A novel role for LONP1 in connecting mitochondrial proteostasis with nuclear epigenetics

About This Grant

SUMMARY This proposal investigates the critical role of the mitochondrial protease LONP1 in linking organelle proteostasis with nuclear transcription through the regulation of key metabolites from the tricarboxylic acid (TCA) cycle. The study addresses a significant knowledge gap: how disruptions in mitochondrial protein homeostasis affect nuclear gene regulation and metabolic adaptation. Based on initial findings, it is hypothesized that LONP1 regulates essential metabolites, such as succinate and α-ketoglutarate. LONP1 regulates their levels by degrading TCA cycle enzymes. These metabolites have opposing effects on histone and DNA demethylation. Preliminary data show that loss of LONP1 leads to decreased transcription of mitochondrial genes, likely due to loss of nuclear epigenetic marks, particularly through the erasure of H3K4me1 enhancers. The findings suggest that LONP1 modulates nuclear transcription by altering succinate levels, affecting transcription factors such as c-MYC, and thus impacting mitochondrial function and cellular stress responses. The proposed research is structured around two specific aims: (Aim 1) to determine how LONP1 influences the balance of TCA cycle metabolites that regulate nuclear epigenetic modifications, and (Aim 2) to elucidate how changes in these metabolites, driven by LONP1, affect histone modifications and transcriptional regulation, focusing on the MYC regulon and H3 methylation. Aim 2 further explores whether enhancer rearrangements, such as oncogenic translocations, disrupt metabolic control of c-MYC, providing insight into how cancers bypass mitochondrial regulation. This study will also investigate the histone demethylases most sensitive to fluctuations in metabolite levels. Advanced genetic models will be utilized, including a conditional Lonp1 mouse model, human iPSC-derived fibroblasts, and clinically relevant multiple myeloma cell lines—a disease in which LONP1 is frequently upregulated. This research is significant for its integration of cutting-edge multi-omics, organelle-specific metabolomics, and sophisticated genetic tools to uncover how mitochondrial dysfunction impacts nuclear transcription. The findings promise to reveal new insights into mitochondrial-nuclear communication, with broad implications for developing therapeutic strategies targeting metabolic and epigenetic dysregulation in aging, cancer, and related disorders. The innovation lies in the discovery that LONP1, traditionally recognized for its role in mitochondrial protein quality control, is a key regulator of nuclear transcription through its modulation of TCA cycle metabolites. This challenges existing paradigms by demonstrating that mitochondrial dysfunction exerts a broad influence on the nuclear epigenome, reshaping global gene expression programs. The integration of systems-level approaches offers a unique opportunity to unravel a novel feedback loop of bidirectional mitochondrial-nuclear communication, opening future avenues for therapeutic interventions.