Aleksandra Trifunovic Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany
Mitochondrial protein homeostasis relies on chaperones and proteases to maintain proper folding and remove damaged proteins that might otherwise form toxic aggregates. CLPP is highly conserved from bacteria to humans and in concert with CLPX, an ATP-dependent protein unfoldase, forms a 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 by regulating the level of mitoribosome assembly. Consequently, CLPP deficiency results in a mild respiratory chain defect with prevailing Complex I (C 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. To further dissect the role of CLPXP protease in regulation of OXPHOS biogenesis we have analysed 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 C I and upon CLPP dysfunction an entire catalytically active N-module accumulates in a mitochondrial matrix. CLPP dependent N-module accumulation is further exaggerated upon metabolically induced OXPHOS remodelling. Furthermore, CLPXP protease is indispensable for removal of C I N-module upon respiratory chain defect in vivo. Our findings suggest that CLPP plays an unforeseen role in remodelling of Complex I upon metabolic fuel switch and its activity can modulate Complex I stability upon diseases-related respiratory chain dysfunction.
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