bims-lypmec 2026-05-03 papers

Br J Pharmacol. 2026 Apr 26.

Curcumin controls lysosomal acidification and exocytosis to ameliorate lysosomal cholesterol accumulation in Niemann-Pick type C disease.

Hongyu Chen, Mengli Zhao, Yu Luo, Xiaohe Chu, Dan Li.

BACKGROUND AND PURPOSE: Niemann-Pick type C disease (NPCD) is a rare and fatal lysosomal storage disorder. There are limited therapies for NPCD, although multiple small-molecule compounds have shown therapeutic potential for NPCD. Curcumin (CUR), a polyphenolic compound enriched in turmeric, has cholesterol-lowering effects via regulating intestinal cholesterol absorption and liver cholesterol synthesis. CUR normalises sphingolipid trafficking and stimulates exosome/microvesicle release, increases cytosolic Ca2+ levels, and enhances lysosomal activation via mTOR suppression and TFEB activation. How CUR specifically targets lysosomal cholesterol has not been fully clarified.
EXPERIMENTAL APPROACH: Effects of curcumin on lysosomal cholesterol accumulation were evaluated in NPC1 cell models. Filipin staining, immunofluorescence, surface LAMP1 and NAGase activity and Cathepsin B activity were investigated to evaluate lysosomal cholesterol, TFEB translocation, lysosomal exocytosis and hydrolytic activity. Lysosomal acidification was determined by Lysotracker Red, Oregon Green, and sfGFP/mCherry transfection. CRISPR/Cas9 and siRNA interference were used to investigate the role of TFEB/TFE3 and TRPML1 in curcumin-induced cholesterol reduction.
KEY RESULTS: CUR alleviates lysosomal cholesterol accumulation in NPC1 cells in a TFEB- and TFE3-dependent manner. CUR enhanced lysosomal acidity and promoted calcium-dependent lysosomal exocytosis, which contributed to CUR-mediated lysosomal cholesterol clearance. The combination of CUR with specific agonists (ML-SAs) of MCOLN1/TRPML1, a lysosomal cation channel required for lysosomal exocytosis, improved lysosomal cholesterol clearance.
CONCLUSION AND IMPLICATIONS: CUR reduces lysosomal cholesterol accumulation in NPC1 cells by activating TFEB/TFE3 pathways and promoting Ca2+- and TRPML1-dependent lysosomal exocytosis. These findings support curcumin and its analogues as potential therapeutics for NPCD and other diseases of lysosomal storage.

Keywords: NPC1; cholesterol; curcumin; lysosomal acidification; lysosome exocytosis

DOI: https://doi.org/10.1111/bph.70448

Diabetes. 2026 Apr 30. pii: db250901. [Epub ahead of print]

Lysosomal Ion Channel TRPML1 Contributes to Neuropathic Pain Associated With Diabetic Peripheral Neuropathy in Mice.

Yuanhong Yang, Silin Teng, Yihong Zhang, Yong-Hua Ji, Hongjie Wang, Zhi-Yong Tan.

ARTICLE HIGHLIGHTS: A lysosomal ion channel, TRPML1, contributes to neuropathic pain associated with diabetic peripheral neuropathy (DPN). TRPML1 of dorsal root ganglion neurons contributes to type 2 DPN pain. Astrocyte TRPML1 contributes to type 1 DPN pain. Lysosomal ion channels may be novel mechanisms and targets for DPN pain.

DOI: https://doi.org/10.2337/db25-0901

EMBO Rep. 2026 Apr 27.

Mitochondrial protein import stress causes lysosomal damage and progressive tissue atrophy.

Nicholas A Brennan, Xiaowen Wang, Arnav Rana, Sanaea Z Bhagwagar, Jason Horton, Patricia M Kane, Xin Jie Chen.

Mitochondrial and lysosomal abnormalities co-occur in aging-related diseases with progressive tissue atrophy. It remains unclear whether these two pathogenic pathways affect tissue homeostasis independently, convergently or epistatically. We show that mitochondrial protein import stress causes vacuolar damage in yeast, manifested by V-ATPase disassembly, and vacuolar deacidification and fragmentation. In a mouse model of mitochondrial protein import stress induced by overloading of the nuclear-encoded ANT1 protein, we observe progressive muscle atrophy independent of bioenergetic defects. Like in yeast mutants with severe vacuolar damage, genes involved in amino acid uptake/biosynthesis, one-carbon metabolism, lysosomal biogenesis and iron homeostasis are activated in the skeletal muscle of Ant1-transgenic mice. The affected muscles accumulate glycogen, lipofuscin and poorly processed multivesicular bodies. Despite activation of lysosomal repair and lysophagic pathways, autophagic flux is severely stalled. During aging, various proteolytic cathepsins are increasingly released from the lysosomal lumen into the cytosol. Together with proteasomal activation, this may contribute to unbalanced proteostasis, reduced myofiber size and skeletal muscle atrophy. Our study therefore discovered an evolutionarily conserved mitochondria-to-lysosome proteotoxic axis that affects tissue mass homeostasis during aging.

