Mitochondrial translocation of TFEB regulates complex I and inflammation
Ontology highlight
ABSTRACT:
SUBMITTER: Dr. Chiara Calabrese
PROVIDER: S-SCDT-10_1038-S44319-024-00058-0 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:TFEB is a master regulator of autophagy, lysosome biogenesis, mitochondrial metabolism, and immunity that works primarily through transcription controlled by cytosol-to-nuclear translocation. Emerging data indicate additional regulatory interactions at the surface of organelles such as lysosomes. Here we show that TFEB has a non-transcriptional role in mitochondria, regulating the electron transport chain complex I to down-modulate inflammation. Proteomics analysis reveals extensive TFEB co-immunoprecipitation with several mitochondrial proteins, whose interactions are disrupted upon infection with S. Typhimurium. High resolution confocal microscopy and biochemistry confirms TFEB localization in the mitochondrial matrix. TFEB translocation depends on a conserved N-terminal TOMM20-binding motif and is enhanced by mTOR inhibition. Within the mitochondria, TFEB and protease LONP1 antagonistically co-regulate complex I, reactive oxygen species and the inflammatory response. Consequently, during infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines, contributing to innate immune pathogenesis.
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Project description:Carbon monoxide (CO) can confer protection against cellular stress, whereas the potential involvement of autophagy and lysosomal biogenesis remains incompletely understood. We demonstrate here that the activation of protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) with CO increased the nuclear translocation of transcription factor EB (TFEB). PERK activation by CO increased intracellular Ca2+ concentration and the phosphatase activity of calcineurin against TFEB. Moreover, we found that in the deficiency of TFEB, CO not only failed to recruit Parkin to the mitochondria but also failed to increase expression of lysosomal genes such as Lamp1, CathB, and TPP1. Therefore, we suggest that CO increases mitophagy through TFEB nuclear translocation by PERK-calcinuerin activation. In addition, the inhibition of TFEB with siRNA against TFEB abrogated the increase of mtDNA with CO, markers of mitochondrial biogenesis such as PGC1α, NRF1, and TFAM, and the mitochondrial proteins COX II, COX IV, and cytochrome c. To investigate the effects of CO on mitochondrial homeostasis in vivo, mice were treated with lipopolysaccharide (LPS)/D-galactosamine (D-GalN). CO inhalation reduced liver injury after challenge with LPS/GalN. Furthermore, CO inhalation increased TFEB activation, mitophagy and mitochondrial biogenesis in mice treated with LPS/GalN. Our findings describe novel mechanisms underlying CO-dependent cytoprotection in hepatocytes and liver tissue via activation of TFEB-dependent mitophagy and associated induction of both lysosomal and mitochondrial biogenesis.
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Project description:Reversible phosphorylation of the transcription factor EB (TFEB) coordinates cellular responses to metabolic and other stresses. During nutrient replete and stressor-free conditions, phosphorylated TFEB is primarily localized to the cytoplasm. Stressor-mediated reduction of TFEB phosphorylation promotes its nuclear translocation and context-dependent transcriptional activity. In this study, we explored targeted dephosphorylation of TFEB as an approach to activate TFEB in the absence of nutrient deprivation or other cellular stress. Through an induction of proximity between TFEB and several phosphatases using the AdPhosphatase system, we demonstrate targeted dephosphorylation of TFEB in cells. Furthermore, by developing a heterobifunctional molecule BDPIC (bromoTAG-dTAG proximity-inducing chimera), we demonstrate targeted dephosphorylation of TFEB-dTAG through induced proximity to bromoTAG-PPP2CA. Targeted dephosphorylation of TFEB-dTAG by bromoTAG-PPP2CA with BDPIC at the endogenous levels is sufficient to induce nuclear translocation and some transcriptional activity of TFEB.
