U.S. Department of Health and Human Services

Getting Heme into Hemoglobin

​A recent investigation determined that a gene called Tmem14c is required for heme production within the mouse red blood cell. Heme is an iron-containing molecule that is important for many biological processes. Heme combines with globin proteins to form hemoglobin, which carries oxygen in red blood cells from the lungs to the rest of the body. Notably, there is virtually no “free” heme in the human body due to the potent heme-scavenging system in the blood. Within cells, heme levels are maintained by a balance of heme production, degradation, and distribution. The mechanisms of heme production and degradation have been intensively studied over several decades. However, the critical steps and location within the red blood cell where heme production takes place are largely unknown.

Building on their previous finding that initially identified the Tmem14c gene as having a role in heme production in the mitochondrial compartment of the red blood cell, researchers mechanistically dissected the functional role of this gene using biochemical, molecular biology, cell biology, pharmacologic, and genetic methods. The Tmem14c gene was found to be “turned on” in mouse embryonic tissues such as the yolk sac, liver, bone marrow, liver, spleen, and blood vessels—yolk sac, liver, and bone marrow play a role in red blood cell production in the embryo. The investigators also reported that the TMEM14C protein was produced in embryonic liver. To learn more about its possible function, the researchers determined that the protein is found associated with mitochondria, the home of cellular energy production. The researchers then examined blood cells derived from mouse embryonic stem cells that had been modified to no longer contain a functional Tmem14c gene. The resulting Tmem14c deficiency caused a decrease in the percentage of hemoglobin-containing red blood cells. In mice, Tmem14c deficiency (resulting from the combination of both copies of the Tmem14c gene being non-functional) was found to be lethal in at the embryonic stage, evidence that this gene is essential for normal development. In contrast, mice with one copy of the non-functional gene were viable and fertile and had normal levels of red blood cells.

To examine its potential role in heme production, the ability of embryonic liver tissue to produce heme was assessed in the absence or presence of a functional Tmem14c gene. The investigators reported a buildup of pre-heme molecules in the absence but not presence of Tmem14c—indicating that a functioning gene is required for complete heme production. 

This study provides valuable insight into the role of Tmem14c in heme production and hemoglobin-containing red blood cells. Future studies may determine whether the human version of this gene contributes to fewer red blood cells than normal (anemia) in people with various blood disorders.

Yien YY, Robledo RF, Schultz IJ, Takahashi-Makise N, Gwynn B, Bauer DE, Dass A, Yi G, Li L, Hildick-Smith GJ, Cooney JD, Pierce EL, Mohler K, Dailey TA, Miyata N, Kingsley PD, Garone C, Hattangadi SM, Huang H, Chen W, Keenan EM, Shah DI, Schlaeger TM, DiMauro S, Orkin SH, Cantor AB, Palis J, Koehler CM, Lodish HF, Kaplan J, Ward DM, Dailey HA, Phillips JD, Peters LL, and Paw BH. TMEM14C is required for erythroid mitochondrial heme metabolism. J Clin Invest 124: 4294-4304, 2014.