bims-mecosi 2025-04-20 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–04–20
eight papers selected by
Verena Kohler, Umeå University

Phosphatidate phosphatase Lipin1 alters mitochondria-associated endoplasmic reticulum membranes (MAMs) homeostasis: effects which contribute to the development of diabetic encephalopathy.
Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis.
Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering.
The Extended Synaptotagmins of Physcomitrium patens.
Anxa10 and neuropathic pain: Insights into dysregulation of endoplasmic reticulum-mitochondria contact tethering complex and therapeutic potential.
Serine-129 phosphorylated α-synuclein drives mitochondrial dysfunction and calcium dysregulation in Parkinson's disease model.
Massage-Mimicking Nanosheets Mechanically Reorganize Inter-organelle Contacts to Restore Mitochondrial Functions in Parkinson's Disease.
Cardioprotective effect of senotherapy in chronically obese middle-aged female rats may be mediated by a MERCSs/Nrf2 interaction.

J Neuroinflammation. 2025 Apr 18. 22(1): 111

Phosphatidate phosphatase Lipin1 alters mitochondria-associated endoplasmic reticulum membranes (MAMs) homeostasis: effects which contribute to the development of diabetic encephalopathy.

Shan Huang, Mengyu Hua, Wei Liu, Ziyun Zhuang, Xiaolin Han, Xiaochen Zhang, Zhonghao Liang, Xiaojing Liu, Nengjun Lou, Shuyan Yu, Shihong Chen, Xianghua Zhuang.

  Diabetic encephalopathy (DE) is a common, chronic central nervous system complication of diabetes mellitus, and represents a condition without a clear pathogenesis or effective therapy. Findings from recent studies have indicated that a dyshomeostasis of mitochondria-associated endoplasmic reticulum membranes (MAMs) may be involved in the development of neurodegenerative diseases such as DE. MAMs represent a dynamic contact site between mitochondrial and endoplasmic reticulum (ER) membranes, where phospholipid components are exchanged with each other. Previous work within our laboratory has revealed that Lipin1, a critical enzyme related to phospholipid synthesis, is involved in the pathogenesis of DE. Here, we show that Lipin1 is downregulated within the hippocampus of a DE mouse model, an effect which was accompanied with a decrease in MAMs. Knockdown of Lipin1 in the hippocampus of normal mice resulted in a reduction of MAMs, ER stress, abnormal mitochondrial function, as well as impaired synaptic plasticity and cognitive function. These same phenomena were observed in the DE model, while an upregulation of Lipin1 within the hippocampus of DE mice improved these symptoms. Low levels of Lipin1 in DE mice were also associated with neuroinflammation, while an overexpression of Lipin1 significantly ameliorated the neuroinflammation observed in DE mice. In conclusion, Lipin1 ameliorates pathological changes associated with DE in a mouse model via prevention of dyshomeostasis in MAMs. Such findings suggest that Lipin1 may be serve as a new potential target for the treatment of DE.

Keywords:  Cognitive dysfunction; Diabetic encephalopathy; Lipin1; MAMs; Mitochondria

DOI:  https://doi.org/10.1186/s12974-025-03441-3
Mol Cell. 2025 Apr 17. pii: S1097-2765(25)00196-0. [Epub ahead of print]85(8): 1487-1508

Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis.

Brandon Chen, Costas A Lyssiotis, Yatrik M Shah.

  Mitochondria serve as central hubs in cellular metabolism by sensing, integrating, and responding to metabolic demands. This integrative function is achieved through inter-organellar communication, involving the exchange of metabolites, lipids, and signaling molecules. The functional diversity of metabolite exchange and pathway interactions is enabled by compartmentalization within organelle membranes. Membrane contact sites (MCSs) are critical for facilitating mitochondria-organelle communication, creating specialized microdomains that enhance the efficiency of metabolite and lipid exchange. MCS dynamics, regulated by tethering proteins, adapt to changing cellular conditions. Dysregulation of mitochondrial-organelle interactions at MCSs is increasingly recognized as a contributing factor in the pathogenesis of multiple diseases. Emerging technologies, such as advanced microscopy, biosensors, chemical-biology tools, and functional genomics, are revolutionizing our understanding of inter-organellar communication. These approaches provide novel insights into the role of these interactions in both normal cellular physiology and disease states. This review will highlight the roles of metabolite transporters, lipid-transfer proteins, and mitochondria-organelle interfaces in the coordination of metabolism and transport.

