Barry H. Paw, MD, PhD

A study led by Barry H. Paw, MD, PhD, with Yvette Y. Yien, PhD, BWH Division of Hematology, discovered that the inner mitochondrial membrane protein, TMEM14C, is critical for import of a molecule called protoporphyrinogen IX into the mitochondrial matrix for heme synthesis and hemoglobin production in red cells. Heme is part of a chemical group known as porphyrins. Heme plays an important role in redox reactions and is the critical component of the oxygen-carrying protein, hemoglobin.

Heme synthesis involves multiple porphyrin intermediates and several mitochondrial enzymes. The heme biosynthesis intermediates are trafficked through the mitochondria during synthesis, and these trafficking steps constitute key regulatory junctures. Disruption of trafficking may result in anemia due to insufficient heme synthesis. The researchers sought to identify heme intermediate transport proteins that are upregulated in terminally differentiating erythroid cells (red blood cells).

Yvette Y. Yien, PhD

Yvette Y. Yien, PhD

TMEM14C was one such transport protein identified, and it is abundant in vertebrate hematopoietic tissue. In pre-clinical models, TMEM14C deficiency produced porphyrin accumulation in fetal liver (site of hematopoietic activity), halting of erythroid maturation, and anemia leading to embryonic death. In TMEM14C-deficient erythroid cells, protoporphyrin IX synthesis was blocked, resulting in an increase in porphyrin precursors. A protoporphyrin IX analog was able to ameliorate the heme synthesis defect in TMEM14C-deficient cells, demonstrating that TMEM14C operates in the final steps of heme synthesis.

“We found that TMEM14C plays a critical and conserved role in normal red cell development and is required for erythroid heme metabolism in vertebrate species. Unexplained anemias in humans might be caused by defects in TMEM14c,” said Paw.

The study was published Oct. 1, 2014 in The Journal of Clinical Investigation.