PT  - JOURNAL ARTICLE
AU  - Maria Patron
AU  - Daryna Tarasenko
AU  - Hendrik Nolte
AU  - Mausumi Ghosh
AU  - Yohsuke Ohba
AU  - Yvonne Lasarzewski
AU  - Zeinab Alsadat Ahmadi
AU  - Alfredo Cabrera-Orefice
AU  - Akinori Eyiama
AU  - Tim Kellermann
AU  - Elena I. Rugarli
AU  - Ulrich Brandt
AU  - Michael Meinecke
AU  - Thomas Langer
TI  - Regulation of mitochondrial proteostasis by the proton gradient
AID  - 10.1101/2021.12.12.470907
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.12.12.470907
4099  - http://biorxiv.org/content/early/2021/12/12/2021.12.12.470907.short
4100  - http://biorxiv.org/content/early/2021/12/12/2021.12.12.470907.full
AB  - Mitochondria adapt to different energetic demands reshaping their proteome. Mitochondrial proteases are emerging as key regulators of these adaptive processes. Here, we use a multi-proteomic approach to demonstrate 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.Competing Interest StatementThe authors have declared no competing interest.