Regulation of mitochondrial proteostasis by the proton gradient

Abstract

SummaryMitochondria 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.

Goldilocks calcium and the mitochondrial respiratory chain: too much, too little, just right

“…The membrane potential generated by the electron transport chain (ETC), with a negative matrix charge, provides the electrochemical force necessary for positively charged ions, such as Ca 2+ , to enter. Ca 2+ efflux from the mitochondrial matrix occurs through the Na + /Ca 2+ exchanger (NCLX) (11), located in the inner mitochondrial membrane (IMM), and by a Ca 2+ /H + exchanger, which may have been recently identified (12,13).…”