Mitochondrial–metabolic–calcium network: a central driver of Alzheimer’s disease pathology
New review integrates human, animal, and cellular evidence to reframe AD as a triad-centered disorder
image: Mitochondrial dysfunction manifests as structural damage (swelling, cristae rupture, increased volume/decreased numerical density), energy metabolism abnormalities (reduced COX and Complex I-III activities, elevated lactate/decreased succinate), dynamic imbalance (DRP1 up-regulation/OPA1 down-regulation leading to fragmentation), and autophagy impairment (Aβ-mediated inhibition of PINK1/Parkin), collectively triggering the ATP crisis and ROS accumulation.
Metabolic disturbances form a glucose–lipid–amino acid triad of dysregulation: impaired glucose metabolism involves GLUT1/3 suppression and compensatory glycolysis elevation, exacerbating mitochondrial damage through feedback inhibition; lipid abnormalities drive Aβ deposition via cholesterol accumulation, ApoE4 effects, and membrane fluidity reduction; and amino acid imbalance features glutamate/GABA ratio disruption and ammonia toxicity. Calcium dyshomeostasis arises from NMDA receptor/IP3R hyperactivation, inducing a calcium overload that activates proteases, triggers ROS bursts, promotes tau phosphorylation→NFT formation, and collapses the mitochondrial membrane potential. These three systems interact through positive feedback loops—ROS→mtDNA mutations→ETC damage, Aβ→GLUT inhibition→energy crisis, and calcium overload→mitochondrial permeability transition pore opening. ATP depletion and defective autophagy further transform damaged mitochondria into persistent ROS sources, ultimately driving an irreversible neurodegenerative cascade.
Credit: Tingting Liu, Zongting Rong, Jingwen Li, Haojie Wu, Jianshe Wei
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.