Loss of function of transcription factor EB remodels lipid metabolism and cell death pathways in the cardiomyocyte

Trivedi, Purvi; Bartlett, Jordan; Mercer, Angella; Slade, Logan; Surette, Marc E.; Ballabio, Andrea; Flibotte, Stéphane; Hussein, Bahira; Rodrigues, Brian; Kienesberger, Petra C.; Pulinilkunnil, Thomas

doi:10.1016/j.bbadis.2020.165832

Cited by 23 publications

(19 citation statements)

References 68 publications

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“…TFEB overexpression increases lysosome number and their degradative ability, and induces the biogenesis of autophagosomes, fusion of autophagosomes with lysosomes and autophagic flux [3]. TFEB directly targets and positively regulates peroxisome proliferator activated receptor-γ coactivator 1α (Ppargc1α) and has been shown to regulate energy metabolism in the liver [4] and heart [5, 6]. It also plays a role in mitochondrial autophagy (mitophagy) facilitating parkin-mediated mitochondrial clearance [7].…”

Section: Introductionmentioning

confidence: 99%

“…While TFEB is known for its role in lysosomal biogenesis and autophagy regulation, others have reported the importance of TFEB in the regulation of energy metabolism. Transcriptomic analysis in TFEB -/- cardiomyocytes revealed differentially expressed genes involved in nutrient metabolism, cardiac function, DNA repair and damage and apoptosis [5]. Support for the role of TFEB in regulating energy metabolism is also observed in skeletal muscle with TFEB overexpression (AAV-TFEB), which demonstrated that TFEB controls the expression of genes involved in mitochondrial biogenesis, fatty acid oxidation and oxidative phosphorylation [13].…”

Section: Introductionmentioning

confidence: 99%

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Cardiac Specific Overexpression of Transcription Factor EB (TFEB) in Normal Hearts Induces Pathologic Cardiac Hypertrophy and Lethal Cardiomyopathy

Kenny

Weatherford

Collins

et al. 2021

Preprint

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TFEB promotes lysosomal biogenesis, autophagy, and lysosomal exocytosis. The present study characterized the consequence of inducible TFEB overexpression in cardiomyocytes in vivo. We generated cardiomyocyte-specific doxycycline inducible (Tet off) mice to achieve spatial and temporal control of TFEB overexpression, by crossing TFEB transgenic mice with mice harboring the tTA transgene (TFEB/tTA). Two weeks after doxycycline removal, an 8-fold increase in TFEB protein expression was observed in transgenic hearts. Heart weight normalized to tibia length was increased by 2.5-fold following TFEB overexpression (TFEB/tTA), characterized by induction of markers of pathological hypertrophy, such as Nppa, Nppb and Acta1, progressive contractile dysfunction and cardiac dilatation. Overexpression of TFEB resulted in premature death, associated with high degree AV block. Reversal of TFEB overexpression normalized cardiac structure and function. Mitochondrial respiration and ATP levels were preserved after 2-weeks of TFEB induction, despite reduced mitochondrial (OXPHOS) protein expression, mtDNA content, and altered mitochondrial morphology. Signaling through mTOR was induced in TFEB/tTA mice, and when inhibited by rapamycin treatment for 4 weeks, partially offset left ventricular dysfunction. Transcriptome analysis revealed early suppression of mitochondrial metabolic pathways, induction of fibrosis and altered calcium signaling. MCOLN1, a lysosomal calcium release channel, the calcineurin target RCAN1.4, and the mitochondrial calcium uniporter (MCU) were strikingly induced in TFEB/tTA mice. In summary, persistent overexpression of TFEB in cardiomyocytes promotes pathologic cardiac hypertrophy via suppression of mitochondrial bioenergetic pathways and activation of pro-fibrotic and calcium regulatory pathways.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cardiac Specific Overexpression of Transcription Factor EB (TFEB) in Normal Hearts Induces Pathologic Cardiac Hypertrophy and Lethal Cardiomyopathy

Kenny

Weatherford

Collins

et al. 2021

Preprint

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“…Insulin resistance-induced hyperglycemia and fatty acid overutilization lead to glucolipotoxicity in the heart. Glucolipotoxicity downregulates TFEB and leads to diminished lysosomal function in cardiomyocytes [55] . Reduced nuclear TFEB content and elevated lipid (diacylglycerol and triacylglycerol) accumulation concomitantly occurred in the heart from high-fat high-sucrose diet-fed mice.…”

Section: Tfeb and Cvdsmentioning

confidence: 99%

“…Reduced nuclear TFEB content and elevated lipid (diacylglycerol and triacylglycerol) accumulation concomitantly occurred in the heart from high-fat high-sucrose diet-fed mice. Cardiomyocyte-specific Tfeb KO disturbs not only autophagy and lysosomal function but also metabolic pathways, rendering the heart susceptible to nutrient overload-induced injury in mice [55] .…”

Section: Tfeb and Cvdsmentioning

confidence: 99%

Transcription factor EB regulates cardiovascular homeostasis

Sun

Hamblin

et al. 2021

EBioMedicine

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“…Loss of insulin action or function during obesity and diabetes is known to disrupt energy metabolism in the heart by triggering hyperglycemia and fatty acid over-utilization, leading to glucolipotoxicity. Thomas Pulinilkunnil and his team at Dalhousie University [11] have previously demonstrated that glucolipotoxicity negatively regulates the lysosomal protein degradation pathway or autophagy by inhibiting transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and lysosomal function. In the current paper, they examine nutrient specific and upstream regulators of TFEB in the heart, as well as metabolic alterations in response to the loss of TFEB action, and explore whether these alterations impact on cardiomyocyte function.…”

Section: Tablementioning

confidence: 99%

Targeting metabolic pathways to treat cardiovascular diseases

Glatz

Zuurbier

Larsen

2020

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Loss of function of transcription factor EB remodels lipid metabolism and cell death pathways in the cardiomyocyte

Cited by 23 publications

References 68 publications

Cardiac Specific Overexpression of Transcription Factor EB (TFEB) in Normal Hearts Induces Pathologic Cardiac Hypertrophy and Lethal Cardiomyopathy

Cardiac Specific Overexpression of Transcription Factor EB (TFEB) in Normal Hearts Induces Pathologic Cardiac Hypertrophy and Lethal Cardiomyopathy

Transcription factor EB regulates cardiovascular homeostasis

Targeting metabolic pathways to treat cardiovascular diseases

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