Cross-species screening platforms identify EPS-8 as a critical link for mitochondrial stress and actin stabilization

Abstract

Cross-species genetic screens for mitochondrial regulators revealed EPS-8 as a link between actin stability and mitochondria.

Large-scale genetic screens identify BET-1 as a cytoskeleton regulator promoting actin health and lifespan

“…Interestingly, many mitochondrial genes were found amongst significantly enriched genes (Fig. S1D), though this is consistent with many findings that have previously revealed actin-mitochondrial interactions (Fehrenbacher et al, 2004; Higuchi et al, 2013; Moehle et al, 2021; Tharp et al, 2021).…”

“…Interestingly, many mitochondrial genes were found amongst significantly enriched genes (Fig. S1D), though this is consistent with many findings that have previously revealed actin-mitochondrial interactions (Fehrenbacher et al, 2004;Higuchi et al, 2013;Moehle et al, 2021;Tharp et al, 2021). To follow up on the identified hits and link their contribution to cellular and organismal physiology, we opted for performing a cross-species analysis in the nematode C. elegans with the rationale that genes important for surviving actin stress in two species must be critical regulators of actin health and function.…”

“…To follow up on the identified hits and link their contribution to cellular and organismal physiology, we opted for performing a cross-species analysis in the nematode C. elegans with the rationale that genes important for surviving actin stress in two species must be critical regulators of actin health and function. Indeed, we found in a previous study that similar cross-species screening approaches provided more biologically meaningful data than computational methods alone to identify candidate genes that impact lifespan (Moehle et al, 2021). Therefore, we searched the top ~500 enriched and depleted genes from our screen for evolutionary-conserved orthologs in C. elegans (Kim et al, 2018) and identified a list of ~400 genes.…”

UPRmt and coordinated UPRER in type 2 diabetes

“…In turn, AKT and protein kinase B can be stimulated by excessive ROS, activating the phosphorylated estrogen receptor so that it enhances the activities of proteasome 26S and stimulates the translation of intermembrane space proteases HTRA2, OMI, and the mitochondrial regulator NRF1, hence preserving quality control within the intermembrane space protein (Papa and Germain, 2011). Moreover, the substrate EPS-8/EPS8 of the epidermal growth factor receptor pathway, as a signaling protein adaptor, plays a role in general homeostasis in mitochondria and the regulation of UPR mt by reorganizing the actin cytoskeleton mediated by integrin (Kaspar et al, 2021;Moehle et al, 2021). Rox1 binds mtDNA and performs a TFAM-like function.…”

Hijacking Cellular Stress Responses to Promote Lifespan

“…HSF-1 has also been shown to directly impact the actin cytoskeleton ( Baird et al, 2014 ; Higuchi-Sanabria et al, 2018b ), and many studies have already highlighted the importance of actin as serving as the scaffold for–and regulating the dynamics of–the mitochondria ( Fehrenbacher et al, 2004 ; Boldogh and Pon 2006 ; Higuchi et al, 2013 ; Korobova et al, 2013 ; Manor et al, 2015 ). A large-scale cross-organism screen combining the power of CRISPR-Cas9 screening in human cells ( Shalem et al, 2014 ) and RNAi screening in C. elegans identified EPS-8 as a novel link between actin and mitochondrial homeostasis ( Moehle et al, 2021 ). Specifically, knockdown of eps-8 resulted in hyperstabilization of actin through the integrin, PAT-3.…”