bims-mecosi 2025-08-24 papers

Issue of 2025–08–24
six papers selected by
Verena Kohler, Umeå University

Cell Death Dis. 2025 Aug 18. 16(1): 623

AMPK regulates ARF1 localization to membrane contact sites to facilitate fatty acid transfer between lipid droplets and mitochondria.

Lupeng Chen, Yue Liu, Junzhi Zhang, Tongxing Song, Jian Wu, Zhuqing Ren.

Lipid droplet (LD) -mitochondrion contacts play a crucial role in regulating energy metabolism and fatty acid oxidation in skeletal muscle cells. However, the proteins that regulate these interactions remain poorly understood. Here, we demonstrate that the binding between ADP-ribosylation factor 1(ARF1) and perilipin2 (Plin2) regulates LD-mitochondrion contacts under starvation conditions, facilitating the transfer of fatty acids from LDs to mitochondria. In C2C12 cells, starvation increased ARF1's GTP-binding activity and its localization to mitochondria, enhancing ARF1's binding to Plin2 and facilitating fatty acid flow from LDs to mitochondria. In contrast, knockdown of ARF1 reduced LD-mitochondrion interactions and blocked fatty acids transfer. Additionally, ARF1-mediated interactions were regulated by AMPK; inhibiting AMPK activity reduced ARF1 localization to LDs and mitochondria, and blocked LD-mitochondrion interactions. In mice, starvation increased ARF1 expression in muscle tissue and LD-mitochondrion contacts. Conversely, inhibiting ARF1 led to lipid accumulation in muscle tissue. In conclusion, our work suggests that ARF1 is a critical regulator of LD-mitochondrion interactions and plays a significant role in energy metabolism regulation in skeletal muscle.

DOI: https://doi.org/10.1038/s41419-025-07957-7

Food Sci Nutr. 2025 Aug;13(8): e70776

Tea Polyphenol Modulates Mitochondria-Associated Endoplasmic Reticulum Membrane of Hippocampal Neurons Targeting Grp75 to Ameliorate Memory Impairment in the Aged T2DM Rats.

Mengqian Shi, Le Cheng, Chenhui Lv, Wenjuan Feng, Xi Wang, Shuangzhi Chen, Chenyang Li, Lushan Xue, Cheng Zhang, Xuemin Li, Haifeng Zhao.

Tea polyphenol (TP), as the most abundant and unique functional substance of tea, has been widely studied for the neuroprotective effects. Previous studies also found that TP improves the memory impairment of the aged T2DM rats, but the underlying molecular mechanism has not been fully clarified. The model of aged T2DM was induced by injecting D-galactose and STZ intraperitoneally, as well as feeding with a high-glucose-fat diet in rats, and D-galactose and D-glucose were used in PC12 cells. Memory function, mitochondrial damage, mitochondria-associated endoplasmic reticulum membrane (MAM), Ca2+, and apoptosis were detected to investigate the role of TP and its main functional component EGCG in the association between mitochondria and the endoplasmic reticulum. In addition, to further verify whether EGCG reduces apoptosis by regulating MAM, molecular docking and Grp75-siRNA were used. TP intervention alleviates memory impairment, improves insulin resistance, downregulates the expressions of the MAM-related proteins and MAM structure, and reduces apoptosis. Subsequently, EGCG intervention attenuates the interaction of MAM, as p-IP3R1-Grp75 and Grp75-VDAC1, and inhibits the mitochondrial Ca2+ level. In the experiments to validate the mechanism, the results showed that EGCG not only directly connects to Grp75 physically, but Grp75-siRNA combined with EGCG inhibits mitochondrial Ca2+ overload and cell apoptosis by regulating MAM. TP modulates MAM of hippocampal neurons targeting Grp75 to ameliorate memory impairment in the aged T2DM rats, which presents fresh molecular perspectives on the neuroprotective role of TP in T2DM-related memory impairment.

Keywords: T2DM; aged; memory; mitochondria‐associated endoplasmic reticulum membrane; tea polyphenol

DOI: https://doi.org/10.1002/fsn3.70776

Free Radic Biol Med. 2025 Aug 15. pii: S0891-5849(25)00906-2. [Epub ahead of print]240 108-123

FUNDC1-dependent mitochondrial-ER membranes mediate mitochondrial dysfunction and melanocyte damage under oxidative stress.

Jingjing Ma, Mengsha Yuan, Sen Guo, Tianwen Gao, Chunying Li, Ling Liu.

