Mitochondrial Reprogramming Along the Gut–Brain Axis in Chemotherapy‐Induced Cognitive Impairment: A Narrative Review
5 affiliations
- 1Department of Biochemistry Kasturba Medical College Mangalore Manipal Academy of Higher Education Manipal India manipal.edu
- 2Department of Pathology Kasturba Medical College Mangalore Manipal Academy of Higher Education Manipal India manipal.edu
- 3Manipal Institute of Applied Physics Manipal Academy of Higher Education Manipal India manipal.edu
- 4Department of Anatomy Kasturba Medical College Manipal Academy of Higher Education Manipal India manipal.edu
- 5Department of Medicine Kasturba Medical College Mangalore Manipal Academy of Higher Education Manipal India manipal.edu
Abstract
Chemotherapy‐induced cognitive impairment (CICI), often referred to as “chemobrain,” is a frequently persistent complication that significantly affects memory, attention, executive function, and overall quality of life among cancer survivors. Although mitochondrial dysfunction, oxidative stress, neuroinflammation, and gut microbiota dysbiosis have each been implicated in its pathogenesis, the way these processes interact to drive cognitive decline remains incompletely understood. In this narrative review, we explore the current evidence supporting mitochondrial reprogramming as a central mechanistic link connecting chemotherapy‐induced alterations in the gut–brain axis to neuronal dysfunction. Here, mitochondrial reprogramming encompasses not only overt mitochondrial damage but also adaptive and maladaptive alterations in mitochondrial bioenergetics, biogenesis, mitophagy, and metabolic signaling in response to chemotherapeutic stress. We discuss how oxidative stress, impaired mitochondrial quality control, and key inflammatory and stress‐response pathways, including Nrf2/Keap1, NF‐κB, the AMPK–SIRT1–PGC‐1α axis, and mtDNA‐mediated cGAS–STING signaling, may converge to promote neuronal injury and cognitive impairment. We further examine the contribution of chemotherapy‐induced gut dysbiosis and microbiota‐derived metabolites, such as short‐chain fatty acids (SCFAs) and lipopolysaccharide (LPS), in modulating mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) integrity via the gut–brain axis. Importantly, we differentiate findings derived directly from CICI models from those extrapolated from related fields such as neurodegenerative disorders, aging, and microbiome research, while highlighting current knowledge gaps and the scarcity of clinical data. Finally, we discuss promising therapeutic strategies aimed at restoring mitochondrial homeostasis and modulating the gut microbiota and outline priority areas for future research to facilitate the translation of these mechanistic insights into effective clinical interventions for cancer survivors.
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BibTeX
@article{malhotra2026mitochondrial,
title = {{Mitochondrial Reprogramming Along the Gut–Brain Axis in Chemotherapy‐Induced Cognitive Impairment: A Narrative Review}},
author = {Amisha Malhotra and Gayathri M. Rao and Aradhana Marathe and Sharada Rai and V. Samyuktha Rani and Ajeetkumar Patil and Dinesh Upadhya and M. Chakrapani},
journal = {Oxidative Medicine and Cellular Longevity},
year = {2026},
month = oct,
doi = {10.1155/omcl/5350976},
url = {https://doi.org/10.1155/omcl/5350976},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mitochondrial Reprogramming Along the Gut–Brain Axis in Chemotherapy‐Induced Cognitive Impairment: A Narrative Review
AU - Amisha Malhotra
AU - Gayathri M. Rao
AU - Aradhana Marathe
AU - Sharada Rai
AU - V. Samyuktha Rani
AU - Ajeetkumar Patil
AU - Dinesh Upadhya
AU - M. Chakrapani
PY - 2026
DA - 2026/10/28
JO - Oxidative Medicine and Cellular Longevity
DO - 10.1155/omcl/5350976
UR - https://doi.org/10.1155/omcl/5350976
AB - Chemotherapy‐induced cognitive impairment (CICI), often referred to as “chemobrain,” is a frequently persistent complication that significantly affects memory, attention, executive function, and overall quality of life among cancer survivors. Although mitochondrial dysfunction, oxidative stress, neuroinflammation, and gut microbiota dysbiosis have each been implicated in its pathogenesis, the way these processes interact to drive cognitive decline remains incompletely understood. In this narrative review, we explore the current evidence supporting mitochondrial reprogramming as a central mechanistic link connecting chemotherapy‐induced alterations in the gut–brain axis to neuronal dysfunction. Here, mitochondrial reprogramming encompasses not only overt mitochondrial damage but also adaptive and maladaptive alterations in mitochondrial bioenergetics, biogenesis, mitophagy, and metabolic signaling in response to chemotherapeutic stress. We discuss how oxidative stress, impaired mitochondrial quality control, and key inflammatory and stress‐response pathways, including Nrf2/Keap1, NF‐κB, the AMPK–SIRT1–PGC‐1α axis, and mtDNA‐mediated cGAS–STING signaling, may converge to promote neuronal injury and cognitive impairment. We further examine the contribution of chemotherapy‐induced gut dysbiosis and microbiota‐derived metabolites, such as short‐chain fatty acids (SCFAs) and lipopolysaccharide (LPS), in modulating mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) integrity via the gut–brain axis. Importantly, we differentiate findings derived directly from CICI models from those extrapolated from related fields such as neurodegenerative disorders, aging, and microbiome research, while highlighting current knowledge gaps and the scarcity of clinical data. Finally, we discuss promising therapeutic strategies aimed at restoring mitochondrial homeostasis and modulating the gut microbiota and outline priority areas for future research to facilitate the translation of these mechanistic insights into effective clinical interventions for cancer survivors.
SN - 1942-0900
SN - 1942-0994
ER -