Language
English
Publication Date
1-3-2023
Journal
Journal of Clinical Investigation
DOI
10.1172/JCI154684
PMID
36301669
PMCID
PMC9797342
PubMedCentral® Posted Date
1-3-2023
PubMedCentral® Full Text Version
Post-print
Abstract
Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identified a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that resulted in atrophy of the spleen and thymus and caused a peripheral white blood cell deficiency. We demonstrated that the leukopenia was caused by α-fetoprotein, which required copper and the cell surface receptor CCR5 to promote white blood cell death. We further showed that α-fetoprotein expression was upregulated in several cell types upon inhibition of oxidative phosphorylation. Collectively, our data argue that α-fetoprotein may be secreted by bioenergetically stressed tissue to suppress the immune system, an effect that may explain the recurrent or chronic infections that are observed in a subset of mitochondrial diseases or in other disorders with secondary mitochondrial dysfunction.
Keywords
Mice, Animals, Copper, alpha-Fetoproteins, Mitochondria, Mitochondrial Diseases, Immunosuppression Therapy, Metabolism, Mitochondria
Published Open-Access
yes
Recommended Citation
Jett, Kimberly A; Baker, Zakery N; Hossain, Amzad; et al., "Mitochondrial Dysfunction Reactivates α-Fetoprotein Expression That Drives Copper-Dependent Immunosuppression in Mitochondrial Disease Models" (2023). Faculty and Staff Publications. 2265.
https://digitalcommons.library.tmc.edu/baylor_docs/2265
Graphical Abstract
Included in
Biological Phenomena, Cell Phenomena, and Immunity Commons, Biomedical Informatics Commons, Genetics and Genomics Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Medical Specialties Commons