PGC-1α: Looking behind the Sweet Treat for Porphyria

Porphyrias are a group of genetic disorders caused by mutations in enzymes of the heme biosynthesis pathway. Acute attacks of porphyria, reputedly the disease that incapacitated the British sovereign King George III (see this Cell cover), are precipitated by fasting and are treated by infusing heme or glucose, although the underlying molecular mechanisms remain unclear. In this issue of Cell, Handschin et al. (2005) reveal that a transcriptional coactivator called PGC-1␣ is a key player in both induction of porphyria by fasting and amelioration of the symptoms by glucose treatment. The porphyrin heme is the crucial iron bound prosthetic group of hemoglobins that enables red blood cells to carry oxygen. All nucleated cells require heme for production of functional respiratory cytochrome proteins. About 85% of heme biosynthesis takes place in ery-throid cells, and this heme is destined for incorporation into hemoglobins (reviewed in Kauppinen, 2005). Most of the heme that is not produced in red blood cells is made by the liver and then incorporated into various heme proteins such as members of the cytochrome P450 family. De novo heme biosynthesis is carried out by the sequential actions of eight distinct enzymes (see Figure 1A). The first and rate-limiting step of the pathway is catalyzed by the enzyme δ-aminolevulinic acid (ALA) synthase (ALAS), which promotes condensation of gly-cine and succinyl CoA to form ALA. Mammals have two ALAS genes: the housekeeping gene ALAS-1 is ubiquitously expressed, whereas ALAS-2 is specific to ery-throid cells. Given that excess heme is toxic to cells, it is not surprising that the heme biosynthetic pathway is tightly regulated. For example, both the expression and activity of ALAS-1 are inhibited by heme via feedback mechanisms. In addition, heme biosynthesis can be upregulated in response to an increase in demand, perhaps best illustrated by the drug-induced increase in the production of cytochrome P450 family members in the liver, which metabolize drugs. Reflecting the requirement of cytochrome P450 proteins for heme, many drugs concomitantly induce expression of the ALAS-1 gene (Podvinec et al., 2004). Ironically, such drug-mediated induction of ALAS-1 expression in turn can precipitate a porphyria attack in susceptible individuals. Porphyrias are caused by loss-of-function mutations in any of the seven enzymes of the heme biosynthetic pathway apart from ALAS-1 (Kauppinen, 2005). These mutations lead to overproduction and accumulation of different heme biosynthetic intermediates depending on which enzyme is affected. Mutations in four of the enzymes cause …