Paper

Mitochondrial dysfunction triggers secretion of the immunosuppressive factor α-fetoprotein

Cobine, Paul A, Savard, Christopher, Boulet, Aren, Hossain, Amzad, Leary, Scot C, Mochoruk, Karen, Battersby, Brendan J, Yilmaz, Orhan, Byung-Eun, Kim, Barretto, Kris, Decoteau, John, Ioannou, George, Gohil, Vishal M M, Baker, Zakery N, Lowden, Christopher, Ghosh, Sagnika, Hai-Ying, Mary Cheng, Ng, Philip, Jett, Kimberly A, Yuan, Sai

2021

Overview

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. Competing Interest Statement The authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Atrophy / Bioenergetics / CCR5 protein / Cell Biology / Cell death / Cell surface / Copper / Etiology / Immune system / Leukopenia / Metabolic disorders / Mitochondria / Oxidative phosphorylation / Phosphorylation / Spleen / α-Fetoprotein