The endoplasmic reticulum protein FAM134B acts as a regulator of mitochondrial morphology.

The endoplasmic reticulum (ER) and mitochondria are known to affect myriad cellular mechanisms processes. More recently, dynamic association between them has been identified in different eukaryotes; these interactions vary in their composition and involvement in regulation of intracellular machineries. FAM134B (also known as RETREG1), originally identified as an oncogene, regulates ER membrane shape and curvature. It is a key ER-phagy or reticulophagy receptor, which promotes autophagy of not only the ER but also simultaneous dual autophagy of ER and mitochondria. Although it is known that FAM134B can potentiate contact with mitochondria, its direct involvement in affecting mitochondrial dynamics remains unexplored. Here, we show that FAM134B can interact with the canonical fission-promoting protein DRP1 (also known as DNM1L). Functional depletion of FAM134B leads to local actin rearrangement and reduced DRP1 recruitment onto mitochondria, resulting in hyperfusion. A decrease in FAM134B levels is observed with aging in rat brains, cell and mouse models of Parkinson's disease and samples derived from individuals with disease. Our study establishes FAM134B as the ER partner that helps in maintaining mitochondrial morphology and dynamics.