title: Drosophila clueless is involved in Parkin-dependent mitophagy by promoting VCP-mediated Marf degradation.
abstract: PINK1/Parkin-mediated mitochondrial quality control (MQC) requires valosin-containing protein (VCP)-dependent Mitofusin/Marf degradation to prevent damaged organelles from fusing with the healthy mitochondrial pool, facilitating mitochondrial clearance by autophagy. Drosophila clueless (clu) was found to interact genetically with PINK1 and parkin to regulate mitochondrial clustering in germ cells. However, whether Clu acts in MQC has not been investigated. Here, we show that overexpression of Drosophila Clu complements PINK1, but not parkin, mutant muscles. Loss of clu leads to the recruitment of Parkin, VCP/p97, p62/Ref(2)P and Atg8a to depolarized swollen mitochondria. However, clearance of damaged mitochondria is impeded. This paradox is resolved by the findings that excessive mitochondrial fission or inhibition of fusion alleviates mitochondrial defects and impaired mitophagy caused by clu depletion. Furthermore, Clu is upstream of and binds to VCP in vivo and promotes VCP-dependent Marf degradation in vitro Marf accumulates in whole muscle lysates of clu-deficient flies and is destabilized upon Clu overexpression. Thus, Clu is essential for mitochondrial homeostasis and functions in concert with Parkin and VCP for Marf degradation to promote damaged mitochondrial clearance.
authors.affiliation: Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri, Kansas City, MO 64110, USA and.
authors.forename: Zong-Heng
authors.initials: ZH
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66506, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Clark
authors.affiliation: Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri, Kansas City, MO 64110, USA and Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66506, USA geisbrechte@ksu.edu.
authors.forename: Erika R
authors.initials: ER
authors.lastname: Geisbrecht
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics; D063306:Mitophagy / Q000235:genetics; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D000074405:Valosin Containing Protein; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000251:Adenosine Triphosphatases; D029721:Drosophila Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D000074405:Valosin Containing Protein; C527117:Marf protein, Drosophila; C531978:ab protein, Drosophila; C111567:parkin protein; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C585179:ter94 protein, Drosophila