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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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 6

AFP promotes activation and apoptosis of both mouse and human WBCs via the cell surface receptor CCR5.

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AFP promotes activation and apoptosis of both mouse and human WBCs via t...
(A) PBMCs isolated from peripheral blood of Sco1hep mice have an increased number of cells that stain positive for the activation marker CD44 and the apoptotic marker annexin V when compared with PBMCs isolated from Controls (n = 6). (B) PBMCs isolated from Control mice that were cultured in media containing Sco1hep plasma are activated earlier and demonstrate a progressive increase in cell surface expression of the apoptotic marker annexin V relative to PBMCs cultured in Control plasma (n = 3). (C) Cells analyzed in B show blebbing (a sign of apoptosis) as early as 12–24 hours in culture and loss of cellularity after 72 hours in culture in response to culturing with Sco1hep but not Control plasma. (D) Human PBMC viability is also reduced in media containing Sco1hep plasma, and can be rescued with the CCR5 antagonist maraviroc. mPBMCs and hPBMCs, PBMCs of mouse and human origin, respectively (mPBMCs, n = 3; hPBMCs n = 2; each replicate contained a triplicate for each experimental condition). Scale bars: 50 μm (C and D).