title: Drosophila type XV/XVIII collagen mutants manifest integrin mediated mitochondrial dysfunction, which is improved by cyclosporin A and losartan.
abstract: Vertebrate collagen types XV and XVIII are broadly distributed basement membrane components, classified into a structurally distinct subgroup called "multiplexin collagens". Mutations in mammalian multiplexins are identified in some degenerative diseases such as Knobloch syndrome 1 (KNO1) or skeletal/cardiac myopathies, however, these progressive properties have not been elucidated. Here we investigated Drosophila mutants of Multiplexin (Mp), the only orthologue of vertebrate collagen types XV and XVIII, to understand the pathogenesis of multiplexin-related diseases. The mp mutants exhibited morphological changes in cardiomyocytes and progressive dysfunction of the skeletal muscles, reminiscent phenotypes observed in Col15a1-null mice. Ultrastructural analysis revealed morphologically altered mitochondria in mutants' indirect flight muscles (IFMs), resulting in severely attenuated ATP production and enhanced reactive oxygen species (ROS) production. In addition, mutants' IFMs exhibited diminished βPS integrin clustering and abolished focal adhesion kinase (FAK) phosphorylation. Furthermore, mutants' defective IFMs are improved by the administrations of cyclosporin A, an inhibitor against mitochondrial permeability transition pore (mPTP) opening or losartan, an angiotensin II type 1 receptor (AT1R) blocker. Thus, our results suggest that Mp modulates mPTP opening and AT1R activity through its binding to integrin and that lack of Mp causes unregulated mPTP opening and AT1R activity, leading to mitochondrial dysfunctions. Hence, our results provide new insights towards the roles of multiplexin collagens in mitochondrial homeostasis and may serve as pharmacological evidences for the potential use of cyclosporin A or losartan for the therapeutic strategies.
authors: Department of Human Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita, Okayama 7008558, Japan. momo@cc.okayama-u.ac.jp
authors: Ryusuke
authors: R
authors: Momota
authors: Masahiro
authors: M
authors: Narasaki
authors: Takaaki
authors: T
authors: Komiyama
authors: Ichiro
authors: I
authors: Naito
authors: Yoshifumi
authors: Y
authors: Ninomiya
authors: Aiji
authors: A
authors: Ohtsuka
mesh_terms: D000818:Animals; D043170:Collagen Type XVIII / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D004330:Drosophila; D016023:Integrins / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D043170:Collagen Type XVIII; D016023:Integrins; D017382:Reactive Oxygen Species; D016572:Cyclosporine; D019808:Losartan