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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 Article has an altmetric score of 7

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

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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 4

AFP expression is increased in response to impaired organelle function and is directly responsible for the leukopenia observed in several mitochondrial disease models.

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AFP expression is increased in response to impaired organelle function a...
(A) AFP is significantly enriched in hep relative to Control plasma. Volcano plot with dotted lines indicating a 2-fold change and adjusted P-value significance threshold of 0.1. A green or red symbol indicates a protein whose abundance is significantly up- or downregulated, respectively. Gray symbols denote proteins whose abundance is not significantly different (NS) between the 2 groups. (B) AFP abundance is markedly upregulated in Sco1hep, Coa5hep, and Cox10hep plasma. Plasma was pooled (minimum of 2 males and 2 females per pool) and depleted of immunoglobulins and albumin prior to Western blotting. The Ponceau S–stained membrane indicates relative loading across lanes. (C) AFP progressively accumulates in Sco1hep plasma (n = 4–7; P27, P < 0.05; P37, P < 0.0001; P47, P < 0.0001). (D) PBMC viability is rescued by immunodepleting AFP from Sco1hep plasma. Culture media supplemented with PBS and plasma incubated with αSLC25A3, an antibody isotype control, served as internal controls. Original magnification, ×60 (same scale as in Figure 3, B and C; Figure 5, D and E; and Figure 6, C and D). (E) Control mice develop a leukopenia following serial injection with Sco1hep plasma (n = 3–4; P < 0.01) or 1 μg of recombinant AFP (rAFP) (n = 5; P < 0.01). Control mice injected with Control plasma or albumin served as internal controls. (F and G) Inhibition of the mitochondrial respiratory chain elevates AFP abundance in C2C12 myoblasts. (H and I) AFP levels increase in C2C12 myoblasts and human B lymphoblasts upon inhibition of COX. For panels F–I, β-actin was used as a loading control and data are shown as mean ± SD (n = 3). *P < 0.05, **P < 0.005. Significance was assessed using a 2-tailed Student’s t test (C, E, G, and I). NS, not significant.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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