BACKGROUND: Mitochondria play a pivotal role in oxidative stress-induced melanocyte destruction in vitiligo. FUN14 domain containing 1 (FUNDC1), a mitochondrial outer-membrane protein, has an important role in mitochondrial function by regulating mitophagy and mitochondria-associated endoplasmic reticulum membranes (MAM). However, the role of FUNDC1 in melanocyte damage under oxidative remains unclear.
OBJECTIVES: To determine the contribution of FUNDC1 to oxidative stress-triggered melanocyte damage in vitiligo.
METHODS: We treated human melanocyte cell line PIG1 with H2O2 to establish an oxidative stress model. Cell viability, mitochondrial function and dynamics as well as mitophagy were detected. The transmission electron microscopy was used to assess MAM structure. FUNDC1 was then knocked down to examine its effects on MAM structure and mitochondrial function under H2O2 treatment. Additionally, we compared FUNDC1 expression, MAM structure and mitochondrial function between PIG1 cells and human vitiligo melanocyte cell line PIG3V. Finally, FUNDC1 expression and MAM structure were analyzed in vitiligo lesions and healthy control skin.
RESULTS: H2O2 treatment significantly increased intracellular H2O2 level, mitochondrial superoxide and lipid peroxide (LPO), while decreased glutathione (GSH) level in PIG1 cells. Impaired cell viability and mitochondrial function as well as excessive mitochondrial fission in PIG1 cells were observed after H2O2 incubation. However, H2O2 treatment didn't induce mitophagy but enhanced FUNDC1 expression and altered MAM structure. FUNDC1 knockdown inhibited H2O2-induced changes of MAM structure, mitochondrial calcium overloading, mitochondrial dysfunction, and recovered cell viability under oxidative stress. Interestingly, persistent H2O2 exposure reduced FUNDC1 expression, leading to MAM formation deficiency, excessive mitochondrial fusion and compromised mitochondrial function in the human vitiligo melanocyte cell line PIG3V. Finally, the decreased FUNDC1 expression and dysregulated MAM formation were confirmed in vitiligo lesions.
CONCLUSIONS: FUNDC1-dependent MAM structure mediates oxidative stress-induced mitochondrial dysfunction and melanocytes damage in vitiligo, suggesting that FUNDC1 and its associated MAM structure are potential targets for vitiligo treatment.

Keywords: FUNDC1; MAM structure; Melanocytes; Mitochondria; Oxidative stress; Vitiligo

DOI: https://doi.org/10.1016/j.freeradbiomed.2025.08.027

bioRxiv. 2025 Aug 13. pii: 2025.08.12.669915. [Epub ahead of print]

Regulation of the cell wall integrity pathway at the contact site between mating partners in yeast.

Erin R Curtis, Daniel J Lew.

The fungal cell wall is constantly remodeled to allow cell growth, but any holes in the cell wall would lead to catastrophic lysis. The "Cell Wall Integrity" pathway (CWI) detects cell wall defects and promotes cell wall thickening or repair to protect cell integrity. However, cell walls must be removed at contact sites between fusing cells during mating or mycelium formation. Here we show that in Saccharomyces cerevisiae , the CWI is downregulated specifically at the contact site between mating cells. A key component of the CWI, Pkc1, accumulated at polarity sites (shmoo tips) in cells exposed to mating pheromone, but not at contact sites. Pkc1 exclusion required a cell wall protein, Fig2, induced by pheromone. In mutants lacking Fig2, cell wall removal was delayed, blocked, or even reversed after transient fusion, leading to reduced mating. These results suggest that Fig2 designates the contact site as a "safe" spot to degrade the cell wall.
eTOC: Curtis and Lew show that the fungal "Cell Wall Integrity" repair pathway is silenced at contact sites between mating partners to allow cell wall degradation and fusion. They identify a cell wall protein needed to distinguish the contact site as a safe spot for wall removal.

DOI: https://doi.org/10.1101/2025.08.12.669915

J Exp Bot. 2025 Aug 20. pii: eraf378. [Epub ahead of print]

Plant Plastids: From Evolutionary Origins to Functional Specialization and Organelle Interactions.

Luciana Renna, Alessio Papini, Stefano Mancuso, Federica Brandizzi, Giovanni Stefano.

Plastids are highly diverse organelles that play critical roles in supporting life on Earth. Among them, chloroplasts enable photosynthesis, providing phototrophic capabilities to eukaryotes such as plants, algae, and photosynthetic protists. The functions of plastids are indispensable for the survival and development of life. Plastids are widely recognized as endosymbiotic organelles with a single origin. They exhibit morphological diversity, tissue specificity, and the ability to adapt to specific cellular functions. Despite this understanding, significant questions remain unanswered, such as how genetic material from the endosymbiont was transferred and integrated into the host nucleus, the timeline for the full integration of the endosymbiont into the host cell, and the processes by which plastids specialized and adapted to various cell types. While plastids have unique features and specialized roles, they are neither autonomous nor physically isolated. Instead, they interact with other subcellular compartments through yet-to-be-characterized membrane domains or specialized structures. This review explores the origin and evolution of plastids, their protein import machinery, compartmentalization, and interactions with other cellular compartments, while highlighting key unanswered questions in these areas.

Keywords: Endomembrane Compartments; Inter-organellar Communication; Membrane Contact Sites; Organelles; Plastids

DOI: https://doi.org/10.1093/jxb/eraf378

Nat Commun. 2025 Aug 19. 16(1): 7699

Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury.

Liuwei Huang, Yanting Shen, Xiaoling Pan, Jiaqi Li, Caizhen Li, Lixin Ruan, Sitan He, Lanlan Huang, Kangyi Liu, Xin Zhao, Jian Geng, Jie Guo, Fan Fan Hou, Jun Wang.

Acute kidney injury (AKI) can lead to chronic kidney disease (CKD), a transition driven by cellular senescence, a state of irreversible cell-cycle arrest. However, the molecular mechanisms promoting this pathological process remain unclear. Here we show that the channel protein Pannexin1 (Panx1) promotes this detrimental senescence and subsequent kidney fibrosis. We found that Panx1 functions in a noncanonical role as a calcium (Ca2+) leak channel within the endoplasmic reticulum (ER), a key intracellular calcium store. This Panx1-mediated leak occurs at contact sites between the ER and mitochondria, leading to mitochondrial calcium overload, dysfunction, and the generation of pro-senescence signals. Genetically deleting Panx1 in male mouse models of AKI attenuates renal senescence and fibrosis. These findings, validated in human kidney tissue, identify ER-resident Panx1 as a critical driver of kidney disease progression and a potential therapeutic target.

DOI: https://doi.org/10.1038/s41467-025-63152-4