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

• Published in: The Journal of clinical investigation 2023-01, Vol.133 (1), p.1-13
• Main Authors: 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, Yuan, Sai, Abdalla, Osama Hmh, Lowden, Christopher, Kim, Byung-Eun, Cheng, Hai-Ying Mary, Battersby, Brendan J, Gohil, Vishal M, Leary, Scot C
• Format: Article
• Language: English
• Subjects: Adenoviruses; alpha-Fetoproteins - metabolism; Animals; Atrophy; Bioenergetics; Biomedical research; Blood; CCR5 protein; Cell death; Cell surface; Copper; Copper - metabolism; Cytochrome; Disease; Etiology; Gene expression; Homeostasis; Immune system; Immunosuppression; Immunosuppression Therapy; Infections; Leukopenia; Liver; Metabolic disorders; Metabolism; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial Diseases - metabolism; Oxidative phosphorylation; Pathogenesis; Phosphorylation; Physiology; Spleen; Thymus gland; α-Fetoprotein
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI154684

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.