Predictive Data Modeling of CISD2 Activation for Neuroprotection: Insights from In Silico and Machine Learning Approaches

Abstract

The optimal operation of mitochondria and the endoplasmic reticulum (ER) relies on CISD2, also known as CDGSH iron-sulfur domain 2. Changes in CISD2 relate to neurodegenerative diseases like Parkinson's disease (PD) & Alzheimer's disease (AD). Found primarily in the endoplasmic reticulum including mitochondria, CISD2 is a component within the CDGSH protein family as well as alters redox balance, mitochondrial integrity, including calcium (Ca2+) homeostasis within these organelles. Often marked by mitochondrial malfunction, oxidative stress, and cell death, neurodegenerative diseases cover regions where CISD2 is absolutely important.  Amyloid-beta (Aβ) accumulates in Alzheimer's disease to cause mitochondrial calcium excess, oxidative stress, and mitochondrial damage. This stimulates the mitochondrial permeability transition pore (MPTP), releasing cytochrome c (CytC) and so activating caspases (CASP3 and CASP9), hence causing neuronal death. By means of the IRE1α and PERK pathways, Aβ disturbs Ca2+ homeostasis, induces the unfolded protein response (UPR), and promotes caspase 12 (CASP12)-mediated death. CISD2 mitigates oxidative damage and contributes to the stabilization of the mitochondrial membrane, thereby functioning as a protective agent against these phenomena.  In neurodegenerative illnesses, diminished CISD2 levels exacerbate oxidative stress and mitochondrial injury, hence leading to neuronal death. Activated microglia and astrocytes, responding to Aβ toxicity, induce neuroinflammation, which accelerates dementia. Enhancing CISD2 expression has been shown to safeguard mitochondria, reduce reactive oxygen species (ROS), and prevent cell death. Furthermore, by maintaining Ca2+ homeostasis, CISD2 mitigates ER stress and pro-apoptotic signaling; hence, elevated CISD2 expression indicates a protective effect against neurodegeneration by diminishing oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress.  The natural flavonoid Liquiritigenin, found in licorice root, significantly enhances the expression of CISD2, hence augmenting mitochondrial integrity and stabilizing the endoplasmic reticulum in neurodegenerative models. Molecular docking and in silico research indicate that liquiritigenin and other small molecules bind to CISD2, hence activating its protective functions. Liquiritigenin reduces oxidative stress, mitochondrial damage, and endoplasmic reticulum stress by increasing CISD2 expression, hence decelerating neurodegeneration. Targeting CISD2 with Liquiritigenin or analogous chemicals may reduce neuroinflammation and improve mitochondrial health, thereby offering a viable treatment strategy for Alzheimer's disease and other neurodegenerative illnesses.