title: The Mitochondrial m-AAA Protease Prevents Demyelination and Hair Greying.
abstract: The m-AAA protease preserves proteostasis of the inner mitochondrial membrane. It ensures a functional respiratory chain, by controlling the turnover of respiratory complex subunits and allowing mitochondrial translation, but other functions in mitochondria are conceivable. Mutations in genes encoding subunits of the m-AAA protease have been linked to various neurodegenerative diseases in humans, such as hereditary spastic paraplegia and spinocerebellar ataxia. While essential functions of the m-AAA protease for neuronal survival have been established, its role in adult glial cells remains enigmatic. Here, we show that deletion of the highly expressed subunit AFG3L2 in mature mouse oligodendrocytes provokes early-on mitochondrial fragmentation and swelling, as previously shown in neurons, but causes only late-onset motor defects and myelin abnormalities. In contrast, total ablation of the m-AAA protease, by deleting both Afg3l2 and its paralogue Afg3l1, triggers progressive motor dysfunction and demyelination, owing to rapid oligodendrocyte cell death. Surprisingly, the mice showed premature hair greying, caused by progressive loss of melanoblasts that share a common developmental origin with Schwann cells and are targeted in our experiments. Thus, while both neurons and glial cells are dependant on the m-AAA protease for survival in vivo, complete ablation of the complex is necessary to trigger death of oligodendrocytes, hinting to cell-autonomous thresholds of vulnerability to m-AAA protease deficiency.
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Shuaiyu
authors.identifier: http://orcid.org/0000-0003-3985-8728
authors.initials: S
authors.lastname: Wang
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Julie
authors.initials: J
authors.lastname: Jacquemyn
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Sara
authors.identifier: http://orcid.org/0000-0002-1123-8319
authors.initials: S
authors.lastname: Murru
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Paola
authors.identifier: http://orcid.org/0000-0003-1181-2621
authors.initials: P
authors.lastname: Martinelli
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Barth
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.|Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langer
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.|Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.|Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Carien M
authors.initials: CM
authors.lastname: Niessen
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.|Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Elena I
authors.initials: EI
authors.lastname: Rugarli
mesh_terms: D049069:ATP-Dependent Proteases / Q000096:biosynthesis / Q000235:genetics*; D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D003711:Demyelinating Diseases / Q000235:genetics*; D006197:Hair / Q000254:growth & development / Q000378:metabolism*; D006801:Humans; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009186:Myelin Sheath / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism
chemical_list: D049069:ATP-Dependent Proteases; C546907:Afg3l1 protein, mouse; C542395:Afg3l2 protein, mouse; D008666:Metalloendopeptidases; C114583:m-AAA proteases; D000074183:ATPases Associated with Diverse Cellular Activities