Regulation of mitochondrial proteostasis by the proton gradient
Por:
Patron M., Tarasenko D., Nolte H., Kroczek L., Ghosh M., Ohba Y., Lasarzewski Y., Ahmadi Z.A., Cabrera-Orefice A., Eyiama A., Kellermann T., Rugarli E.I., Brandt U., Meinecke M., Langer T.
Publicada:
1 ene 2022
Resumen:
Mitochondria adapt to different energetic demands reshaping their proteome. Mitochondrial proteases are emerging as key regulators of these adaptive processes. Here, we use a multiproteomic approach to demonstrate the regulation of the m-AAA protease AFG3L2 by the mitochondrial proton gradient, coupling mitochondrial protein turnover to the energetic status of mitochondria. We identify TMBIM5 (previously also known as GHITM or MICS1) as a Ca2+/H+ exchanger in the mitochondrial inner membrane, which binds to and inhibits the m-AAA protease. TMBIM5 ensures cell survival and respiration, allowing Ca2+ efflux from mitochondria and limiting mitochondrial hyperpolarization. Persistent hyperpolarization, however, triggers degradation of TMBIM5 and activation of the m-AAA protease. The m-AAA protease broadly remodels the mitochondrial proteome and mediates the proteolytic breakdown of respiratory complex I to confine ROS production and oxidative damage in hyperpolarized mitochondria. TMBIM5 thus integrates mitochondrial Ca2+ signaling and the energetic status of mitochondria with protein turnover rates to reshape the mitochondrial proteome and adjust the cellular metabolism. © 2022 The Authors. Published under the terms of the CC BY 4.0 license.
Filiaciones:
Max Planck Institute for Biology of Ageing, Cologne, Germany
Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany
Heidelberg University Biochemistry Center (BZH), Heidelberg, Germany
Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
Institute for Genetics, University of Cologne, Cologne, Germany
All Open Access; Green
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