Unraveling the mystery of the ring: Tracking heme dynamics in living cells.

Heme is an essential protein cofactor used by nearly all forms of life to perform a wide range of tasks, from shuttling electrons to keep photosynthesis running to moving the oxygen we breathe from our lungs throughout our bodies (1). Most of the heme in humans is produced in erythroid cells, which can contain up to 1 billion heme molecules per cell (2). Because free heme that is not bound to proteins is toxic, many students are taught that all heme in erythroid or other cells is bound or being degraded. At best, this picture is incomplete, and, at worst, it obscures fundamental biological questions. One might wonder how bound heme is first loaded into proteins in the various organelles of cells. In addition, new data suggest that unbound or labile heme may be an important signaling molecule (3, 4). Although there have long been tools to study heme structure and synthesis in vitro, as well as tools to study the total heme content in populations of cells, there are few tools to study the dynamics of labile heme in individual, live cells (5). In recent work in PNAS, Hanna et al. (6) develop a new genetically encoded fluorescent sensor for heme, HS1, and uncover the dynamic regulation of resting labile heme, document the mobilization of labile heme in response to NO, and identify glyceraldehyde phosphate dehydrogenase (GAPDH) as a heme buffer in yeast.