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 1

Ablation of Sco1 expression in hepatocytes results in an unexpected reduction in circulating white blood cell counts and atrophy of the thymus and spleen.

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Ablation of Sco1 expression in hepatocytes results in an unexpected redu...
(A) Progressive leukopenia in Sco1hep mice (2-way ANOVA with Bonferroni’s post hoc test, n = 5–20; P < 0.01) and (B) disproportionate reduction in the wet weights of the Sco1hep spleen and thymus at P37 (n = 8; P < 0.01) and P47 (n = 13; P < 0.001); 2-tailed Student’s t test. (C) Selective thinning of the Sco1hep thymic cortex. Top row: Control. Bottom row: Sco1hep. Scale bars: 2 mm and 800 μm (P47 Sco1hep thymus). (D) Adenoviral restoration of SCO1 expression in the liver leads to (E) rescue of splenic and thymic atrophy (n = 5) and (F) normalization of WBC counts (n = 3–5). Mice were injected on P21 via cardiac puncture with vehicle or helper-dependent adenovirus harboring a Sco1 cDNA under the control of a liver-specific promoter and harvested at P47. Control, wild-type littermates; BW, body weight; WBC and RBC, white and red blood cells, respectively.