Keywords:  endoplasmic reticulum; inter-organellar communication; mitochondria; organellar metabolism; organelle membrane contact sites

DOI:  https://doi.org/10.1016/j.molcel.2025.03.003
Nat Commun. 2025 Apr 17. 16(1): 3401

Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering.

Koki Nakamura, Saeko Aoyama-Ishiwatari, Takahiro Nagao, Mohammadreza Paaran, Christopher J Obara, Yui Sakurai-Saito, Jake Johnston, Yudan Du, Shogo Suga, Masafumi Tsuboi, Makoto Nakakido, Kouhei Tsumoto, Yusuke Kishi, Yukiko Gotoh, Chulhwan Kwak, Hyun-Woo Rhee, Jeong Kon Seo, Hidetaka Kosako, Clint Potter, Bridget Carragher, Jennifer Lippincott-Schwartz, Franck Polleux, Yusuke Hirabayashi.

Mitochondria-ER membrane contact sites (MERCS) represent a fundamental ultrastructural feature underlying unique biochemistry and physiology in eukaryotic cells. The ER protein PDZD8 is required for the formation of MERCS in many cell types, however, its tethering partner on the outer mitochondrial membrane (OMM) is currently unknown. Here we identify the OMM protein FKBP8 as the tethering partner of PDZD8 using a combination of unbiased proximity proteomics, CRISPR-Cas9 endogenous protein tagging, Cryo-electron tomography, and correlative light-electron microscopy. Single molecule tracking reveals highly dynamic diffusion properties of PDZD8 along the ER membrane with significant pauses and captures at MERCS. Overexpression of FKBP8 is sufficient to narrow the ER-OMM distance, whereas independent versus combined deletions of these two proteins demonstrate their interdependence for MERCS formation. Furthermore, PDZD8 enhances mitochondrial complexity in a FKBP8-dependent manner. Our results identify a novel ER-mitochondria tethering complex that regulates mitochondrial morphology in mammalian cells.

DOI: https://doi.org/10.1038/s41467-025-58538-3
Plants (Basel). 2025 Mar 25. pii: 1027. [Epub ahead of print]14(7):

The Extended Synaptotagmins of Physcomitrium patens.

Alexander Kaier, Maria Ntefidou.

  Membrane contact sites (MCSs) between the endoplasmic reticulum and the plasma membrane enable the transport of lipids without membrane fusion. Extended Synaptotagmins (ESYTs) act at MCSs, functioning as tethers between two membrane compartments. In plants, ESYTs have been mainly investigated in A. thaliana and shown to maintain the integrity of the plasma membrane, especially during stress responses like cold acclimatization, mechanical trauma, and salt stress. ESYTs are present at the MCSs of plasmodesmata, where they regulate defense responses by modulating cell-to-cell transfer of pathogens. Here, the analysis of ESYTs was expanded to the bryophyte Physcomitrium patens, an extant representative of the earliest land plant lineages. P. patens was found to contain a large number of ESYTs, distributed over all previously established classes and an additional class not present in A. thaliana. Motif discovery identified regions in the Synaptotagmin-like mitochondrial (SMP) domain that may explain phylogenetic relationships as well as protein function. The adaptation mechanisms of P. patens necessary to conquer land and its simple tissue structure make it highly suitable as a model organism to study ESYT functions in tip growth, stress responses, and plasmodesmata-mediated transport, and open new directions of research regarding the function of MCSs in cellular processes and plant evolution.

Keywords:  Physcomitrium patens; bryophytes; extended synaptotagmins; lipid transport proteins; membrane contact sites; plasmodesmata; tip growth

DOI:  https://doi.org/10.3390/plants14071027
Biochim Biophys Acta Mol Basis Dis. 2025 Apr 16. pii: S0925-4439(25)00201-7. [Epub ahead of print] 167856

Anxa10 and neuropathic pain: Insights into dysregulation of endoplasmic reticulum-mitochondria contact tethering complex and therapeutic potential.

Fei-Fei Wu, Bo-Zhi Liu, Yun-Qiang Huang, Chang-Lei Zhu, Yu-Lu Xia, Kun-Long Zhang, Shu-Jiao Li, Yan-Ling Yang, Ya-Yun Wang.

