Summary: Far from the overly simplistic understanding of mitochondria as ‘the powerhouse of the cell’, these organelles play crucial roles not only in the production of ATP, but also in a wide variety of other biochemical processes, making mitochondrial function a key determinant of cellular health. Disruption of mitochondrial homeostasis contributes to a number of chronic diseases, including metabolic, neurodegenerative, and cardiovascular disorders, cancer, and even aging. Mitochondria undergo constant surveillance and homeostatic rebalancing to avoid spiraling into a dysfunctional cascade that will inevitably trigger apoptosis or other cell death pathways. A variety of readouts, including mitochondrial proteostasis and bioenergetics, are constantly tracked and these inputs are integrated into coherent, retrograde signaling programs that coordinate gene expression with the nucleus. The most studied of these is the mitochondrial unfolded protein response (UPRmt), which primarily responds to compromised mitochondrial protein import. Recent results from my lab have increasingly demonstrated that another key component of mitochondrial surveillance is the ESRE pathway. The ESRE (ethanol and stress response element) pathway is comprised of evolutionarily-conserved genes containing a strongly conserved, 11-nucleotide motif (TCTGCGTCTCT) in their promoters. These genes were first identified by their upregulation during acute ethanol exposure, but we have demonstrated that the ESRE pathway detects mitochondrial damage, specifically increased mitochondrial reactive oxygen species. Importantly, compromised ESRE function reduced survival during stress and overexpression of ESRE machinery extended lifespan in unstressed conditions. Recent discoveries from my lab have identified box C/D snoRNPs and the Mediator subunit MDT-15/MED15 as critical regulators of ESRE activity. Finally, we have identified a strong candidate for the transcription factor that binds the ESRE motif. Despite our recent progress, critical gaps remain in our understanding of how ESRE contributes to mitochondrial health. Questions of particular interest include: how is the signal for ESRE activation propagated to the nucleus once it is detected? Have we correctly identified the transcription factor that binds the ESRE motif? What is the mechanism used by box C/D snoRNPs to regulate ESRE function? Is MDT-15 acting in a non-canonical role to regulate ESRE activity? We will continue to use a variety of biochemical, genetic, and cell biological techniques, supplemented with new ‘omics-based approaches to expand our understanding of this network and its role in maintaining mitochondrial health. This enhanced understanding will be key to translating our discoveries into tangible gains in improvements in health across the lifespan.

PROJECT NARRATIVE Mitochondria undergo constant surveillance, integrating a variety of signals into a cohesive feedback program that coordinates with the nucleus to ensure prompt homeostatic rebalancing critical for optimal mitochondrial function and cellular health. My lab has been instrumental in studying mitochondrial surveillance, with a particular focus on the ESRE network and its interactions with other protective mechanisms. Identifying the relationship between mitochondrial damage and changes in lipid homeostasis, propagation of the ESRE-activating signal to the nucleus, and how changes in RNA metabolism are coordinated to ensure a prompt response will help identify methods to promote improved health across the human lifespan.