A salvage pathway maintains highly functional respiratory complex I

Karolina Szczepanowska (), Katharina Senft, Juliana Heidler, Marija Herholz, Alexandra Kukat, Michaela Nicole Höhne, Eduard Hofsetz, Christina Becker, Sophie Kaspar, Heiko Giese, Klaus Zwicker, Sergio Guerrero-Castillo, Linda Baumann, Johanna Kauppila, Anastasia Rumyantseva, Stefan Müller, Christian K. Frese, Ulrich Brandt, Jan Riemer, Ilka Wittig and Aleksandra Trifunovic ()
Additional contact information
Karolina Szczepanowska: University of Cologne
Katharina Senft: University of Cologne
Juliana Heidler: Goethe University
Marija Herholz: University of Cologne
Alexandra Kukat: University of Cologne
Michaela Nicole Höhne: University of Cologne
Eduard Hofsetz: University of Cologne
Christina Becker: University of Cologne
Sophie Kaspar: University of Cologne
Heiko Giese: Goethe-Universität Frankfurt am Main
Klaus Zwicker: Goethe-University Frankfurt
Sergio Guerrero-Castillo: Radboud University Medical Center
Linda Baumann: University of Cologne
Johanna Kauppila: Max Planck Institute for Biology of Aging
Anastasia Rumyantseva: University of Cologne
Stefan Müller: University of Cologne
Christian K. Frese: University of Cologne
Ulrich Brandt: Radboud University Medical Center
Jan Riemer: University of Cologne
Ilka Wittig: Goethe University
Aleksandra Trifunovic: University of Cologne

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Regulation of the turnover of complex I (CI), the largest mitochondrial respiratory chain complex, remains enigmatic despite huge advancement in understanding its structure and the assembly. Here, we report that the NADH-oxidizing N-module of CI is turned over at a higher rate and largely independently of the rest of the complex by mitochondrial matrix protease ClpXP, which selectively removes and degrades damaged subunits. The observed mechanism seems to be a safeguard against the accumulation of dysfunctional CI arising from the inactivation of the N-module subunits due to attrition caused by its constant activity under physiological conditions. This CI salvage pathway maintains highly functional CI through a favorable mechanism that demands much lower energetic cost than de novo synthesis and reassembly of the entire CI. Our results also identify ClpXP activity as an unforeseen target for therapeutic interventions in the large group of mitochondrial diseases characterized by the CI instability.

Date: 2020
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DOI: 10.1038/s41467-020-15467-7

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