Microglial Vulnerability to Mitochondrial Proteotoxic Stress: A Failed-Resolution Framework for Neurodegeneration
4 affiliations
- 1Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430061, China
- 2College of Acupuncture-Moxibustion and Orthopaedics, Hubei University of Chinese Medicine, Wuhan 430061, China
- 3Hubei International Science and Technology Cooperation Base of Preventive Treatment by Acupuncture and Moxibustion, Wuhan 430061, China
- 4Hubei Shizhen Laboratory, Wuhan 430061, China
Abstract
Microglial responses to mitochondrial protein stress are best evaluated by connecting the initiating protein burden to its processing and functional consequences. This review develops an outcome-based failed-resolution framework that integrates burden trajectory, clearance or repair, and lesion-relevant functional recovery. Stress-response activation is evaluated separately from successful proteostasis restoration. Failed resolution requires persistent initiating burden AND insufficient corresponding processing AND inadequate functional recovery after a defined withdrawal or rescue interval; these are measurement domains, not obligatory biological stages. Matched human induced pluripotent stem cell-derived neural cultures show preferential microglial aggregate-associated signals and multidomain senescence-associated changes under common exposure, while vulnerability at an equivalent intracellular burden remains to be tested. Substrate-resolved turnover and functional measurements anchor the interpretation of stress markers, bulk autophagy and extracellular-cargo uptake. Proteostasis status, functional adequacy and cell fate are assessed independently, allowing a persistent phenotype after burden clearance to be distinguished from ongoing unresolved stress. Resource competition between mitochondrial maintenance and phagolysosomal work is a testable hypothesis supported by component findings. Human cellular, organoid and animal studies define these components; their complete integration in adult microglia in vivo remains untested. The framework provides falsifiable comparisons and selective-rescue tests for linking protein handling to cell-specific recovery.
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BibTeX
@article{liu2026microglial,
title = {{Microglial Vulnerability to Mitochondrial Proteotoxic Stress: A Failed-Resolution Framework for Neurodegeneration}},
author = {Xinyuan Liu and Shuyu Xu and Shuai Zhang and Weixian Li and Jiangmin Chen and Mengying Zhao and Chaoyuan Ye and Yuancheng Liu and Guangya Liu and Yanjun Du and Qing Tian},
journal = {Biomolecules},
year = {2026},
month = nov,
doi = {10.3390/biom16111596},
url = {https://www.mdpi.com/2218-273X/16/11/1596},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Microglial Vulnerability to Mitochondrial Proteotoxic Stress: A Failed-Resolution Framework for Neurodegeneration
AU - Xinyuan Liu
AU - Shuyu Xu
AU - Shuai Zhang
AU - Weixian Li
AU - Jiangmin Chen
AU - Mengying Zhao
AU - Chaoyuan Ye
AU - Yuancheng Liu
AU - Guangya Liu
AU - Yanjun Du
AU - Qing Tian
PY - 2026
DA - 2026/11/02
JO - Biomolecules
DO - 10.3390/biom16111596
UR - https://www.mdpi.com/2218-273X/16/11/1596
AB - Microglial responses to mitochondrial protein stress are best evaluated by connecting the initiating protein burden to its processing and functional consequences. This review develops an outcome-based failed-resolution framework that integrates burden trajectory, clearance or repair, and lesion-relevant functional recovery. Stress-response activation is evaluated separately from successful proteostasis restoration. Failed resolution requires persistent initiating burden AND insufficient corresponding processing AND inadequate functional recovery after a defined withdrawal or rescue interval; these are measurement domains, not obligatory biological stages. Matched human induced pluripotent stem cell-derived neural cultures show preferential microglial aggregate-associated signals and multidomain senescence-associated changes under common exposure, while vulnerability at an equivalent intracellular burden remains to be tested. Substrate-resolved turnover and functional measurements anchor the interpretation of stress markers, bulk autophagy and extracellular-cargo uptake. Proteostasis status, functional adequacy and cell fate are assessed independently, allowing a persistent phenotype after burden clearance to be distinguished from ongoing unresolved stress. Resource competition between mitochondrial maintenance and phagolysosomal work is a testable hypothesis supported by component findings. Human cellular, organoid and animal studies define these components; their complete integration in adult microglia in vivo remains untested. The framework provides falsifiable comparisons and selective-rescue tests for linking protein handling to cell-specific recovery.
SN - 2218-273X
ER -