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Project description:Background Nuclear-to-mitochondrial communication regulating gene expression and mitochondrial function is a critical process following cardiac ischemic injury. In this study, we determined that cyclin C, a component of the Mediator complex, regulates cardiac and mitochondrial function in part by modifying mitochondrial fission. We tested the hypothesis that cyclin C functions as a transcriptional cofactor in the nucleus and a signaling molecule stimulating mitochondrial fission in response to stimuli such as cardiac ischemia. Methods and Results We utilized gain- and loss-of-function mouse models in which the CCNC (cyclin C) gene was constitutively expressed (transgenic, CycC cTg) or deleted (knockout, CycC cKO) in cardiomyocytes. The knockout and transgenic mice exhibited decreased cardiac function and altered mitochondria morphology. The hearts of knockout mice had enlarged mitochondria with increased length and area, whereas mitochondria from the hearts of transgenic mice were significantly smaller, demonstrating a role for cyclin C in regulating mitochondrial dynamics in vivo. Hearts from knockout mice displayed altered gene transcription and metabolic function, suggesting that cyclin C is essential for maintaining normal cardiac function. In vitro and in vivo studies revealed that cyclin C translocates to the cytoplasm, enhancing mitochondria fission following stress. We demonstrated that cyclin C interacts with Cdk1 (cyclin-dependent kinase 1) in vivo following ischemia/reperfusion injury and that, consequently, pretreatment with a Cdk1 inhibitor results in reduced mitochondrial fission. This finding suggests a potential therapeutic target to regulate mitochondrial dynamics in response to stress. Conclusions Our study revealed that cyclin C acts as a nuclear-to-mitochondrial signaling factor that regulates both cardiac hypertrophic gene expression and mitochondrial fission. This finding provides new insights into the regulation of cardiac energy metabolism following acute ischemic injury.
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Project description:Cells respond to mitochondrial energetic stress with rapid activation of the AMP-activated protein kinase (AMPK), which acutely inhibits anabolism and stimulates catabolism. AMPK also induces sustained transcriptional reprogramming of metabolism. The TFEB transcription factor is a major effector of AMPK signals, inducing lysosome genes following energetic stress. Yet the molecular mechanism underlying how AMPK activates TFEB remains unresolved. We demonstrate here that AMPK directly phosphorylates five conserved serine residues in FNIP1, which suppresses the function of the FLCN/FNIP1 RagC GAP complex, in turn controlling TFEB lysosomal localization. We demonstrate that FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB, which is fully separable from AMPK control of canonical mTORC1 signaling. Using a non-phosphorylatable allele of FNIP1, we show that in parallel to lysosomal biogenesis, AMPK induces mitochondrial biogenesis via TFEB-dependent induction of PGC1a mRNA. This signaling from mitochondrial stress is also independent of amino-acid control of the Rags and TFEB, which still proceed normally in cells bearing the AMPK-non phosphorylatable allele of FNIP1. Taken together, mitochondrial energetic stress triggers AMPK/FNIP1-dependent TFEB nuclear translocation, inducing transcriptional waves of lysosomal and mitochondrial biogenesis.
2023-05-08 | GSE218827 | GEO
Project description:Lysosomes are the terminal organelles of the autophagic-endocytic pathway and play a key role in the degradation of autophagic contents. We previously reported that a natural compound oblongifolin C (OC) increased the number of autophagosomes and impaired the degradation of P62, most likely via suppression of lysosomal function and blockage of autophagosome-lysosome fusion. However, the precise mechanisms of how OC inhibits the lysosome-autophagy pathway remain unclear. In the present study, we investigated the effect of OC on transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, lysosomal function and autophagy. We showed that treatment with OC (15 μM) markedly enhanced the nuclear translocation of TFEB in HeLa cells, concomitantly reduced the interaction of TFEB with 14-3-3 proteins. We further demonstrated that OC caused significant inhibition of mTORC1 along with TFEB nuclear translocation, and OC-mediated TFEB nuclear translocation was dependent on mTORC1 suppression. Intriguingly, this increased nuclear TFEB was accompanied by reduced TFEB luciferase activity, increased lysosomal pH and impaired cathepsin enzyme activities. In HeLa cells, treatment with OC (7.5 μM) resulted in about 30% of cell death, whereas treatment with hydroxycitrate, a caloric restriction mimetic (20 μM) did not affect the cell viability. However, cotreatment with OC and hydroxycitrate caused significantly great cytotoxicity (>50%). Taken together, these results demonstrate that inhibition of lysosome function is mediated by OC, despite evident TFEB nuclear translocation.
