학술논문
Mitochondrial dysfunction reactivates α-fetoprotein expression that drives copper-dependent immunosuppression in mitochondrial disease models.
Document Type
Journal Article
Author
Jett, Kimberly A.; Baker, Zakery N.; Hossain, Amzad; Boulet, Aren; Cobine, Paul A.; Ghosh, Sagnika; Ng, Philip; Yilmaz, Orhan; Barreto, Kris; DeCoteau, John; Mochoruk, Karen; Ioannou, George N.; Savard, Christopher; Sai Yuan; Abdalla, Osama H. M. H.; Lowden, Christopher; Byung-Eun Kim; Hai-Ying Mary Cheng; Battersby, Brendan J.; Gohil, Vishal M.
Source
Subject
*LEUCOCYTES
*CELL receptors
*CELL death
*MITOCHONDRIA
*LEUCOPENIA
*MITOCHONDRIAL pathology
*COPPER surfaces
*OXIDATIVE phosphorylation
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Language
ISSN
0021-9738
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 identify a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that results in atrophy of the spleen and thymus and causes a peripheral white blood cell deficiency. We demonstrate that the leukopenia is caused by α-fetoprotein, which requires copper and the cell surface receptor CCR5 to promote white blood cell death. We further show that α-fetoprotein expression is upregulated in several cell types upon inhibition of oxidative phosphorylation, including a muscle cell model of Barth syndrome. Collectively, our data argue that α-fetoprotein secreted by bioenergetically stressed tissue suppresses the immune system, an effect which may explain the recurrent infections that are observed in a subset of mitochondrial diseases or in other disorders with mitochondrial involvement. [ABSTRACT FROM AUTHOR]