Structural insights into Mitoguardin-1-mediated mitochondrial contact surfaces in fusion and lipid binding

Mitochondrial fusion is essential for organelle homeostasis 1 , 2 and is regulated by MFN1/2, Mito-PLD, and the Mitoguardin (MIGA) family 3 , 4 . MIGA proteins localize to the outer mitochondrial membrane 5 , where they have been implicated in mitochondrial fusion and lipid homeostasis through interactions with Mito-PLD and membrane contact sites 6 , 7 . In particular, MIGA2 promotes triglyceride synthesis at mitochondria-associated membrane contact sites 8 , whereas MIGA1/2 deficiency causes defects in lipid metabolism in vivo 9 . Human MIGA1 contains four conserved domains 10 , an N-terminal TM, a coiled-coil domain, an FFAT motif, and a C-terminal LD-targeting domain (Supplementary Fig. S1a ) 11 , 12 . However, despite its established roles in mitochondrial fusion and lipid homeostasis 13 , 14 , the structural basis of MIGA1 oligomerization, the molecular determinants of lipid binding, and their relationship to mitochondrial fusion remain unknown.