Mitochondrial dysfunction reactivates α-fetoprotein expression that drives copper-dependent immunosuppression in mitochondrial disease models
Kimberly A. Jett, … , Vishal M. Gohil, Scot C. Leary
Kimberly A. Jett, … , Vishal M. Gohil, Scot C. Leary
Published October 27, 2022
Citation Information: J Clin Invest. 2023;133(1):e154684. https://doi.org/10.1172/JCI154684.
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Research Article Metabolism

Mitochondrial dysfunction reactivates α-fetoprotein expression that drives copper-dependent immunosuppression in mitochondrial disease models

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.

Authors

Kimberly A. Jett, Zakery N. Baker, Amzad Hossain, Aren Boulet, Paul A. Cobine, Sagnika Ghosh, Philip Ng, Orhan Yilmaz, Kris Barreto, John DeCoteau, Karen Mochoruk, George N. Ioannou, Christopher Savard, Sai Yuan, Osama H.M.H. Abdalla, Christopher Lowden, Byung-Eun Kim, Hai-Ying Mary Cheng, Brendan J. Battersby, Vishal M. Gohil, Scot C. Leary

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Figure 2

The reduction in peripheral WBC counts in hepatocytes is positively correlated with the bioenergetic deficit in the liver.

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The reduction in peripheral WBC counts in hepatocytes is positively corr...
(A) Coa5hep (n = 6; P < 0.001) and (B) Cox10hep (n = 15–16; P < 0.01) mice also exhibit a significant leukopenia. (C) Coa5hep mice (purple bars) have a disproportionate reduction in the wet weight of the spleen (n = 6; P < 0.01) and thymus (n = 5; P < 0.001), while Cox10hep mice (blue bars) exhibit significant yet milder atrophy of the spleen (n = 14; P < 0.05). Significance was assessed using a 2-tailed Student’s t test (A–C). (D) Total WBC counts are positively correlated with liver ATP content in all 3 hep mouse models (linear regression R2 = 0.99; P = 0.001). P47 Sco1hep and P64 Cox10hep livers have higher levels of (E) the phosphorylated form of eIF2α, an ISR marker, and (F) the Atf6 transcript, a marker of ER stress (1-way ANOVA with Tukey’s post hoc test, n = 4–6; P < 0.005, Sco1hep model; P < 0.02, Cox10hep model).