Figure 4.

Higd1a regulates the dynamic equilibrium of mitochondria. By interacting with OPa1, Higd1a postpones the cleavage of the long Opa1 (L-Opa1) isoform to the short Opa1 (S-Opa1) isoform, which facilitates the fusion of mitochondria. The L-Opa1 anchors on MIM and is generated by cleavage of the mitochondrial targeting sequence of Opa1 precursor protein. The S-Opa1 is produced by further proteolyzing the N terminus of L-Opa1. Silencing of Higd1a leads to impaired mitochondrial fusion, loss of mtDNA, disorganization of cristae, and growth retardation of the cells. Higd1a functions as a negative regulator of γ secretase complex activation to decrease the production of amyloid-β (Aβ), which induces excessive fragmentation of mitochondria and causes defective mitophagy. Consistent with less activation of γ secretase complex, Higd1a attenuates mitochondrial damage as indicated by reduced reactive oxygen species (ROS) production, less severe mitochondrial swelling and increased ATP production, which indicates improved dynamic equilibrium of mitochondria.