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
Published Open-Access
yes
Keywords
Mice, Animals, Copper, alpha-Fetoproteins, Mitochondria, Mitochondrial Diseases, Immunosuppression Therapy, Metabolism, Mitochondria
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.
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