  The stability of membrane contact sites is critically dependent on Endoplasmic Reticulum mitochondria contact tethering complexes (EMCTCs), and dysregulation of these sites has been implicated in neuropathic diseases. In this study, we examined the role of Annexin A10 (Anxa10), a calcium-dependent protein, in neuropathic pain by investigating its influence on EMCTCs dysregulation. Using RNA sequencing, western blotting, and behavioral assays, we observed that spared nerve injury (SNI)-induced neuropathic pain significantly increased Anxa10 expression levels within the spinal dorsal horn (SDH) of mice. By employing cell-specific gene regulation via the Cre/loxp system, we utilized loxp-modified adeno-associated virus vectors to modulate Anxa10 expression in GAD2-Cre (inhibitory neurons), vGlut2-Cre (excitatory neurons), and Fos-Cre (activity-induced neurons) transgenic mice. Our results demonstrated that specific down-regulation of Anxa10 in excitatory neurons within the SDH alleviated neuropathic pain, whereas up-regulation of Anxa10, regardless of cell type, induced spontaneous pain in mice. Ultrastructural analysis of the endoplasmic reticulum (ER) and mitochondria, as well as double immunofluorescence staining, revealed that downregulation of Anxa10 mitigated the SNI-induced reduction in ER-mitochondrial distance. Additionally, it attenuated the SNI-induced upregulation of key components of EMCTCs, including IP3R, GRP75, and VDAC1, while preventing the SNI-induced downregulation of NCX3 expression. Furthermore, we formulated and validated the hypothesis that SGK1 and PI3K are positioned downstream of Anxa10. The up-regulation of Anxa10 compromised mitochondrial integrity and disrupted mitochondrial networks, ultimately leading to elevated oxidative stress. Collectively, these findings suggest that Anxa10 represents a promising therapeutic target for correcting EMCTCs dysregulation and mitigating neuropathic pain.

Keywords:  Annexin A10; Endoplasmic reticulum mitochondria contact tether complexes; Excitatory neurons; Neuropathic pain; Spinal dorsal horn

DOI:  https://doi.org/10.1016/j.bbadis.2025.167856
Front Aging Neurosci. 2025 ;17 1538166

Serine-129 phosphorylated α-synuclein drives mitochondrial dysfunction and calcium dysregulation in Parkinson's disease model.

Jie Jiao, Weijin Liu, Ge Gao, Hui Yang.

  Phosphorylation of α-synuclein at serine-129 (p-α-syn) is a hallmark of Parkinson's disease (PD) and constitutes nearly 90% of α-synuclein in Lewy bodies, playing a critical role in disease progression. Despite its pathological significance, the molecular targets and mechanisms driving p-α-syn-induced toxicity, particularly mitochondrial dysfunction, remain poorly understood. In this study, we observed mitochondrial dysfunction in primary cortical neurons derived from mice overexpressing human α-synuclein (h-α-syn), which also exhibit elevated levels of p-α-syn. Notably, inhibiting Ser129 phosphorylation improved mitochondrial function, underscoring the role of p-α-syn in mitochondrial damage. To investigate the molecular mechanism, we performed co-immunoprecipitation (CO-IP) combined with mass spectrometry (MS) to identify p-α-syn binding proteins. This analysis identified protein tyrosine phosphatase interacting protein 51 (PTPIP51) and vesicle-associated membrane protein-associated protein B (VAPB) as key binding partners. Both proteins are localized in the mitochondria-associated endoplasmic reticulum mem-brane (MAM) and essential for calcium transfer between the endoplasmic reticulum (ER) and mitochondria. Our results showed that p-α-syn binds to PTPIP51 and VAPB, disrupting calcium signaling between the ER and mitochondria. Importantly, inhibition of Ser129 phosphorylation partially rescued calcium homeostasis. These findings uncover a novel mechanism by which p-α-syn drives mitochondrial dysfunction and calcium dysregulation through its interactions with MAM-associated proteins, providing new insights into its role in PD pathogenesis and potential therapeutic targets.

