Abstract: Autophagy is prevalent in eukaryotic organisms. Massive research efforts have focused on the mechanism and functionality of autophagy in eukaryotes, for example, their role in human diseases. However, little is known about how this fundamental pathway evolved; in particular, there is an absence of research in prokaryotes. Here, we carried out a comparative genomics analysis among 84 species ranging from eukaryotes to eubacteria and archaebacteria. We found that most of the core proteins in the autophagy pathway were ubiquitous in eukaryotes, whereas the distribution of proteins involved in selective autophagy were limited. In prokaryotes, distant homologs of autophagy-related proteins were also found. Species in Cyanobacteria and Euryarchaeota possess relatively more of these homologs compared to other prokaryotes, which indicated the prokaryotic origin of some autophagy-related proteins. Phylogenic tree analysis and the distribution of homologs suggested that the presence of proteins involved in autophagosome formation should be an important sign of autophagy. Furthermore, we found that distribution of mitochondrial protein importing-related proteins was quite similar to that of autophagy-related proteins in eukaryotes and that their phylogenic profile was closer to that of several core autophagy proteins compared with 16S/18S ribosomal RNAs, suggesting the engulfment of mitochondria may be the driving force for the evolution of autophagy. Autophagy may have evolved as a quality control system for mitochondria at the very beginning of evolution of eukaryotes. This research shed light on the prokaryotic origin of autophagy and provided a new perspective that mitochondria and autophagy may interplay during the course of eukaryotic evolution.

Key words: autophagy, Cyanobacteria, eukaryotes, Euryarchaeota, evolution, homology search, mitochondria, prokaryotes