Intercellular Mitochondria Transfer as a Bioenergetic Rescue Mechanism in CNS Injury: Mechanisms, Therapeutic Potential, and Translational Barriers.

Authors

Afra Wasama Islam, Swapna Bejoy, Prarthana Motdhare, Afrah Riyas, Chris Puthenpurayil Abraham, Mehadiya Afreen Hussain

Published in

Molecular neurobiology. Volume 63. Issue 1. Oct 30, 2026. Epub Oct 30, 2026.

Abstract

Acute central nervous system (CNS) injuries, including ischemic stroke, traumatic brain injury, and spinal cord injury, are characterized by profound mitochondrial dysfunction that drives secondary neuronal damage through ATP depletion, oxidative stress, and calcium dysregulation. Neuronal survival is critically dependent on mitochondrial integrity, making bioenergetic failure a central determinant of injury progression. In this context, intercellular mitochondria transfer has emerged as a potential adaptive mechanism through which functional mitochondria are delivered from donor cells-primarily astrocytes, microglia, and mesenchymal stem cells-to metabolically compromised neurons. Mitochondria transfer occurs via both contact-dependent pathways, such as tunneling nanotubes, and contact-independent mechanisms, including extracellular vesicles and free mitochondrial release. These processes are regulated by signaling pathways such as CD38/cADPR-mediated calcium flux and MIRO1-dependent mitochondrial trafficking, facilitating organelle mobilization and uptake. Functionally, transferred mitochondria have been associated with improved oxidative phosphorylation, reduced reactive oxygen species accumulation, altered calcium homeostasis, and modulation of survival pathways including PI3K/Akt and MAPK/ERK signaling in selected experimental models; however, the extent to which these effects are directly dependent on mitochondria transfer remains incompletely established. Preclinical evidence across multiple CNS injury models demonstrates improved neuronal viability, enhanced synaptic function, and attenuation of neurodegenerative processes following mitochondria transfer. However, whether mitochondria transfer represents a primary driver of neurorepair or a secondary compensatory response remains unresolved. In addition, inconsistencies in mechanistic pathways, variability in transfer efficiency, and limited reproducibility across experimental systems hinder translational interpretation. Therapeutic approaches including exogenous mitochondria transplantation, stem cell-mediated delivery, and bioengineered mitochondrial systems show promise but face substantial barriers related to targeting specificity, mitochondrial viability, immunogenicity, and lack of standardized protocols. This review critically evaluates the molecular mechanisms, functional consequences, and therapeutic potential of intercellular mitochondria transfer in CNS injury. It further highlights key limitations and knowledge gaps that must be addressed to determine whether mitochondria transfer can be effectively harnessed as a clinically viable strategy for neuro-restoration.

PMID:
42961624
Bibliographic data and abstract were imported from PubMed on 31 Oct 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.