Li, X.; Voronin, D.; Bhattacharyya, R.; Klein, J.; Haas, M.; Cho, W. J.; Robinson, C. G.; Throm, R. E.; Wu, G.; Li, C.; Sapkota, Y.; Niemi, N.; Pruett-Miller, S. M.; Opferman, J. T.; Chang, C.-L.

Mitochondria and lipid droplets (LDs) are functionally coupled to coordinate fatty acid utilization and storage. However, a comprehensive understanding of mitochondria-LD alliances remains elusive. We have identified a previously unrecognized role for optical atrophy 1 (OPA1), a mitochondrial fusion factor, in the regulation of fatty acid release from LDs. We demonstrated that OPA1's exon 4 adapts an amphipathic helix to target OPA1 to LDs. OPA1 localized to LDs promote fatty acid release by facilitating the recruitment of lipases to LDs. In addition, OPA1's residence on LDs competes with its mitochondrial entry, influencing mitochondria fusion and connectivity. Furthermore, the S158N polymorphism within OPA1's exon 4 exhibiting attenuated fatty acid release from LDs is associated with changes in metabolic traits in pediatric cancer survivors. Altogether, our findings reveal that OPA1 actively mediates fatty acid release from LDs and provide a mechanistic link between OPA1 and human metabolism.