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

Abstract

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 smallconductance 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.

The Potential of Ferroptosis-Targeting Therapies for Alzheimer’s Disease: From Mechanism to Transcriptomic Analysis

“…This caspase-independent process is accompanied by mitochondrial fragmentation and enlarged cristae (Dixon et al, 2012). The rescue of mitochondria (Jelinek et al, 2018), decrease of mitochondria-associated endoplasmic reticulum membranes (MAMs) interaction (Guo et al, 2019) and small conductance calcium-activated potassium (K Ca 2/SK) channel activation have the potential to protect from ferroptotic cell death (Krabbendam et al, 2020).…”

Involvement of NDPK-B in Glucose Metabolism-Mediated Endothelial Damage via Activation of the Hexosamine Biosynthesis Pathway and Suppression of O-GlcNAcase Activity

“…The experiments were conducted and the measurements were obtained according to the standard instructions. The results were analyzed as described [ 26 ] using the Wave software and the Seahorse Report Generator (Agilent Technologies, Germany).…”

PEG out through the pores with the help of ESCRTIII

“…In the field of ferroptosis, the use of prototypic synthetic drugs such as erastin or RLS3 is a potential limitation of the ferroptotic model. Two parallel approaches can be considered to strengthen the findings by Pedrera et al: 1) the use of a physiological compound such as glutamate, to inhibit the system Xc-, inducing ferroptosis in an adequate cell model, such as cell types lacking NMDA/AMPA receptors [9,10], 2) characterizing ferroptosis in vivo demonstrating that the pro-inflammatory and propagatory phenotype in tissue parenchyma can be prevented by activating the ESCRT-III complex in models of chronic disease.…”