Miga Promotes Mitochondrial Fusion And Regulates Autophagy

Mitochondrion is a highly dynamic organelle which undergoes frequent fusion and fission under physiological conditions,a process called mitochondrial dynamics.Mitochondrial fusion protein Mfn,Opal,mitochondrial fission proteins Drpl,Fisl are the main regulators of mitochondrial dynamics.Mutations in these proteins have been associated with severe neurodegenerative disease,such as CMT,ADOP and etc.Thus,it is critical to find new components in mitochondrial dynamics regulation and elucidate the molecular mechanisms how malfunction of mitochondrial dynamics leads to neurodegenerative diseases.Here,in a forward genetic screen that aimed to identify neurodegenerative mutants in Drosophila,we identified a lethal mutant which displayed progressive photoreceptor cell loss and damaged mitochondria in retina.The mutant corresponded to a novel gene mitochondrial guardin(miga),the function of which was largely unknown from fly to mammal.We first discovered that it localised in mitochondria.Loss function of Miga led to mitochondrial fragmentation whereas its over-expression resulted in mitochondrial elongation and clustering.More interestingly,it interacted with another well known mitochondrial fusion protein MitoPLD,which hydrolyses cardiolipin to phosphatic acid,a lipid essential for mitochondrial fusion.Furthermore,Miga is in a complex with alpha subunit of mitochondrial tri-functional protein(MTP),MTPa.However,MTPa has no interaction with MitoPLD.It has been reported that MTP has IV strong cardiolipin binding affinity and mutations in MTP leads to CMT in patients.Thus,we hypothesis that Miga may act as a scaffold protein which binds with MTP and MitoPLD.Miga presents cardiolipin to MitoPLD from MTP.Then MitoPLD hydrolyses cardiolipin to phosphatic acid which promotes mitochondrial fusion.In addition to its function on mitochondrial fusion,Miga also regulates autophagy.Autophagic substrates,such as ATG8,P62,formed large puncta that were not able to enter into lysosome for degradation upon starvation in the mutant cells,indicating some defects in miga mutant clone cells.Also,these autophagy defects that observed are rather specific since loss of several important mitochondrial proteins,including mitochondrial fusion machinery Marf,does not cause similar defects.Surprisingly,loss of Miga dramatically up-regulated lysotracker staining in the fed cells,suggesting an induction of autophagy.It has been reported that MTPa may interact with Atg8 and P62.We found that MTPa interacts with Miga.We will further test whether Miga regulates autophagy through MTPa.This study might provide new insights into the relationship between mitochondria and autophagy.