Mitoguardin Regulates Mitochondrial Fusion through MitoPLD and Is Required for Neuronal Homeostasis

• Published in: Molecular cell 2016-01, Vol.61 (1), p.111-124
• Main Authors: Zhang, Yongping, Liu, Xiaoman, Bai, Jian, Tian, Xuejun, Zhao, Xiaocui, Liu, Wei, Duan, Xiuying, Shang, Weina, Fan, Heng-Yu, Tong, Chao
• Format: Article
• Language: English
• Subjects: Animals; Drosophila; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Female; Genotype; HEK293 Cells; HeLa Cells; Homeostasis; Humans; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Mitochondria - enzymology; Mitochondria - pathology; Mitochondrial Dynamics; mitochondrial fusion; Mitochondrial Membranes - enzymology; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; MitoPLD; Mutation; neurodegeneration; Neurons - enzymology; Neurons - pathology; NIH 3T3 Cells; Phenotype; Phospholipase D - genetics; Phospholipase D - metabolism; Photoreceptor Cells, Invertebrate - enzymology; Protein Multimerization; RNA Interference; Transfection
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2015.11.017

Mitochondria undergo frequent morphological changes through fission and fusion. Mutations in core members of the mitochondrial fission/fusion machinery are responsible for severe neurodegenerative diseases. However, the mitochondrial fission/fusion mechanisms are poorly understood. We found that the loss of a mitochondrial protein encoding gene, mitoguardin (miga), leads to mitochondrial defects and neurodegeneration in fly eyes. Mammals express two orthologs of miga: Miga1 and Miga2. Both MIGA1 and MIGA2 form homotypic and heterotypic complexes on the outer membrane of the mitochondria. Loss of MIGA results in fragmented mitochondria, whereas overexpression of MIGA leads to clustering and fusion of mitochondria in both fly and mammalian cells. MIGA proteins function downstream of mitofusin and interact with MitoPLD to stabilize MitoPLD and facilitate MitoPLD dimer formation. Therefore, we propose that MIGA proteins promote mitochondrial fusion by regulating mitochondrial phospholipid metabolism via MitoPLD. [Display omitted] •The miga mutant maintains neuronal homeostasis in fly photoreceptor cells•MIGA1/2 are mitochondrial outer membrane proteins regulating mitochondrial fusion•MIGA1/2 function occurs downstream of the mitofusin proteins•MIGA1/2 regulate mitochondrial fusion through MitoPLD The loss of miga leads to mitochondrial defects and neurodegeneration in fly eyes. MIGA proteins localize on the mitochondrial outer membrane and regulate mitochondrial fusion by facilitating MitoPLD dimer formation.