pathogenic progression of ischemia-associated CNS diseases. In recent years, growing evidence has indicated that mitochondrial dysfunction interplays with ferroptosis to aggravate cerebral ischemia injury. However, the potential connections between mitochondrial dysfunction and ferroptosis in cerebral ischemia have not yet been clarified. Thus, we analyzed the underlying mechanism between mitochondrial dysfunction and ferroptosis in ischemia-associated CNS diseases. We also discovered that GSH depletion and GPX4 inactivation cause lipoxygenase activation and calcium influx following cerebral ischemia injury, resulting in MPTP opening and mitochondrial dysfunction. Additionally, dysfunction in mitochondrial electron transport and an imbalanced fusion-to-fission ratio can lead to the accumulation of ROS and iron overload, which further contribute to the occurrence of ferroptosis. This creates a vicious cycle that continuously worsens cerebral ischemia injury. In this study, our focus is on exploring the interplay between mitochondrial dysfunction and ferroptosis, which may offer new insights into potential therapeutic approaches for the treatment of ischemia-associated CNS diseases.

Progress of medicinal plants and their active metabolites in ischemia-reperfusion injury of stroke: a novel therapeutic strategy based on regulation of crosstalk between mitophagy and ferroptosis

“…As Lin QS et al ( Lin et al, 2023 ) found that mitophagy could regulate iron ion levels through the ROS/HO-1/GPX4 axis, thereby alleviating cisplatin-induced ferroptosis in renal tubular epithelial cells. Another study indicated that the activity of mitophagy may be inhibited during the progression of ischemia-reperfusion injury in stroke, leading to excessive accumulation of iron ions in cells and subsequently inducing ferroptosis ( Tian et al, 2023 ). On the other hand, the dysregulation of iron metabolism and the occurrence of ferroptosis also control the autophagic flux of mitochondria in the ischemia-reperfusion injury model of stroke.…”

Heavy Metals Interactions with Neuroglia and Gut Microbiota: Implications for Huntington’s Disease

“…Mitochondrial dysfunction is a hallmark of ferroptosis and a necessary condition for the perpetuation of these reactions. In fact, increased Fe uptake promotes the generation of destructive hydroxyl radicals through the Fenton reaction thus perpetuating the chain reaction of lipid peroxidation, ultimately compromising membrane integrity [107], which leads to cell membrane disruption and cell death. Unlike apoptosis and necrosis, ferroptosis presents with its own cellular pathways.…”

β-asarone induces viability and angiogenesis and suppresses apoptosis of human vascular endothelial cells after ischemic stroke by upregulating vascular endothelial growth factor A

“…Clinically, β-asarone is utilized to treat fever, delirium, phlegm, forgetfulness, dementia, deafness, tinnitus, heartburn, traumatic injury, and so on ( Hei et al, 2020 ; Saki et al, 2020 ). The cascade reactions induced by cerebral ischemia include the release of excitatory amino acids, apoptosis, intracellular calcium influx overload, inflammation, activation of calcium-dependent enzymes, nitric oxide free radical production, and so on ( She et al, 2023 ; Shin et al, 2020 ; Tian et al, 2023 ). β-asarone has been confirmed to have antioxidant and anti-inflammatory properties ( Shi et al, 2021 ).…”