Center for Molecular Medicine Cologne

Thomas Langer - C 9

Impaired mitochondrial proteostasis in CLPB associated disease

Abstract

Mitochondrial dysfunction is a common cause of inherited multisystem disease that often involves the nervous system. Mutations in the putative mitochondrial AAA+ chaperone CLPB have recently been associated with a pleiotropic syndrome characterized by progressive brain atrophy, intellectual disability, cataracts, neutropenia, and 3-methlyglutaconic aciduria. We have identified CLPB as a substrate of the rhomboid protease PARL and localized CLPB to the intermembrane space (IMS) of mitochondria. Our observations lead to the central hypothesis of the project that impaired mitochondrial proteostasis and possibly impaired retrograde stress signaling is of pathogenic relevance in CLPB-associated disease.

To model the loss of CLPB in disease, we will generate Clpb-/- mice using CRISPR/Cas9-mediated genome editing and use human Clpb-/- cells expressing catalytic inactive CLPB or variants harboring pathogenic missense mutations. We will identify specific substrates of CLPB by label-free, quantitative mass spectroscopy and employ proteome-wide approaches and gene expression profiling to determine how CLPB affects mitochondrial proteostasis under various stress conditions. Together, these experiments will define how mutations in CLPB affect the functional integrity of mitochondria and cause disease.

Clinical/medical relevance and sustainability in disease understanding

The current project aims at elucidating the pathogenic mechanism of a mitochondrial disorder caused by mutations in the AAA+ chaperone CLPB. Patients accumulate 3-methlyglutaconic acid in the urine, a characteristic of an emerging class of mitochondrial diseases apparently associated with the loss of mitochondrial membrane integrity. A detailed understanding of the pathogenic mechanism will thus contribute to validate the suitability of 3-methlyglutaconic acid a diagnostic biomarker.

Hammerschmidt, P., Ostkotte, D., Nolte, H., Gerl, M.J., Jais, A., Brunner, H.L., Sprenger, H.G., Awazawa, M., Nicholls, H.T., Turpin-Nolan, S.M., Langer, T., Kruger, M., Brugger, B., and Bruning, J.C. (2019). CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondrial Fragmentation in Obesity. Cell 177, 1536-52 e23.

Miliara, X., Tatsuta, T., Berry, J.L., Rouse, S.L., Solak, K., Chorev, D.S., Wu, D., Robinson, C.V., Matthews, S., and Langer, T. (2019). Structural determinants of lipid specificity within Ups/PRELI lipid transfer proteins. Nat Commun 10, 1130.

Schorling, D.C., Becker, J., Pechmann, A., Langer, T., Wirth, B., and Kirschner, J. (2019). Discrepancy in redetermination of SMN2 copy numbers in children with SMA. Neurology 93, 267-9.

Sprenger, H.G., Wani, G., Hesseling, A., Konig, T., Patron, M., MacVicar, T., Ahola, S., Wai, T., Barth, E., Rugarli, E.I., Bergami, M., and Langer, T. (2019). Loss of the mitochondrial i-AAA protease YME1L leads to ocular dysfunction and spinal axonopathy. EMBO Mol Med 11.

Brandt C, Nolte H, Henschke S, Engstrom Ruud L, Awazawa M, Morgan DA, Gabel P, Sprenger HG, Hess ME, Gunther S, Langer T, Rahmouni K, Fenselau H, Kruger M, and Bruning JC (2018). Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation. Cell 175, 1321-1335 e1320.

Saita S, Tatsuta T, Lampe PA, Konig T, Ohba Y, and Langer T (2018). PARL partitions the lipid transfer protein STARD7 between the cytosol and mitochondria. EMBO J 37.

Sprenger HG, Wani G, Hesseling A, Konig T, Patron M, MacVicar T, Ahola S, Wai T, Barth E, Rugarli EI, Bergami M, and Langer T (2018). Loss of the mitochondrial i-AAA protease YME1L leads to ocular dysfunction and spinal axonopathy. EMBO Mol Med10.15252/emmm.201809288.

Patron M, Sprenger HG, and Langer T (2018). m-AAA proteases, mitochondrial calcium homeostasis and neurodegeneration. Cell Res 28, 296-306.

Saita S, Nolte H, Fiedler KU, Kashkar H, Venne AS, Zahedi RP, Kruger M, and Langer T (2017). PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis. Nat Cell Biol 19, 318-28.

Tatsuta T, and Langer T (2017a). Intramitochondrial phospholipid trafficking. Biochim Biophys Acta 1862, 81-9.

Tatsuta T, and Langer T (2017b). Prohibitins. Curr Biol 27, R629-R31.

Vukotic M, Nolte H, Konig T, Saita S, Ananjew M, Kruger M, Tatsuta T, and Langer T (2017). Acylglycerol Kinase Mutated in Sengers Syndrome Is a Subunit of the TIM22 Protein Translocase in Mitochondria. Mol Cell 67, 471-83 e7.

Prof. Dr. Thomas Langer CMMC Cologne
Prof. Dr. Thomas Langer

Max Planck Institute for Biology of Ageing / RG location - CECAD Building

Principal Investigator C 9

+49 221 478 84263

+49 221 478 6276

Max Planck Institute for Biology of Ageing / RG location - CECAD Building

Joseph-Stelzmann-Straße 9B

50931 Cologne

http://www.genetik.uni-koeln.de/groups/Langer/

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