A Proteolytic Hub in Mitochondria Regulating Mitophagy and Cell Death
Zusammenfassung der Projektergebnisse
Mitochondria are essential metabolic and cellular signaling hubs, whose function declines with age and whose dysfunction is associated with various diseases, including cardiomyopathies, obesity and prevalent neurodegenerative disorders. The functional integrity of mitochondria depends on evolutionary conserved proteases localized in mitochondria, which serve quality control functions, regulate mitochondrial biogenesis and facilitate the metabolic rewiring of mitochondria in response to altered physiological demands. We have identified a proteolytic hub in the mitochondrial inner membrane, termed the SPY complex, which is composed of the ATP-dependent protease YME1L, the rhomboid protease PARL and the membrane scaffold protein SLP2. The constituents of SPY complexes were functionally linked to mitochondrial dynamics, mitophagy and cell death pathways, suggesting that these processes are regulated within spatially defined membrane domains in mitochondria. We have combined experiments in mice and cultured cells with various proteomic approaches to further define the function of SPY complexes and its constituents. Tissue-specific YME1L deficient mice show mitochondrial fragmentation, which causes cardiomyocyte death in the heart, while we observed axonal degeneration of only selected neurons in the spinal cord and ocular dysfunction upon ablation of Yme1l in the nervous system. PARL-based proteomic approaches allowed the identification of several novel substrate proteins in mitochondria, including the lipid transfer protein STARD7 and the pro-apoptotic protein Smac/DIABLO, which associate with SPY complexes. Intramembrane cleavage by PARL is emerging as a novel mechanism to drive the dual localization of proteins to mitochondria and the cytosol, an important regulatory step during mitophagy and cell death. YME1L, on the other hand, was found to rewire the mitochondrial proteome to allow metabolic adaptation. Similarly, SLP2 membrane scaffolds broadly affect the mitochondrial proteome, interacting with protein translocases and numerous metabolite carrier proteins. SPY complexes are demonstrated to regulate the apoptotic program along two distinct pathways. Fragmentation and restructuring of mitochondria controlled by YME1L facilitates the release of cytochrome c, whereas release of Smac/DIABLO depends on its proteolytic processing by PARL. Thus, SPY complexes are spatially defined proteolytic hubs in the inner membrane of mitochondria with important regulatory roles for cell fate decisions.
Projektbezogene Publikationen (Auswahl)
- (2015) Imbalanced OPA1 processing and mitochondrial fragmentation causes heart failure in mice. Science 350, 1221-1233
Wai, T., García-Prieto, J., Baker, M.J., Merkwirth, C., Benit, P., Rustin, P., Rupérez, F.J., Barbas, C., Ibañez, B., and Langer, T.
(Siehe online unter https://doi.org/10.1126/science.aad0116) - (2016) The membrane scaffold SLP2 anchors a proteolytic hub in mitochondria containing PARL and the i-AAA protease YME1L. EMBO Rep. 17, 1844-1856
Wai, T., Saita, S., Nolte, H., Müller, S., König, T., Richter-Dennerlein, R., Sprenger, H.-G., Madrenas, J., Mühlmeister, M., Brandt, U., Krüger, M., and Langer, T.
(Siehe online unter https://doi.org/10.15252/embr.201642698) - (2017) PARL mediates Smac/DIABLO proteolytic maturation in mitochondria to promote apoptosis. Nat. Cell Biol. 19, 318-328
Saita, S., Nolte, H., Fiedler, K.U., Kashkar, H., Venne, A.S., Zahedi, R.P., Krüger, M., and Langer, T.
(Siehe online unter https://doi.org/10.1038/ncb3488) - (2018) PARL partitions the lipid transfer protein STARD7 between the cytosol and mitochondria. EMBO J. 37: e97909
Saita, S., Tatsuta, T., Lampe, P.A., König, T., Ohba, Y., and Langer, T.
(Siehe online unter https://doi.org/10.15252/embj.201797909) - (2019) Loss of the mitochondrial i-AAA protease YME1L leads to ocular dysfunction and spinal axonopathy. EMBO Mol. Medicine 11: e9288
Sprenger, H.S., Wani, G., Hesseling, A., König, T., Patron, M., MacVicar, T., Ahola, S., Wai, T., Barth, E., Rugarli, E.I., Bergami, M. and, Langer, T.
(Siehe online unter https://doi.org/10.15252/emmm.201809288) - (2019) Mitochondrial proteolysis and metabolic control. CSH Perspectives in Biology
Aloha, S., Langer, T., MacVicar, T.
(Siehe online unter https://doi.org/10.1101/cshperspect.a033936) - (2019). Lipid signalling drives proteolytic rewiring of mitochondria by YME1L. Nature 575(7782), 361–365
MacVicar, T., Ohba, Y., Nolte, H., Mayer, FC., Tatsuta, T., Sprenger, HG., Lindner, B., Zhao, Y., Li, J., Bruns, C., Krüger, M., Habich, M., Riemer, J., Scharzer, R., Pasparakis, M., Henschke, S., Brüning, JC., Zamboni, N. and Langer, T.
(Siehe online unter https://doi.org/10.1038/s41586-019-1738-6) - (2020). Mitochondrial proteases – multifaceted regulators of mitochondrial plasticity. Ann. Rev. Biochem., 89:501-285
Deshwal, S., Fiedler, K.U., Langer, T.
(Siehe online unter https://doi.org/10.1146/annurev-biochem-062917-012739) - (2020). Regulation of mitochondrial plasticity by the i-AAA protease YME1L. Biol. Chem. 26;401(6-7):877-890
Ohba, Y., MacVicar, T. and Langer, T.
(Siehe online unter https://doi.org/10.1515/hsz-2020-0120) - (2021). ComplexFinder: A software package for the analysis of native protein complex fractionation experiments. BBA – Bioenergetics 1862, 148444
Nolte, H. and Langer, T.
(Siehe online unter https://doi.org/10.1016/j.bbabio.2021.148444)
