CLPP is a modulator of Complex I biogenesis. Karolina Szczepanowska1,2, Katharina Senft1,2,Christina Becker1,2, Christian K. Frese1, Alexandra Kukat1,2, Eduard Hofsetz1,2 , Priyanka Maiti1,2 and Aleksandra Trifunovic1,2 1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), D-50931 Cologne, Germany 2Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, D-50931 Cologne, Germany
CLPP is highly conserved from bacteria to humans. In concert with CLPX, an ATP-dependent protein unfoldase, CLPP forms the bulky proteasome-like machinery (ClpXP) residing in the matrix of animal cell mitochondria. We have recently presented evidences that mammalian CLPP has an essential role in determining the performance of mitochondrial protein synthesis. In heart mitochondria CLPP impacts the translation by regulating the level of mitoribosome assembly. Consequently, CLPP deficiency results in a mild respiratory chain defect with prevailing Complex I dysfunction. Through a proteomic approach and the use of a catalytically inactive CLPP we produced the first comprehensive list of possible mammalian ClpXP substrates involved in the regulation of mitochondrial translation, oxidative phosphorylation and a number of metabolic pathways. We further show that the defect in mitoribosomal assembly in heart is the consequence of ERAL1 accumulation, a putative 12S rRNA chaperone and novel ClpXP substrate. Our data suggested that the timely removal of ERAL1 from the small ribosomal subunit is essential for the efficient maturation of mitoribosomes and a normal rate of mitochondrial translation. To further dissect the role of CLPXP protease in regulation of OXPHOS biogenesis we have analyzed the respiratory chain components revealed as CLPP substrates in our proteomic screen. We showed that CLPXP protease is required for turnover of N-module part of matrix-exposed peripheral arm of Complex I and upon CLPP dysfunction an entire catalytically active N-module accumulates in a mitochondrial matrix. Furthermore, CLPXP protease is indispensable to clearing removal of Complex I N-module upon respiratory chain defect in vivo. Surprisingly, the CLPXP-dependent preservation of N-module stabilizes the fully assembled Complex I in a number of respiratory chain deficient cell culture models. Our findings suggest that CLPXP protease plays an unforeseen role in regulation of Complex I stability upon diseases-associated respiratory chain dysfunction and arise new targets for therapy of mitochondrial diseases.
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