Mitochondria-originated redox signalling regulates KLF-1 to promote longevity in Caenorhabditis elegans
Johannes CW Hermeling,
Marija Herholz,
Linda Baumann,
Estela Cepeda Cores,
Aleksandra Zečić,
Thorsten Hoppe,
Jan Riemer,
Aleksandra Trifunovic
Affiliations
Johannes CW Hermeling
Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), Germany; Institute for Mitochondrial Diseases and Ageing, Medical Faculty, University of Cologne, Cologne, D-50931, Germany
Marija Herholz
Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), Germany; Institute for Mitochondrial Diseases and Ageing, Medical Faculty, University of Cologne, Cologne, D-50931, Germany
Linda Baumann
Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), Germany; Institute for Mitochondrial Diseases and Ageing, Medical Faculty, University of Cologne, Cologne, D-50931, Germany
Estela Cepeda Cores
Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), Germany; Institute for Mitochondrial Diseases and Ageing, Medical Faculty, University of Cologne, Cologne, D-50931, Germany
Aleksandra Zečić
Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), Germany; Institute for Mitochondrial Diseases and Ageing, Medical Faculty, University of Cologne, Cologne, D-50931, Germany
Thorsten Hoppe
Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), Germany; Center for Molecular Medicine Cologne (CMMC), Cologne, D-50931, Germany; Institute for Genetics, University of Cologne, Cologne, D-50674, Germany
Jan Riemer
Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), Germany; Institute for Biochemistry, University of Cologne, Cologne, D-50931, Germany
Aleksandra Trifunovic
Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), Germany; Institute for Mitochondrial Diseases and Ageing, Medical Faculty, University of Cologne, Cologne, D-50931, Germany; Center for Molecular Medicine Cologne (CMMC), Cologne, D-50931, Germany; Corresponding author. CECAD Research CenterUniversity of Cologne, Joseph-Stelzmann-Str. 26, Cologne, D-50931, Germany.
Alternations of redox metabolism have been associated with the extension of lifespan in roundworm Caenorhabditis elegans, caused by moderate mitochondrial dysfunction, although the underlying signalling cascades are largely unknown. Previously, we identified transcriptional factor Krüppel-like factor-1 (KLF-1) as the main regulator of cytoprotective longevity-assurance pathways in the C. elegans long-lived mitochondrial mutants. Here, we show that KLF-1 translocation to the nucleus and the activation of the signalling cascade is dependent on the mitochondria-derived hydrogen peroxide (H2O2) produced during late developmental phases where aerobic respiration and somatic mitochondrial biogenesis peak. We further show that mitochondrial-inducible superoxide dismutase-3 (SOD-3), together with voltage-dependent anion channel-1 (VDAC-1), is required for the life-promoting H2O2 signalling that is further regulated by peroxiredoxin-3 (PRDX-3). Increased H2O2 release in the cytoplasm activates the p38 MAPK signalling cascade that induces KLF-1 translocation to the nucleus and the activation of transcription of C. elegans longevity-promoting genes, including cytoprotective cytochrome P450 oxidases. Taken together, our results underline the importance of redox-regulated signalling as the key regulator of longevity-inducing pathways in C. elegans, and position precisely timed mitochondria-derived H2O2 in the middle of it.
