Legends of deathly pale vampires that rise from their graves at night to search for human blood may have been inspired partly by a rare disease known as porphyria. This is caused by defects in haeme production. Haem gives blood its characteristic red colour and its ability to carry oxygen. People with some forms of porphyria are sensitive to sunlight and suffer from anaemia — key features of Dracula. Although porphyria may have coloured Bram Stoker's famous literary creation, scientists know little about the disease's molecular origins. Work by John Schuetz and his colleagues at the St Jude Children's Research Hospital in Tennessee has provided some answers. These could lead to new ways of treating the disease.

For a long time, Schuetz had been studying different ATP-binding cassette (ABC) transporters. These are proteins that help move different molecules, such as nucleotides and lipids, across cell membranes. In 1997, his group isolated a new transporter, known as ABCB6. “For a long time it was an orphan transporter — we didn't know what it did,” says Schuetz. ABCB6's function remained a mystery until two postdocs in Schuetz's lab took the lead on a project to uncover its role. They showed that ABCB6 localizes to the outer membrane of mitochondria, where it binds to a small molecule known as porphyrin, from which haem is made (see page 586).

This was contrary to conventional wisdom, which held that the transporter protein could not reside in the outer mitochondrial membrane because the membrane contained no other such proteins. “The biggest hurdle was overcoming criticism from others in the field,” says Schuetz. But this scepticism only motivated the group to make an air-tight case for their theory.

Credit: BIOMEDICAL COMMUNICATIONS, ST JUDE CHILDREN'S RESEARCH HOSPITAL

The first clue Schuetz and his colleagues had about their protein's function was that it localizes to the mitochondria. By scouring microarray expression databases, they discovered that ABCB6 is most prevalent in red blood cells, particularly at a time early in development when the cells are actively synthesizing haem. They knew that, during this process, porphyrin must travel from the cytoplasm, where it is made, into mitochondria, where it binds iron to make haeme. Schuetz's group did not think porphyrin, which has a negative charge, could enter mitochondria — also negatively charged — alone, as others had proposed. “It would be like putting two magnets with opposite poles together,” says Schuetz. He and his team therefore reasoned that the job of ABCB6 might be to help carry porphyrin across the mitochondrial membrane.

Pinpointing the tranporter's localization to the outer mitochondrial membrane — where it could bind freshly made porphyrin in the cytoplasm — and demonstrating a direct correlation between its activity and haem production in red blood cells proved their instinct was correct. The team's work suggests that some types of porphyria might stem from factors that interfere with the transport, rather than the synthesis, of porphyrin. “The mechanism of drug-induced porphyrias has not been explained. This might give us a molecular handle to start investigating the process,” adds Schuetz. If the team's hypothesis is correct, restoring the function of ABCB6 may provide relief from disease symptoms and help some porphyria patients lead more normal lives. It might have saved Count Dracula a lot of sleepless nights.