title: Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration.
abstract: Mitochondrial AAA (ATPases Associated with diverse cellular Activities) proteases i-AAA (intermembrane space-AAA) and m-AAA (matrix-AAA) are closely related and have major roles in inner membrane protein homeostasis. Mutations of m-AAA proteases are associated with neuromuscular disorders in humans. However, the role of i-AAA in metazoans is poorly understood. We generated a deletion affecting Drosophila i-AAA, dYME1L (dYME1L(del)). Mutant flies exhibited premature aging, progressive locomotor deficiency and neurodegeneration that resemble some key features of m-AAA diseases. dYME1L(del) flies displayed elevated mitochondrial unfolded protein stress and irregular cristae. Aged dYME1L(del) flies had reduced complex I (NADH/ubiquinone oxidoreductase) activity, increased level of reactive oxygen species (ROS), severely disorganized mitochondrial membranes and increased apoptosis. Furthermore, inhibiting apoptosis by targeting dOmi (Drosophila Htra2/Omi) or DIAP1, or reducing ROS accumulation suppressed retinal degeneration. Our results suggest that i-AAA is essential for removing unfolded proteins and maintaining mitochondrial membrane architecture. Loss of i-AAA leads to the accumulation of oxidative damage and progressive deterioration of membrane integrity, which might contribute to apoptosis upon the release of proapoptotic molecules such as dOmi. Containing ROS level could be a potential strategy to manage mitochondrial AAA protease deficiency.
authors.affiliation: Laboratory of Molecular Genetics, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Qi
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Genetics, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Daniels
authors.affiliation: National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD, USA.
authors.forename: G
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular Genetics, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster; D055786:Gene Knockout Techniques; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D009410:Nerve Degeneration / Q000201:enzymology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D029721:Drosophila Proteins; D017382:Reactive Oxygen Species; D008666:Metalloendopeptidases; C000611538:YME1L protein, zebrafish