Abstract
Monitoring mitochondrial function is crucial for organismal survival. This task is performed by mitochondrial surveillance or quality control pathways, which are activated by signals originating from mitochondria and relayed to the nucleus (retrograde response) to start transcription of protective genes. In Caenorhabditis elegans, several systems are known to play this role, including the UPRmt, MAPKmt, and the ESRE pathways. These pathways are highly conserved and their loss compromises survival following mitochondrial stress. In this study, we found a novel interaction between the box C/D snoRNA core proteins (snoRNPs) and mitochondrial surveillance and innate immune pathways. We showed that box C/D, but not box H/ACA, snoRNPs are required for the full function of UPRmt and ESRE upon stress. The loss of box C/D snoRNPs reduced mitochondrial mass, mitochondrial membrane potential, and oxygen consumption rate, indicating overall degradation of mitochondrial function. Concomitantly, the loss of C/D snoRNPs increased immune response and reduced host intestinal colonization by infectious bacteria, improving host resistance to pathogenesis. Our data may indicate a model wherein box C/D snoRNP machinery regulates a "switch" of the cell's activity between mitochondrial surveillance and innate immune activation. Understanding this mechanism is likely to be important for understanding multifactorial processes, including responses to infection and aging.
Highlights
All living organisms require the maintenance of cellular homeostasis under conditions very different than their surroundings
Multiple cellular pathways are dedicated to actively monitoring mitochondrial status, termed as the mitochondrial surveillance system, to provide better defense towards variety of stresses
We report that the Box C/D snoRNA core proteins, normally associated with modification of ribosomal RNA, play a role in mitochondrial surveillance and innate immune pathways
Summary
All living organisms require the maintenance of cellular homeostasis under conditions very different than their surroundings. Given the central role of mitochondria in energy production, biosynthesis of heme groups, lipid metabolism, the regulation of iron and calcium homeostasis, and production of reactive oxygen species (ROS), it should be no surprise that mitochondria are impacted by disease and infection [11–13]. They are subjected to several important surveillance pathways. The two best known are the PINK1/Parkin axis for macroautophagic mitochondrial recycling (commonly known as mitophagy) and the unfolded protein response in mitochondria (UPRmt) [14–17] Both systems monitor the functionality of mitochondrial protein import and they have been thoroughly investigated in various model organisms, including C. elegans, yeast, and mice. Under similar conditions of compromised mitochondrial import, the key transcription factor ATFS-1/ATF5 is redirected from mitochondria, where it would be degraded, to the nucleus, where it regulates the expression of chaperones and other stress mediators
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