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Dysfunction of the CD38-Miro1 Axis Disrupts Astrocyte-neuron Mitochondrial Transfer in Alzheimer's Disease: Mechanisms and Therapeutic Restoration

By Abdelaziz AM, Shokr MM, Fathy MK, Fawzy MN
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Editor's note
Astrocytes can rescue dying neurons by shipping them mitochondria—a compensatory lifeline that fails catastrophically in Alzheimer's disease. This review maps an emerging pathway (CD38-Miro1 signaling through tunneling nanotubes) where multiple AD hallmarks converge to block this cellular rescue, positioning mitochondrial transfer dysfunction as a unifying mechanism of neurodegeneration. Neuroscientists and AD researchers should attend closely; the identified druggable nodes offer testable therapeutic entry points.

Source: europepmc · Origin: EG · Abdelaziz AM, Shokr MM, Fathy MK, Fawzy MN. · Journal of molecular neuroscience : MN · 2026-05-25

URL: https://pubmed.ncbi.nlm.nih.gov/42184087/

AI rationale (5/5, tier: emerging): Directly addresses mitochondrial transfer between cells (core INCLUDE), Miro1 trafficking, calcium signaling, and AD neurodegeneration intersection.

Alzheimer's disease (AD) is characterized by early bioenergetic failure, contributing to synaptic dysfunction and neuronal vulnerability. This review examines a critical compensatory mechanism, the transfer of functional mitochondria from astrocytes to neurons, and its profound failure in AD. We detail the coordinated molecular cascade of this mitochondrial shunt, initiated by neuronal distress signals that activate astrocytic CD38. CD38-generated cyclic ADP-ribose triggers calcium release, which then binds to the mitochondrial Rho GTPase Miro1, modulating mitochondrial trafficking and promoting peripheral positioning via kinesin motor complexes for intercellular transport through tunneling nanotubes (TNTs). Transient, localized Ca²⁺ signals bias mitochondria toward docking at the plasma membrane for export, whereas sustained pathologic Ca²⁺ overload impairs trafficking via motor disengagement and Miro1 dysfunction. In AD, this rescue pathway is catastrophically disrupted by NAD+ depletion, Aβ-induced calcium dysregulation, tau-mediated microtubule instability, and oxidative stress, leading to inhibited CD38 signaling, Miro1 dysfunction/impairment, and TNT dismantlement. We systematically explain how this multi-level impairment initiates a vicious cycle of bioenergetic collapse. We also look at promising treatment options that could help restore this shunt, such as NAD+ augmentation to reactivate CD38, Miro1 stabilizers to help with trafficking, and interventions to keep TNT intact. Targeting the astrocyte-neuron mitochondrial shunt may represent an innovative, disease-modifying strategy that could transform the therapeutic framework from simple protein clearance to the proactive restoration of intercellular metabolic support, offering a promising direction for next-generation AD therapeutics.

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Published 2026-05-26 · Last kit-update 2026-05-26