Keywords:  Parkinson’s disease; calcium transport; mitochondrial dysfunction; phosphorylation; α-synuclein

DOI:  https://doi.org/10.3389/fnagi.2025.1538166
Adv Sci (Weinh). 2025 Apr 13. e2413376

Massage-Mimicking Nanosheets Mechanically Reorganize Inter-organelle Contacts to Restore Mitochondrial Functions in Parkinson's Disease.

Tianqi Li, Liwen Huang, Chenxiao Guo, Jing Ren, Xi Chen, Yachu Ke, Zengyu Xun, Wenzhuo Hu, Yilin Qi, Heping Wang, Zhongying Gong, Xing-Jie Liang, Xue Xue.

  Parkinson's disease (PD) is exacerbated by dysfunction of inter-organelle contact, which depends on cellular responses to the mechanical microenvironment and can be regulated by external mechanical forces. Delivering dynamic mechanical forces to neural cells proves challenging due to the skull. Inspired by the effects of massage; here PEGylated black phosphorus nanosheets (PEG-BPNS), known for their excellent biocompatibility, biodegradability, specific surface area, mechanical strength, and flexibility, are introduced, which are capable of adhering to neural cell membrane and generating mechanical stimulation with their lateral size of 200 nm, exhibiting therapeutic potential in a 1-methyl-4-phenyl-1,2,3,6-te-trahydropyridine-induced PD mouse model by regulating inter-organelle contacts. Specifically, it is found that 200 nm PEG-BPNS, acting as "NanoMassage," significantly increase plasma membrane tension, as evidenced by fluorescent lipid tension reporter fluorescence lifetime analysis. This mechanical force modulates actin reorganization, subsequently regulating the contacts between actin, mitochondria, and endoplasmic reticulum, further controlling mitochondrial fission and mitigating mitochondrial dysfunction in PD, exhibiting therapeutic efficacy via intranasal administration. These findings provide a noninvasive strategy for applying mechanical stimulation to deep brain areas and elucidate the mechanism of NanoMassage mediating inter-organelle contacts, suggesting the rational design of "NanoMassage" to remodel inter-organelle communications in neurodegenerative disease treatment.

Keywords:  Parkinson's disease; inter‐organelle contacts; mechanical stimulation; mitochondria; nanosheets

DOI:  https://doi.org/10.1002/advs.202413376
J Nutr Biochem. 2025 Apr 16. pii: S0955-2863(25)00086-5. [Epub ahead of print] 109923

Cardioprotective effect of senotherapy in chronically obese middle-aged female rats may be mediated by a MERCSs/Nrf2 interaction.

Alejandro Silva-Palacios, Alejandra María Zúñiga-Muñoz, Elizabeth Soria-Castro, Edith Álvarez-León, Mario Nieto, Gabriela Navarrete-Anastasio, Roxana Carbó, Wylly Ramsés García-Niño, Paola Stephanie López-Cervantes, Verónica Salas-Venegas, Rosa Pamela Flores-Torres, Armando Luna-López, Cecilia Zazueta, Mina Königsberg.

  Hypercaloric intake promotes the development of obesity, a risk factor for cardiovascular disease (CVD). In recent years, it has been suggested that senescent cells have negative implications for the outcome of these chronic pathologies, and senotherapy has emerged as a novel intervention to reduce damage to the organism. However, it is unclear whether the accumulation of senescent cells induces alterations at the cardiac level in rats fed a hypercaloric diet (HD) and if the use of senotherapeutics can reverse it. To address this question, we used middle-aged female rats fed HD from 21 days to 15 months of age. Under our experimental conditions, rats exhibited cardiac hypertrophy and fibrosis, accumulation of senescent cells, changes in mitochondrial morphology, and oxidative stress. Rats were treated for two months with senolytic (dasatinib + quercetin, DQ) or senomorphic (sulforaphane, SFN) agents. Interestingly, the HD rats showed cardiac improvement after the treatment. Our data suggest a possible link mechanism between Nrf2 activation and mitochondria-endoplasmic reticulum contact sites (MERCSs) preservation, activated by SFN rather than by the DQ combination, which allowed cardiac structure maintenance in HD rats decreasing the harmful effects of senescent cells.

Keywords:  MERCSs; Nrf2; Obesity; cardiac damage; dasatinib; quercetin; sulforaphane

DOI:  https://doi.org/10.1016/j.jnutbio.2025.109923