Prem Ponka - Professor

Jewish General Hospital
Lady Davis Institute
3755 Cote Ste. Catherine Road
Montréal, Québec
H3T 1E2

(514) 340-8260 ext 25289

prem.ponka [at]


Research Area:  Physiology and Pathophysiology of Blood

Research Description:

Iron (Fe) is an essential nutrient required for oxygen transfer, energy production, and cell growth. While it is necessary for life, it is highly toxic in excess, and Fe balance in the body must be strictly regulated. Current research focuses on:

(1) The biochemistry and molecular biology of intracellular iron and heme metabolism in erythroid cells:

Delivery of Fe to most cells occurs following the binding of diferric transferrin (Tf) to its cognate receptors on the cell membrane following which the Tf-receptor complexes are internalized via endocytosis. Iron is released from Tf within endosomes by a combination of Fe3+ reduction by Steap3 and a decrease in pH (~ 5.5); Fe2+ is then transported through the endosomal membrane by the divalent metal transporter 1, DMT1. In erythroid cells, more than 90% of Fe2+ enters mitochondria where ferrochelatase inserts Fe2+ into protoporphyrin IX to form heme. The intracellular path of iron from endosomes to ferrochelatase is still obscure or, at best, controversial. The prevailing opinion is that Fe, after its export from endosomes, spreads into the cytosol, from where the metal mysteriously finds its way into mitochondria.

In contrast, Dr. Ponka discovered that the highly efficient transport of Fe toward ferrochelatase in erythroid cells requires a direct interaction between Tf-endosomes and mitochondria ("kiss-and-run" mechanism). He and his colleagues demonstrated that 1) endosome mobility is essential for the efficient incorporation of Fe from transferrin into heme, 2) in erythroid cells, endosomes continuously traverse the cytosol and touch mitochondria, and 3) the highly efficient transport of Fe to erythroid cell mitochondria requires the direct interaction between endosomes and mitochondria. These reports represent a “paradigm shift” in the field of intracellular Fe homeostasis, and document the first example of an inter-organellar interaction involved in the delivery of an exogenous micronutrient to a target organelle. The Ponka lab now focuses on the identification of the molecular partners involved in the endosme-mitochondria interaction in developing red blood cells (RBC).

(2) Investigation of the role of heme oxygenase 1 (HO-1) in the pathophysiology of β-thalassemia

Dr. Ponka’s laboratory has recently provided, for the first time, unequivocal evidence that heme oxygenase (HO-1), the only physiological mechanism for heme degradation, is expressed in erythroid cells. Ponka and his co-workers demonstrated that levels of this enzyme increase during maturation of developing RBC where HO-1 acts as a co-regulator of heme synthesis. Based on this novel and crucial finding, The Ponka group hypothesized that in thalassemic erythroblasts, characterized by an imbalance in the synthesis of α- and β-globins (with hemes attached to them), unshielded “free” heme may be responsible for the damage (caused by oxidative stress) in developing RBC. They provided evidence for this hypothesis by showing that β-thalassemic mice injected with tin-protoporphyrin IX (a competitve HO inhibitor) have increased hemoglobin levels and red blood cell counts. These investigators plan to asses effects of non-competitive inhibitors of HO as well as inhibitors of glycine transport, which reduce heme synthesis, on β-thalassemia intermedia mice Results of these studis will be crucially important for the development of novel strategies in the treatment of thalassemias.

Education:  M.D. Ph.D., Charles University (Prague)

Selected Recent Publications:

Garcia-Santos D, Hamdi A, Saxova Z, Fillebeen C, Pantopoulos K, Horvathova M, Ponka P. Inhibition of heme oxygenase ameliorates anemia and reduces iron overload in β-thalassemia mouse model. Blood. 131:236-246, 2018. This article was featured in “This Week in Blood”, a snapshot of the hottest studies from each week’s issue, hand-picked by Editor-in-Chief of Blood.

Garcia-Santos D, Schranzhofer M, Bergeron R, Sheftel AD, Ponka P. Extracellular glycine is necessary for optimal hemoglobinization of erythroid cells. Haematologica. 102:1314-1323, 2017.

Ponka P, Sheftel AD, English AM, Bohle DS, Garcia-Santos D. Do mammalian cells need to export and import heme? Trends Biochem Sci. 42:395-406, 2017.

Hamdi A, Roshan TM, Kahawita TM, Mason AB, Sheftel AD and Ponka P. Erythroid cell mitochondria receive endosomal iron by a "kiss-and-run" mechanism. BBA-MCR.1863:2859-2867, 2016.

Ponka P, Prchal JT. Polyclonal and Hereditary Sideroblastic Anemias (Invited Chapter; peer reviewed). In: Williams Hematology, 9 th edition, Chapter 59 (Lichtman MA et al. eds.) McGraw-Hill, pp. 915-922, 2016.

Gasiorek JJ, Mikhael M, Garcia-Santos D, Hui ST, Ponka P, Blank V. Thioredoxin-interacting protein regulates the differentiation of murine erythroid precursors. Exp Hematol. 43:393-403, 2015.

Ponka P, Tenenbein M, Eaton J. “Iron” (Invited Chapter; peer reviewed). In: Handbook of Toxicology of Metals, Fourth Ed (Nordberg G, Fowler B, Nordberg M, Fridberg L, eds.), Academic Press, pp. 879–902, 2015.

Garcia-Santos D, Schranzhofer M, Horvathova M, Jaberi MM, Bogo Chies JA, Sheftel A, Ponka P. Heme oxygenase 1 is expressed in murine erythroid cells where it controls the level of regulatory heme. Blood. 123: 2269-2277, 2014. This article was accompanied by Editorial Commentary by Brousse V, El Nemer W. Toward unraveling heme regulation. Blood. 123: 2134-2135, 2014.

Huang ML-H, Austin CJD, Sari M-A, Suryo Rahmanto Y, Ponka P, Vyoral D, Richardson DR. Hepcidin bound to α2-macroglobulin reduces ferroportin-1 expression and enhances its activity at reducing serum iron levels. J Biol Chem. 288:25450-25465, 2013.

Ponka P, Koury MJ, Sheftel AD. Erythropoiesis, Hemoglobin Synthesis, and Erythroid Mitochondrial Iron Homeostasis (Invited Chapter; peer reviewed). In: “The Handbook of Porphyrin Science”, (Ferreira, G. C., Kadish, K.M., Smith, K.M. and Guilard, R., eds.) World Scientific Publishers, Singapore, Vol. 27, Chapter 129, pp. 41- 84, 2013.

Whitnall M, Suryo Rahmanto Y, Huang M, Saletta F, Hiu CL, Loka C, Gutiérrez L, Lázaro, FJ, Flemming AJ, St. Pierre TG, Mikhael MR, Lim C, Ponka P*, Richardson DR. Identification of nonferritin mitochondrial iron deposits in a mouse model of Friedreich ataxia. Proc Natl Acad Sci USA. 109: 20590–20595, 2012. *Corresponding author.

Link to Dr. Ponka's publications

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