Journal
EMBO JOURNAL
Volume 41, Issue 16, Pages -Publisher
WILEY
DOI: 10.15252/embj.2021110476
Keywords
mitochondrial calcium; proton gradient; respiratory chain; TMBIM5
Categories
Funding
- EMBO postdoctoral fellowship [ALTF 649-2015, LTFCOFUND2013, GA-2013-609409]
- Japan Society for the Promotion of Science (JSPS)
- Uehara Memorial Foundation
- Osamu Hayaishi Memorial Scholarship for Study Abroad
- European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant [721757]
- German-Israel-Project (DIP) [RA1028/10-2]
- Deutsche Forschungsgemeinschaft [FOR2848, CRC1218, 269925409]
- Netherlands Organization for Scientific Research [TOP 714.017.00 4]
- ProjektDEAL
- Marie Curie Actions (MSCA) [721757] Funding Source: Marie Curie Actions (MSCA)
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Mitochondrial proteases, specifically the m-AAA protease AFG3L2, are regulated by the mitochondrial proton gradient and play a crucial role in reshaping the mitochondrial proteome in response to different energetic demands. TMBIM5, a Ca2+/H+ exchanger in the mitochondrial inner membrane, inhibits the activity of the m-AAA protease and ensures cell survival and respiration. However, persistent hyperpolarization triggers the degradation of TMBIM5 and activation of the m-AAA protease, which facilitates the proteolytic breakdown of respiratory complex I to limit ROS production in hyperpolarized mitochondria.
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.
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