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Cell Death Dis . 2020 Apr 23

SK channel-mediated metabolic escape to glycolysis inhibits ferroptosis and supports stress resistance in C. elegans

Tobias Baumann, Andreas Dunkel, Christian Schmid, Sabine Schmitt, Michael Hiltensperger, Kerstin Lohr, Vibor Laketa, Sainitin Donakonda, Uwe Ahting, Bettina Lorenz-Depiereux, Jan E Heil, Johann Schredelseker, Luca Simeoni, Caroline Fecher, Nina Körber, Tanja Bauer, Norbert Hüser, Daniel Hartmann, Melanie Laschinger, Kilian Eyerich, Stefanie Eyerich, Martina Anton, Matthew Streeter, Tina Wang, Burkhart Schraven, David Spiegel, Farhah Assaad, Thomas Misgeld, Hans Zischka, Peter J Murray, Annkristin Heine, Mathias Heikenwälder, Thomas Korn, Corinna Dawid, Thomas Hofmann, Percy A Knolle, Bastian Höchst, Inge E Krabbendam, Birgit Honrath, Benjamin Dilberger, Eligio F Iannetti, Robyn S Branicky, Tammo Meyer, Bernard Evers, Frank J Dekker, Werner J H Koopman, Julien Beyrath, Daniele Bano, Martina Schmidt, Barbara M Bakker, Siegfried Hekimi, Carsten Culmsee, Gunter P Eckert, Amalia M Dolga

Metabolic flexibility is an essential characteristic of eukaryotic cells in order to adapt to physiological and environmental changes. Especially in mammalian cells, the metabolic switch from mitochondrial respiration to aerobic glycolysis provides flexibility to sustain cellular energy in pathophysiological conditions. For example, attenuation of mitochondrial respiration and/or metabolic shifts to glycolysis result in a metabolic rewiring that provide beneficial effects in neurodegenerative processes. Ferroptosis, a non-apoptotic form of cell death triggered by an impaired redox balance is gaining attention in the field of neurodegeneration. We showed recently that activation of small-conductance calcium-activated K+ (SK) channels modulated mitochondrial respiration and protected neuronal cells from oxidative death. Here, we investigated whether SK channel activation with CyPPA induces a glycolytic shift thereby increasing resilience of neuronal cells against ferroptosis, induced by erastin in vitro and in the nematode C. elegans exposed to mitochondrial poisons in vivo. High-resolution respirometry and extracellular flux analysis revealed that CyPPA, a positive modulator of SK channels, slightly reduced mitochondrial complex I activity, while increasing glycolysis and lactate production. Concomitantly, CyPPA rescued the neuronal cells from ferroptosis, while scavenging mitochondrial ROS and inhibiting glycolysis reduced its protection. Furthermore, SK channel activation increased survival of C. elegans challenged with mitochondrial toxins. Our findings shed light on metabolic mechanisms promoted through SK channel activation through mitohormesis, which enhances neuronal resilience against ferroptosis in vitro and promotes longevity in vivo.

PMID: 32327637