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TFEB Antagonizes Cardiac Hypertrophy and Failure by Enhancing Lysosomal Capacity and Mitochondrial Function
Daniel Daou1,2, Subhajit Das Gupta1,2, Anip Anand1,2
1Department of Internal Medicine (Cardiology) (D.D., S.D.G., A.A., H.I.M., N.J., C.I.I., A.F., V.G.-M., N.N., L.M.-R., D.D.Z., F.O.-S., G.C., F.W., B.A.R., L.I.S., S.L., T.G.G., J.A.H.), UT Southwestern Medical Center, Dallas, TX.
Circulation Research
|June 16, 2026
Summary
Transcription factor EB (TFEB) protects against pathological cardiac remodeling by enhancing lysosomal function and mitochondrial energy production. Loss of TFEB exacerbates heart failure due to impaired protein turnover and signaling pathways.
Area of Science:
- Cardiovascular Biology
- Cellular Metabolism
- Molecular Cardiology
Background:
- Pathological cardiac remodeling and increased energy demand contribute to heart failure (HF).
- Lysosomal processes and mitochondrial function are crucial in cardiac remodeling and HF.
- Transcription factor EB (TFEB) regulates lysosomal genes and mitochondrial function, particularly under stress.
Purpose of the Study:
- To investigate the role of TFEB in cardiomyocyte hypertrophy and pressure overload-induced heart failure.
- To elucidate the molecular mechanisms by which TFEB influences cardiac remodeling and function.
Main Methods:
- Utilized a cardiomyocyte-specific TFEB knockout mouse (CTKO) model subjected to transverse aortic constriction (TAC).
- Assessed cardiac function using echocardiography and performed transcriptomic, proteomic, and metabolomic analyses.
- Employed neonatal rat ventricular myocytes treated with phenylephrine as an in vitro model of hypertrophy.
Main Results:
- TFEB activation in cardiomyocytes triggers a lysosomal gene program under hypertrophic stress.
- CTKO mice exhibited exacerbated hypertrophy and rapid heart failure following TAC, with impaired lysosomal capacity and protein turnover.
- Loss of TFEB led to altered mitochondrial structure, reduced oxidative capacity, and impaired metabolic enzyme expression, alongside decreased AMP-activated protein kinase (AMPK) signaling.
- In vitro and in vivo studies showed that TFEB activation has anti-hypertrophic effects and that exogenous AMPK activation can rescue the hypertrophic response.
Conclusions:
- TFEB antagonizes pathological cardiac remodeling by upregulating lysosomal capacity and maintaining mitochondrial function.
- TFEB plays a critical role in promoting AMPK signaling, which is essential for managing hypertrophic stress.
- These findings highlight TFEB as a key regulator of cardiac adaptation to stress and a potential therapeutic target for heart failure.
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