Hemoglobin alpha is a redox-sensitive mitochondrial-related protein in T-lymphocytes

• Published in: Free radical biology & medicine 2025-02, Vol.227, p.1-11
• Main Authors: Reed, Emily C., Silva, Valeria A., Giebel, Kristen R., Natour, Tamara, Lauten, Tatlock H., Jojo, Caroline N., Schlieker, Abigail E., Case, Adam J.
• Format: Article
• Language: English
• Subjects: Antioxidant; Hba-a1; Hemoglobin; Hydrogen peroxide; Mitochondria; Peroxidase; Redox; T-lymphocyte
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2024.11.044

Hemoglobin subunits, which form the well-characterized, tetrameric, oxygen-carrying protein, have recently been described to be expressed in various non-canonical cell types. However, the exact function of hemoglobin subunits within these cells remains to be fully elucidated. Herein, we report for the first time, the expression of hemoglobin alpha-a1 (Hba-a1) in T-lymphocytes and describe its role as a mitochondrial-associated antioxidant. Within naïve T-lymphocytes, Hba-a1 mRNA and HBA protein are present and highly induced by redox perturbations, particularly those arising from the mitochondria. Additionally, preliminary data using a T-lymphocyte specific Hba-a1 knock-out mouse model indicated that the loss of Hba-a1 led to an exacerbated production of mitochondrial reactive oxygen species and inflammatory cytokines after a stress challenge, further supporting the role of HBA acting to buffer the mitochondrial redox environment. Interestingly, we observed Hba-a1 expression to be significantly upregulated or downregulated depending on T-lymphocyte polarization and metabolic state, which appeared to be controlled by both transcriptional regulation and chromatin remodeling. Altogether, these data suggest Hba-a1 may function as a crucial mitochondrial-associated antioxidant and appears to possess critical and complex functions related to T-lymphocyte activation and differentiation. [Display omitted] •Hemoglobin alpha is expressed and is functional in mouse and human T-lymphocytes.•Activation and polarization of T-lymphocytes dramatically alters hemoglobin expression.•T-lymphocyte hemoglobin impacts mitochondrial function and reactive oxygen species (ROS).•Hemoglobin alpha is redox-responsive in naïve T-lymphocytes, but silenced in activated cells.•Loss of hemoglobin alpha in T-lymphocytes causes potentiated mitochondrial ROS and inflammation.