| First Author | Jett KA | Year | 2023 |
| Journal | J Clin Invest | Volume | 133 |
| Issue | 1 | PubMed ID | 36301669 |
| Mgi Jnum | J:332545 | Mgi Id | MGI:7427321 |
| Doi | 10.1172/JCI154684 | Citation | Jett KA, et al. (2023) Mitochondrial dysfunction reactivates alpha-fetoprotein expression that drives copper-dependent immunosuppression in mitochondrial disease models. J Clin Invest 133(1) |
| abstractText | 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 alpha-fetoprotein, which required copper and the cell surface receptor CCR5 to promote white blood cell death. We further showed that alpha-fetoprotein expression was upregulated in several cell types upon inhibition of oxidative phosphorylation. Collectively, our data argue that alpha-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. |