DOI: https://doi.org/10.1038/s44319-026-00774-9

Pharmacol Res. 2026 Apr 28. pii: S1043-6618(26)00135-0. [Epub ahead of print]228 108220

Mitochondria-lipid droplet communication remodels bioenergetic metabolism in cardiovascular diseases.

Zhongyang Chi, Wei Deng, Saiyang Xie.

The heart's high energy demands are primarily fulfilled through mitochondrial fatty acid (FA) β-oxidation, with lipid droplets (LDs) being the main source of FAs. Research indicates that cardiac lipid homeostasis relies on a dynamic interaction between LDs and mitochondria, facilitated by specialized membrane contact sites (MCSs). These sites are marked by essential proteins such as the Perilipin (PLIN) family, mitochondrial dynamics proteins, and Rab GTPases, forming an efficient pathway for transferring FAs from storage to mitochondrial oxidation. This protective mechanism helps to avert the accumulation of lipotoxic intermediates while supporting lipid synthesis during periods of nutrient surplus. Conversely, the dysregulation of this mitochondria-LD axis is often implicated in various metabolic cardiovascular diseases (CVDs), including heart failure, atherosclerosis, and diabetic cardiomyopathy. Such imbalances lead to interconnected pathological processes, including cardiomyocyte lipotoxicity and mitochondrial dysfunction, which ultimately contribute to myocardial injury and pathological cardiac growth and fibrosis. This review comprehensively examines the current understanding of this intricate organelle crosstalk, emphasizing its structural and functional aspects, diverse biological roles, and significant implications for CVD pathogenesis. A deeper insight into and targeted modulation of this axis could pave the way for innovative therapeutic strategies aimed at addressing metabolic CVDs.

Keywords: Cardiovascular diseases; Lipid droplet; Lipid metabolism; Mitochondria

DOI: https://doi.org/10.1016/j.phrs.2026.108220

J Clin Invest. 2026 May 01. pii: e202528. [Epub ahead of print]136(9):

Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction.

Chai-Wan Kim, Goncalo Vale, Xiaorong Fu, Jeffrey G McDonald, Chongshan Dai, Chao Li, Zhao V Wang, Gaurav Sharma, Chalermchai Khemtong, Craig R Malloy, Stanislaw Deja, Shawn C Burgess, Matthew A Mitsche, Jay D Horton.

Cardiomyocytes primarily rely on fatty acid oxidation (FAO), which provides more than 70% of their energy. However, excessive FAO can disrupt cardiac metabolism by increasing oxygen demand and suppressing glucose utilization through the Randle cycle. Although inhibition of FAO has been investigated in heart failure, its overall therapeutic impact remains uncertain. To determine the consequences of enhanced FAO, we generated cardiomyocyte-specific ACC1 and ACC2 double-knockout (ACC dHKO) mice, which exhibit constitutively elevated FAO. ACC dHKO mice developed dilated cardiomyopathy and heart failure. Lipidomic analysis revealed marked depletion of cardiolipin caused by reduced linoleic acid, a direct consequence of excessive FAO. This cardiolipin deficiency impaired mitochondrial electron transport chain (ETC) activity, leading to mitochondrial dysfunction. Pharmacologic inhibition of FAO with etomoxir or oxfenicine restored cardiolipin levels, normalized ETC activity, and prevented cardiac dysfunction in ACC dHKO mice. These findings demonstrate that unrestrained FAO disrupts both lipid and energy homeostasis, culminating in heart failure in this model. Collectively, these results indicate that although FAO is essential for cardiac energy production, therapeutic strategies aimed at stimulating cardiac FAO may be detrimental rather than beneficial in heart failure.

Keywords: Cardiology; Fatty acid oxidation; Heart failure; Metabolism

DOI: https://doi.org/10.1172/JCI202528