This review published in Genes & Diseases by researchers from the Institute for Brain Sciences Research, Henan University, presents a comprehensive synthesis of research showing that mitochondrial dysfunction, metabolic disruption, and calcium imbalance form a tightly interconnected “pathological triad” that shapes both the onset and advancement of AD.

The review highlights mitochondrial impairment as a central initiating event. Defective oxidative phosphorylation, excessive reactive oxygen species production, impaired mitophagy, and structural abnormalities collectively undermine neuronal energy supply. These mitochondrial defects, the authors note, compromise not only cellular metabolism but also prime neurons for heightened vulnerability to downstream pathological stressors.

Metabolic dysregulation emerges as the second axis of this triad. The authors describe profound disturbances in glucose utilization, lipid metabolism, amino acid balance, and lactate processing across AD models and human tissues. These metabolic abnormalities lead to an energy-deficient state that reinforces mitochondrial stress and fuels excitotoxicity. In particular, the review draws attention to the role of lactate accumulation, lipid peroxidation, and altered glutamate–GABA cycling, highlighting how they form a “metabolic vortex” that accelerates neuronal injury.

The third axis—calcium dyshomeostasis—further amplifies neurodegenerative processes. Sustained calcium overload in neurons and mitochondria, driven by dysregulated calcium channels, disrupted ER–mitochondria signaling, and impaired buffering systems, triggers apoptotic cascades and synaptic dysfunction. The review emphasizes that calcium imbalance is not an isolated abnormality but one that exacerbates both metabolic instability and mitochondrial damage.

Importantly, the authors integrate amyloid-β (Aβ) and tau pathology into this broader triadic model, illustrating how these hallmark proteins interact with and intensify mitochondrial, metabolic, and calcium disturbances. Rather than functioning as the sole drivers of disease, Aβ and tau are positioned as amplifiers within a larger systems-level failure.

The review concludes by outlining therapeutic opportunities that target each dimension of the triad—from mitochondrial stabilizers and metabolic modulators to calcium-regulating compounds. The authors advocate for multi-target, early-intervention strategies that disrupt the self-reinforcing nature of mitochondrial–metabolic–calcium dysfunction.

Ultimately, this three-dimensional framework offers a more holistic understanding of AD pathogenesis and highlights new avenues for therapeutic development that extend beyond traditional amyloid- and tau-centric approaches.

Reference
Title of Original Paper: Three-dimensional interactive network: Mitochondrial-metabolic-calcium homeostasis driving Alzheimer’s disease

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101846

Funding Information:

• The National Natural Science Foundation of China (No. 32161143021, No.81271410)
• The Henan University graduate “Talent Program” of Henan Province, China (No. SYLYC2023092)
• The Henan Natural Science Foundation of China (No. 182300410313)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus Cite Score: 8.4

Impact Factor: 9.4

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