bims-raghud 2025-02-02 papers

Issue of 2025–02–02
four papers selected by
Irene Sambri, TIGEM

Sci Rep. 2025 Jan 27. 15(1): 3319

A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress.

Maja Bencun, Laura Spreyer, Etienne Boileau, Jessica Eschenbach, Norbert Frey, Christoph Dieterich, Mirko Völkers.

Pathological cardiac remodeling is a maladaptive response that leads to changes in the size, structure, and function of the heart. These changes occur due to an acute or chronic stress on the heart and involve a complex interplay of hemodynamic, neurohormonal and molecular factors. As a critical regulator of cell growth, protein synthesis and autophagy mechanistic target of rapamycin complex 1 (mTORC1) is an important mediator of pathological cardiac remodeling. The tumor suppressor folliculin (FLCN) is part of the network regulating non-canonical mTORC1 activity. FLCN activates mTORC1 by functioning as a guanosine triphosphatase activating protein (GAP). Our work has identified a regulatory upstream open reading frame (uORF) localized in the 5'UTR of the FLCN mRNA. These small genetic elements are important regulators of protein expression. They are particularly important for the regulation of stress-responsive protein synthesis. We have studied the relevance of the FLCN uORF in the regulation of FLCN translation. We show that FLCN downregulation through the uORF is linked to cardiomyocyte growth and increased lysosomal activity. In summary, we have identified uORF-mediated control of RNA translation as another layer of regulation in the complex molecular network controlling cardiomyocyte hypertrophy.

Keywords: Folliculin; Hypertrophic growth; Lysosome; TFEB; Translation; Upstream open reading frame

DOI: https://doi.org/10.1038/s41598-025-87107-3

Stem Cell Reports. 2025 Jan 09. pii: S2213-6711(24)00355-2. [Epub ahead of print] 102395

A novel rapalog shows improved safety vs. efficacy in a human organoid model of polycystic kidney disease.

Ramila E Gulieva, Parvaneh Ahmadvand, Benjamin S Freedman.

The mammalian target of rapamycin (mTOR) pathway is a therapeutic target in polycystic kidney disease (PKD), but mTOR inhibitors such as everolimus have failed to show efficacy at tolerated doses in clinical trials. Here, we introduce AV457, a novel rapalog developed to reduce side effects, and assess its dose-dependent safety and efficacy versus everolimus in PKD1-/- and PKD2-/- human kidney organoids, which form cysts in a PKD-specific way. Both AV457 and everolimus reduce cyst growth over time. At intermediate doses, AV457 exhibits an improved safety profile relative to everolimus, with comparable efficacy. Target engagement assays confirm mTOR pathway inhibition and greater selectivity of AV457 for mTOR complex 1 versus complex 2, compared to everolimus. AV457 thus provides a more favorable balance of safety and efficacy for PKD compared to everolimus and merits further consideration as an investigational therapeutic.

Keywords: Akt; IC50; S6; ciliopathy; drug discovery; immunoblot; mTORC1; mTORC2; sirolimus; therapeutic screening

DOI: https://doi.org/10.1016/j.stemcr.2024.102395

Int J Mol Sci. 2025 Jan 18. pii: 806. [Epub ahead of print]26(2):

Autophagy and Mitophagy in Diabetic Kidney Disease-A Literature Review.

Alina Mihaela Stanigut, Liliana Tuta, Camelia Pana, Luana Alexandrescu, Adrian Suceveanu, Nicoleta-Mirela Blebea, Ileana Adela Vacaroiu.

Autophagy and mitophagy are critical cellular processes that maintain homeostasis by removing damaged organelles and promoting cellular survival under stress conditions. In the context of diabetic kidney disease, these mechanisms play essential roles in mitigating cellular damage. This review provides an in-depth analysis of the recent literature on the relationship between autophagy, mitophagy, and diabetic kidney disease, highlighting the current state of knowledge, existing research gaps, and potential areas for future investigations. Diabetic nephropathy (DN) is traditionally defined as a specific form of kidney disease caused by long-standing diabetes, characterized by the classic histological lesions in the kidney, including mesangial expansion, glomerular basement membrane thickening, nodular glomerulosclerosis (Kimmelstiel-Wilson nodules), and podocyte injury. Clinical markers for DN are albuminuria and the gradual decline in glomerular filtration rate (GFR). Diabetic kidney disease (DKD) is a broader and more inclusive term, for all forms of chronic kidney disease (CKD) in individuals with diabetes, regardless of the underlying pathology. This includes patients who may have diabetes-associated kidney damage without the typical histological findings of diabetic nephropathy. It also accounts for patients with other coexisting kidney diseases (e.g., hypertensive nephrosclerosis, ischemic nephropathy, tubulointerstitial nephropathies), even in the absence of albuminuria, such as a reduction in GFR.

Keywords: AMPK-mTOR-Sirt1 pathway; PINK1/Parkin pathway; autophagy; diabetic nephropathy; mitochondrial dysfunction; mitophagy

DOI: https://doi.org/10.3390/ijms26020806

Hum Mol Genet. 2025 Jan 29. pii: ddae199. [Epub ahead of print]

Human TSC2 mutant cells exhibit aberrations in early neurodevelopment accompanied by changes in the DNA Methylome.

Mary-Bronwen L Chalkley, Lindsey N Guerin, Tenhir Iyer, Samantha Mallahan, Sydney Nelson, Mustafa Sahin, Emily Hodges, Kevin C Ess, Rebecca A Ihrie.

Tuberous Sclerosis Complex (TSC) is a debilitating developmental disorder characterized by a variety of clinical manifestations. While benign tumors in the heart, lungs, kidney, and brain are all hallmarks of the disease, the most severe symptoms of TSC are often neurological, including seizures, autism, psychiatric disorders, and intellectual disabilities. TSC is caused by loss of function mutations in the TSC1 or TSC2 genes and consequent dysregulation of signaling via mechanistic Target of Rapamycin Complex 1 (mTORC1). While TSC neurological phenotypes are well-documented, it is not yet known how early in neural development TSC1/2-mutant cells diverge from the typical developmental trajectory. Another outstanding question is the contribution of homozygous-mutant cells to disease phenotypes and whether phenotypes are also present in the heterozygous-mutant populations that comprise the vast majority of cells in patients. Using TSC patient-derived isogenic induced pluripotent stem cells (iPSCs) with defined genetic changes, we observed aberrant early neurodevelopment in vitro, including misexpression of key proteins associated with lineage commitment and premature electrical activity. These alterations in differentiation were coincident with hundreds of differentially methylated DNA regions, including loci associated with key genes in neurodevelopment. Collectively, these data suggest that mutation or loss of TSC2 affects gene regulation and expression at earlier timepoints than previously appreciated, with implications for whether and how prenatal treatment should be pursued.

Keywords: DNA methylation; iPS cells; neurodevelopment; tuberous sclerosis

DOI: https://doi.org/10.1093/hmg/ddae199