Calcium Transients at ER Subdomains Initiate Autophagosome Formation: A Single Spark Can Start a Prairie Fire.

Autophagy is an evolutionarily conserved and tightly regulated lysosome-mediated intracellular bulk degradation pathway by which intracellular macromolecules are sequestered in autophagosomes and delivered to lysosomes for degradation and recycling. Identification of autophagy-related (ATG) genes in yeast has promoted the understanding of the molecular mechanism of autophagosome formation. 1 The proteins encoded by these genes play a crucial role at different steps of autophagosome formation. For example, Atg17/Atg13/Atg1 complexes form condensates and localize on the vacuole membrane, thereby recruiting downstream autophagy proteins to promote the formation of the isolation membrane on the vacuole. 2 Autophagosome biogenesis involves nucleation, expansion, and closure of the isolation membrane. Calcium (Ca 2 + ) is well known as an essential second messenger in eukaryotic cells. 3 Ca 2 + levels are distinct in different sub-cellular compartments and are built up by Ca 2 + channels and pumps located in the plasma membrane and organelles. Due to the resulting highly localized gradients, cytoplasmic Ca 2 + signals display spatiotemporal heterogeneity in the form of sparks,