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 3

A glycoprotein secreted by mice with altered mitochondrial function in the liver is responsible for the observed reduction in peripheral WBC counts.

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A glycoprotein secreted by mice with altered mitochondrial function in t...
(A) Total WBC counts are reduced in Control mice injected with Sco1hep plasma relative to those injected with Control plasma (n = 10; P = 0.02 by 2-tailed Student’s t test). (B) The viability of PBMCs isolated from Control mice is significantly reduced when they are cultured with Sco1hep or Cox10hep plasma. PBMC viability is unaffected by exposure to plasma from mice fed a high-fat (HF) diet. Bar graph on right summarizes the operator-blinded quantitation of dead cells per treatment group expressed as a percentage of the total number of cells (live and dead) per image (n = 3–13 per treatment group, P < 0.0001, both hep models versus PBMCs cultured in FBS alone [–], HF, or Control treatment). (C) PBMC viability is rescued if Sco1hep plasma is boiled or treated with trypsin. Fractionation based on size and the presence of a glycan revealed that the factor(s) that reduces PBMC viability is present in a >50 kDa glycoprotein fraction. Scale bars: 50 μm (B and C). The Control and Sco1hep images in panel B are identical to those denoted as “–” in C because they were part of the same experimental series.