Transcriptional landscape of mitochondrial electron transport chain inhibition in renal cells

Abstract

Analysis of the transcriptomic alterations upon chemical challenge, provides in depth mechanistic information on the compound’s toxic mode of action, by revealing specific pathway activation and other transcriptional modulations. Mapping changes in cellular behaviour to chemical insult, facilitates the characterisation of chemical hazard. In this study, we assessed the transcriptional landscape of mitochondrial impairment through the inhibition of the electron transport chain (ETC) in a human renal proximal tubular cell line (RPTEC/TERT1). We identified the unfolded protein response pathway (UPR), particularly the PERK/ATF4 branch as a common cellular response across ETC I, II and III inhibitions. This finding and the specific genes elaborated may aid the identification of mitochondrial liabilities of chemicals in both legacy data and prospective transcriptomic studies. Graphical abstract

The UPRERgoverns the cell-specific response of human dopaminergic neurons to mitochondrial stress

“…Interestingly, many terms from this analysis also referred to amino acid transport processes, previously shown to be induced via the integrated stress response, in particular the UPR ER -PERK pathway, during ER stress (Harding et al, 2003;Han et al, 2013;Quirós et al, 2017). Several studies have highlighted the role of the UPR ER in response to mitochondrial stress in mammalian cells (Quirós et al, 2017;Krug et al, 2014;Jennings et al, 2023;van der Stel et al, 2022;Carta et al, 2023), and show a predominant role of the PERK-ATF4 pathway, with no or weak activation of the other UPR ER -associated branches, i.e. IRE1-XBP1 or ATF6 pathways.…”

“…In the context of mitochondrial stress, extensive research has unveiled the central role of the integrated stress response (ISR) in human cells (Krug et al, 2014;Quirós et al, 2017;Jennings et al, 2023;van der Stel et al, 2022;Carta et al, 2023), leading to the activation of the PERK-mediated Unfolded Protein Response of the Endoplasmic Reticulum (UPR ER ). PERK-dependent phosphorylation of EIF2α results in the attenuation of general translation, while allowing for selective translation of stress-associated proteins, such as ATF4, which initiates key transcriptional programs promoting pro-survival or pro-apoptotic responses, depending on the severity and duration of the stress (Wek & Cavener, 2007).…”

Definition of the Neurotoxicity-Associated Metabolic Signature Triggered by Berberine and Other Respiratory Chain Inhibitors

“…In this context, it is noteworthy that oxidativeand mitochondrial stress-related responses (expected for the reaction to mitotoxicants) did not feature among the pathway hits. This is a well-known issue of over-representation analysis in several cell types [12,[57][58][59][60][61][62]. Mitotoxicants have a strong propensity to trigger cellular stress related to the transcription factors ATF4 and NRF2.…”