Abstract
BackgroundMitochondrial dysfunction causes or contributes to a wide variety of pathologies, including neurodegenerative diseases, cancer, metabolic diseases, and aging. Cells actively surveil a number of mitochondrial readouts to ensure that cellular homeostasis is maintained.ResultsIn this article, we characterize the role of the ethanol and stress response element (ESRE) pathway in mitochondrial surveillance and show that it is robustly activated when the concentration of reactive oxygen species (ROS) in the cell increases. While experiments were mostly performed in Caenorhabditis elegans, we observed similar gene activation profile in human cell lines. The linear relationship between ROS and ESRE activation differentiates ESRE from known mitochondrial surveillance pathways, such as the mitochondrial unfolded protein response (UPRmt), which monitor mitochondrial protein import. The ability of the ESRE network to be activated by increased ROS allows the cell to respond to oxidative and reductive stresses. The ESRE network works in tandem with other mitochondrial surveillance mechanisms as well, in a fashion that suggests a partially redundant hierarchy. For example, mutation of the UPRmt pathway results in earlier and more robust activation of the ESRE pathway. Interestingly, full expression of ATFS-1, a key transcription factor for the UPRmt, requires the presence of an ESRE motif in its promoter region.ConclusionThe ESRE pathway responds to mitochondrial damage by monitoring ROS levels. This response is conserved in humans. The ESRE pathway is activated earlier when other mitochondrial surveillance pathways are unavailable during mitochondrial crises, potentially to mitigate stress and restore health. However, the exact mechanisms of pathway activation and crosstalk remain to be elucidated. Ultimately, a better understanding of this network, and its role in the constellation of mitochondrial and cellular stress networks, will improve healthspan.
Highlights
Mitochondrial dysfunction causes or contributes to a wide variety of pathologies, including neurodegenerative diseases, cancer, metabolic diseases, and aging
Mitochondrial surveillance pathways exhibit partial redundancy To test the variety of mitochondrial damage that can activate the ethanol and stress response element (ESRE) network, a C. elegans strain carrying a GFP reporter driven by three tandem repeats of the minimal 11-nt ESRE consensus (3XESRE::GFP) [28] was exposed to a panel of mitochondrial poisons including rotenone, TTFA, antimycin A, sodium azide, and carbonyl cyanide 3-chlorophenylhydrazone (CCCP, a protonophore that dissipates the electrochemical gradient across the inner mitochondrial membrane) (Fig. 1a, b)
We studied the activation of the ESRE network and its relationship with other mitochondrial surveillance pathways
Summary
Mitochondrial dysfunction causes or contributes to a wide variety of pathologies, including neurodegenerative diseases, cancer, metabolic diseases, and aging. The expression of transcription factors (TFs) that control tens to hundreds of genes coordinates the complex rearrangement of cellular resources to regain this homeostatic balance. Cellular surveillance programs that detect disruption of normal cellular processes license TF activity by triggering post-translational changes, such as re-localization, phosphorylation, or Tjahjono et al BMC Biology (2020) 18:74 proteolytic cleavage. These patterns have been repeatedly observed across biological phyla for a variety of stresses, including heat shock [1], hypoxia [2], proteostatic disruption in the ER and mitochondria [3,4,5], and many others [6,7,8]
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