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Project description:Dysfunction of the mitochondria is well-known for being associated with cancer progression. In the present study, we analyzed the mitochondria proteomics of lung cancer cell lines with different invasion abilities and found that EGFR is highly expressed in the mitochondria of highly invasive non-small-cell lung cancer (NSCLC) cells. EGF induces the mitochondrial translocation of EGFR; further, it leads to mitochondrial fission and redistribution in the lamellipodia, upregulates cellular ATP production, and enhances motility in vitro and in vivo. Moreover, EGFR can regulate mitochondrial dynamics by interacting with Mfn1 and disturbing Mfn1 polymerization. Overexpression of Mfn1 reverses the phenotypes resulting from EGFR mitochondrial translocation. We show that the mitochondrial EGFR expressions are higher in paired samples of the metastatic lymph node as compared with primary lung tumor and are inversely correlated with the overall survival in NSCLC patients. Therefore, our results demonstrate that besides the canonical role of EGFR as a receptor tyrosine, the mitochondrial translocation of EGFR may enhance cancer invasion and metastasis through regulating mitochondria dynamics.
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Project description:TFEB is a master regulator for transcription of genes involved in autophagy and lysosome biogenesis. Activity of TFEB is inhibited upon its serine phosphorylation by mTOR The overall mechanisms by which TFEB activity in the cell is regulated are not well elucidated. Specifically, the mechanisms of TFEB turnover and how they might influence its activity remain unknown. Here, we show that STUB1, a chaperone-dependent E3 ubiquitin ligase, modulates TFEB activity by preferentially targeting inactive phosphorylated TFEB for degradation by the ubiquitin-proteasome pathway. Phosphorylated TFEB accumulated in STUB1-deficient cells and in tissues of STUB1-deficient mice resulting in reduced TFEB activity. Conversely, cellular overexpression of STUB1 resulted in reduced phosphorylated TFEB and increased TFEB activity. STUB1 preferentially interacted with and ubiqutinated phosphorylated TFEB, targeting it to proteasomal degradation. Consistent with reduced TFEB activity, accumulation of phosphorylated TFEB in STUB1-deficient cells resulted in reduced autophagy and reduced mitochondrial biogenesis. These studies reveal that the ubiquitin-proteasome pathway participates in regulating autophagy and lysosomal functions by regulating the activity of TFEB.
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Project description:Reversible phosphorylation of the transcription factor EB (TFEB) coordinates cellular responses to metabolic and other stresses. During nutrient replete and stressor-free conditions, phosphorylated TFEB is primarily localised to the cytoplasm. Stressor-mediated reduction of TFEB phosphorylation promotes its nuclear translocation and context-dependent transcriptional activity. In this study, we explored targeted dephosphorylation of TFEB as an approach to activate TFEB in the absence of nutrient deprivation or other cellular stress. Through an induction of proximity between TFEB and several phosphatases using the AdPhosphatase system, we demonstrate targeted dephosphorylation of TFEB in cells. Furthermore, by developing a heterobifunctional molecule BDPIC (bromoTAG-dTAG proximity-inducing chimera), we demonstrate targeted dephosphorylation of TFEB-dTAG through induced proximity to bromoTAG-PPP2CA. Targeted dephosphorylation of TFEB-dTAG by bromoTAG-PPP2CA with BDPIC at the endogenous levels is sufficient to induce nuclear translocation and some transcriptional activity of TFEB.
2024-08-09 | PXD053311 | Pride
Project description:Reversible phosphorylation of the transcription factor EB (TFEB) coordinates cellular responses to metabolic and other stresses. During nutrient replete and stressor-free conditions, phosphorylated TFEB is primarily localised to the cytoplasm. Stressor-mediated reduction of TFEB phosphorylation promotes its nuclear translocation and context-dependent transcriptional activity. In this study, we explored targeted dephosphorylation of TFEB as an approach to activate TFEB in the absence of nutrient deprivation or other cellular stress. Through an induction of proximity between TFEB and several phosphatases using the AdPhosphatase system, we demonstrate targeted dephosphorylation of TFEB in cells. Furthermore, by developing a heterobifunctional molecule BDPIC (bromoTAG-dTAG proximity-inducing chimera), we demonstrate targeted dephosphorylation of TFEB-dTAG through induced proximity to bromoTAG-PPP2CA. Targeted dephosphorylation of TFEB-dTAG by bromoTAG-PPP2CA with BDPIC at the endogenous levels is sufficient to induce nuclear translocation and some transcriptional activity of TFEB.
2024-08-09 | PXD053308 | Pride