Different from the rest

The photosynthetic organism Euglena gracilis has an unusual form of the enzyme ATP synthase that can help reconstruct the evolution of this molecular machine.

Structure of the E. gracilis ATP synthase within a membrane. Image credit: Alexander Mühleip (CC BY 4.0)

Every living thing uses the energy-rich molecule called adenosine triphosphate, or ATP, as fuel. It is the universal molecular currency for transferring energy. Cells trade it, mitochondria make it, and the energy extracted from it is used to drive chemical reactions, transport molecules across cell membranes, energize nerve impulses and contract muscles.

ATP synthase is the enzyme that makes ATP molecules. It is a multi-part complex that straddles the inner membrane of mitochondria, the energy factories in cells. The enzyme complex interacts with fatty molecules in the mitochondrial inner membrane, creating a curvature that is required to produce ATP more efficiently. The mitochondrial ATP synthase has been studied in many different organisms, including yeast, algae, plants, pigs, cows and humans. These studies show that most of these ATP synthases are similar to each other, but obtaining a high resolution structure has been a challenge.

Some single-cell organisms have unusual ATP synthases, which provide clues about how the enzyme evolved in pursuit of the most energy efficient arrangement. One such organism is the photosynthetic Euglena gracilis, which is closely related to the human parasites that cause sleeping sickness and Chagas disease.

Now, Mü̈hleip et al. have extracted ATP synthase from E. gracilis and reconstructed its structure using electron cryo-microscopy. The high resolution of this reconstruction allowed for the first time to examine the fatty molecules associated with ATP synthase, called cardiolipins. This is important, because cardiolipins are thought to modulate the rotating motor of the enzyme and affect how the complex sits in the membrane.

The analysis revealed that the ATP synthase in E. gracilis has 29 different protein subunits, 13 of which are only found in organisms of the same family. Some of the newly discovered subunits are glued together by fatty molecules and extend into the surrounding mitochondrial membrane. This distinctive structure suggests an adaptation which likely evolved independently in E. gracilis for efficiency.

These results represent an important advance in the field, and provide direct evidence for the functional roles of cardiolipin. This information will be used to reconstruct the evolution of this mighty molecule and to further study the roles of cardiolipin in energy conversion. Moreover, the analysis identified similarities between the ATP synthase in E. gracilis and human parasites, which could provide new therapeutic targets in disease-causing parasites.