PDZD8 is not the ‘functional ortholog’ of Mmm1, it is a paralog

Authors of a recent paper demonstrate that, like ERMES (ER-mitochondria encounter structure) in fungal cells, PDZD8 (PDZ domain containing 8) tethers mitochondria to the ER in mammalian cells. However, identifying PDZD8 as a “functional ortholog” of yeast Mmm1 (maintenance of mitochondrial morphology protein 1) is at odds with the phylogenetic data. PDZD8 and Mmm1 are paralogs, not orthologs, which affects the interpretation of the data with respect to the evolution of ER-mitochondria tethering. Our phylogenetic analyses show that PDZD8 co-occurs with ERMES components in lineages closely related to animals solidifying its identity as a paralog of Mmm1. Additionally, we identify two related paralogs, one specific to flagellated fungi, and one present only in unicellular relatives of animals. These results point to a complex evolutionary history of ER-mitochondria tethering involving multiple gene gains and losses in the lineage leading to animals and fungi.