The enigmatic ATP supply of the endoplasmic reticulum

The endoplasmic reticulum (ER) is a functionally and morphologically complex cellular organelle largely responsible for a variety of crucial functions, including protein folding, maturation and degradation. Furthermore, the ER plays an essential role in lipid biosynthesis, dynamic Ca²⁺ storage, and detoxification. Malfunctions in ER-related processes are responsible for the genesis and progression of many diseases, such as heart failure, cancer, neurodegeneration and metabolic disorders. To fulfill many of its vital functions, the ER relies on a sufficient energy supply in the form of adenosine-5'-triphosphate (ATP), the main cellular energy source. Despite landmark discoveries and clarification of the functional principles of ER-resident proteins and key ER-related processes, the mechanism underlying ER ATP transport remains somewhat enigmatic. Here we summarize ER-related ATP-consuming processes and outline our knowledge about the nature and function of the ER energy supply.