bims-raghud 2026-06-14 papers

Issue of 2026–06–14
three papers selected by
Irene Sambri, TIGEM

J Transl Med. 2026 Jun 11.

TRPML1 agonists synergize with enzyme replacement therapy in fibroblasts from Pompe disease patients.

Carla Damiano, Antonietta Tarallo, Sandra Strollo, Nadia Minopoli, Anna Valanzano, Antonia Assunto, Maria Rosaria Tuzzi, Nicola Brunetti-Pierri, Andrea Ballabio, Nicolina Cristina Sorrentino, Giancarlo Parenti.

OBJECTIVE: Pompe disease is a severe and progressive metabolic myopathy caused by pathogenic variants of the GAA gene, deficiency of acid alpha-glucosidase (GAA), and lysosomal glycogen storage. The current standard of treatment for PD is enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Despite significant success of ERT in correcting some disease manifestations, limitations of its efficacy have emerged, due to several factors. Poor expression or abnormal intracellular distribution of the cation-independent mannose-6-phosphate receptor (M6PR) at the plasma membrane of specific cells has been identified as one of these factors. Here, we investigated whether activation of Transient Receptor Potential Mucolipin 1 (TRPML1) synergizes with ERT. TRPML1 is a lysosomal ion channel that has been shown to induce multiple effects, including regulation of calcium homeostasis, stimulation of autophagy, activation of lysosomal biogenesis and exocytosis, enhancement of vesicle and membrane trafficking.
METHODS: We studied the effects of two TRPML1 agonists in cultured fibroblasts from Pompe disease patients. Specifically, we analyzed M6PR availability at the plasma membrane of control and mutant cells, level of correction of GAA activity by rhGAA, processing and lysosomal trafficking of the recombinant enzyme.
RESULTS: Treatment with two TRPML1 agonist drugs increased M6PR total amounts and its availability at the plasma membrane and improved M6PR intracellular recycling. The improvements in M6PR distribution translated into better correction of GAA activity in cells incubated with rhGAA and in improved lysosomal trafficking and processing of the recombinant enzyme.
CONCLUSION: These data provide in vitro proof-of-concept evidence supporting the combination of ERT with pharmacological manipulation of secondarily altered M6PR distribution as a strategy to obtain better exposure of cells to therapeutic enzymes.

Keywords: Acid alpha-glucosidase; Enzyme replacement therapy; Lysosomal storage diseases; Pompe disease; TRPML1

DOI: https://doi.org/10.1186/s12967-026-08343-3

Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2528668123

Disruption to TFEB signaling and autophagy in newly formed oligodendrocytes leads to aberrant generation of CNS myelin.

Daniela Barbosa, Aksheev Bhambri, Miguel Vasquez, Yihe Zhang, Gabrielle Sanchez, Katherine J Wert, Natalia V Gounko, Mark H Ellisman, Lu O Sun.

Myelin is a defining feature of the vertebrate nervous system, yet the cellular and molecular mechanisms governing its integrity remain poorly understood. Here, using volume electron microscopy and a knock-in mouse line targeting newly formed oligodendrocytes, we reconstruct early optic nerve myelination and examine retinal ganglion cell axon ensheathment. We observe that newly formed myelin sheaths exhibit membrane protrusions and occasional degenerative myelin "whorls." Conditional disruption of the transcription factor EB (TFEB)-autophagy pathway in newly formed oligodendrocytes significantly increases the abundance of these aberrant myelin structures, indicating that this pathway is required for proper myelin formation and integrity. Importantly, this pathway acts independently of the well-established function of TFEB that represses myelin sheath growth. Together, our findings identify a role for TFEB-dependent autophagy in establishing proper myelin structure during development, providing insights into the oligodendrocyte-intrinsic mechanisms that regulate myelin integrity.

Keywords: axon ensheathment; myelin integrity; newly formed oligodendrocytes; volume electron microscopy

DOI: https://doi.org/10.1073/pnas.2528668123

Int J Mol Sci. 2026 May 26. pii: 4774. [Epub ahead of print]27(11):

The Role of Mitochondria in Polycystic Kidney Disease.

Yuhe Wang, Jianhua Mao, Fei Liu.

Polycystic kidney disease (PKD) is a genetic disorder characterized by renal cyst formation and progressive renal dysfunction, where inflammation, immune responses, and metabolic dysregulation critically drive disease progression, while emerging evidence increasingly links its pathogenesis to mitochondrial dysfunction. Mitochondria, central to cellular energy production, metabolism, and redox homeostasis, exhibit profound abnormalities in PKD, contributing to disease pathogenesis. Current evidence on mitochondrial mechanisms driving PKD progression includes metabolic reprogramming, oxidative stress, disrupted mitochondrial dynamics, and impaired mitophagy. Polycystic kidney disease is caused by mutations in the PKD1 or PKD2 genes, which encode polycystin 1 and polycystin 2. The formation of dysfunctional polycystins (PC1/PC2) is a key event in the pathogenesis of this disease, triggering impaired calcium signaling, increased production of mitochondrial reactive oxygen species (ROS), and reduced oxidative phosphorylation, thereby promoting cyst growth and fibrosis. Key signaling pathways such as mTORC1 hyperactivation, AMPK suppression, and disrupted calcium homeostasis further exacerbate mitochondrial defects. Emerging therapeutic strategies targeting mitochondrial pathways, such as mitochondrial antioxidants, modulators of mitophagy, calcium signaling regulators, and metabolic reprogramming agents, show promise in preclinical models. However, challenges remain in translating these findings to clinical applications, including drug specificity and minimizing off-target effects. This review underscores mitochondria as pivotal players in PKD pathogenesis and highlights their potential as therapeutic targets to mitigate cystogenesis and disease progression.

Keywords: cell signaling; metabolic reprogramming; mitochondria; mitophagy; oxidative stress; polycystic kidney disease

DOI: https://doi.org/10.3390/ijms27114774