bims-lycede 2024-08-25 papers

Issue of 2024‒08‒25
two papers selected by
Sofía Peralta, Universidad Nacional de Cuyo

Mol Pharmacol. 2024 Aug 21. pii: MOLPHARM-AR-2024-000889. [Epub ahead of print]

The Estrogen Receptor-Related Orphan Receptors (ERRs) Regulate Autophagy through TFEB.

McKenna Losby, Matthew Hayes, Aurore Valfort, Danesh H Sopariwala, Ryan Sanders, John K Walker, Weiyi Xu, Vihang A Narkar, Lilei Zhang, Cyrielle Billon, Thomas P Burris.

Autophagy is an essential self-degradative and recycling mechanism that maintains cellular homeostasis. Estrogen receptor-related orphan receptors (ERRs) are fundamental in regulating cardiac metabolism and function. Previously, we showed that ERR agonists improve cardiac function in models of heart failure and induce autophagy in cardiomyocytes. Here, we characterized a mechanism by which ERRs induce the autophagy pathway in cardiomyocytes. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway and has been shown to be important in cardiac autophagy. We discovered that TFEB is a direct ERR target gene whose expression is induced by ERR agonists. Activation of ERR results in increased TFEB expression in both neonatal rat ventricular myocytes and C2C12 myoblast cells. ERR-dependent increases in TFEB expression result in increased expression of an array of TFEB target genes, which are critical for the stimulation of autophagy. Pharmacologically targeting ERR is a promising potential method for the treatment of many diseases where stimulation of autophagy may be therapeutic, including heart failure. Significance Statement Estrogen receptor-related receptor agonists function as exercise mimetics and also display efficacy in animal models of metabolic disease, obesity, and heart failure.

Keywords: drug discovery; heart/cardiac; nuclear receptors; steroids

DOI: https://doi.org/10.1124/molpharm.124.000889

Biochim Biophys Acta Mol Basis Dis. 2024 Aug 22. pii: S0925-4439(24)00471-X. [Epub ahead of print]1870(8): 167477

TRPML1 ameliorates seizures-related neuronal injury by regulating autophagy and lysosomal biogenesis via Ca2+/TFEB signaling pathway.

Tingting Peng, Yinyin Xie, Senfeng Zhao, Xiaoyi Wang, Wanwan Zhang, Yi Xie, Cui Wang, Nanchang Xie.

Alterations in autophagy have been observed in epilepsy, although their exact etiopathogenesis remains elusive. Transient Receptor Potential Mucolipin Protein 1 (TRPML1) is an ion channel protein that regulates autophagy and lysosome biogenesis. To explore the role of TRPML1 in seizures-induced neuronal injury and the potential mechanisms involved, an hyperexcitable neuronal model induced by Mg2+-free solution was used for the study. Our results revealed that TRPML1 expression was upregulated after seizures, which was accompanied by intracellular ROS accumulation, mitochondrial damage, and neuronal apoptosis. Activation of TRPML1 by ML-SA1 diminished intracellular ROS, restored mitochondrial function, and subsequently alleviated neuronal apoptosis. Conversely, inhibition of TRPML1 had the opposite effect. Further examination revealed that the accumulation of ROS and damaged mitochondria was associated with interrupted mitophagy flux and enlarged defective lysosomes, which were attenuated by TRPML1 activation. Mechanistically, TRPML1 activation allows more Ca2+ to permeate from the lysosome into the cytoplasm, resulting in the dephosphorylation of TFEB and its nuclear translocation. This process further enhances autophagy initiation and lysosomal biogenesis. Additionally, the expression of TRPML1 is positively regulated by WTAP-mediated m6A modification. Our findings highlighted crucial roles of TRPML1 and autophagy in seizures-induced neuronal injury, which provides a new target for epilepsy treatment.

Keywords: Autophagy; Epilepsy; Lysosome; TFEB; TRPML1

DOI: https://doi.org/10.1016/j.bbadis.2024.167477