bims-mecosi 2025-10-05 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–10–05
nine papers selected by
Verena Kohler, Umeå University

Mitochondrial dysfunction drives cellular senescence: Molecular mechanisms of inter-organelle communication.
Copper loading may affect rat neurobehaviour by impairing mitochondria-associated endoplasmic reticulum membranes in hippocampal neurons.
Roles of non-specific lipid transfer proteins in plant defense: structural and functional perspectives.
A Review of FUN14 Domain-Containing 1 Involvement in Mitochondrial Biological Processes and Mechanisms Across Various Systems.
N-acetyl-phenylalanine induces hepatic steatosis in MASLD by disrupting ER-mitochondria calcium coupling and mitochondrial lipid oxidation.
Research on the role of endoplasmic reticulum-mitochondria interactions in maintaining calcium homeostasis in skeletal muscle fibers of hibernating Daurian ground squirrels.
Mitochondrial ROS trigger interorganellular signaling and prime ER processes to establish enhanced plant immunity.
Changes in the endoplasmic reticulum‑mitochondria communication in dermal fibroblasts from early‑stage bipolar disorder patients: Skin‑brain axis as a new route to understand the pathophysiology of mental illness?
GPX1-driven selenium nanoplatform reprograms MAMs-mediated organelle crosstalk to reverse inflammatory adipose expansion in thyroid eye disease.

Exp Gerontol. 2025 Oct 01. pii: S0531-5565(25)00242-6. [Epub ahead of print] 112913

Mitochondrial dysfunction drives cellular senescence: Molecular mechanisms of inter-organelle communication.

Ziyue Xie, Xinyu Zhang, Yu Li, Ruigong Zhu.

  Mitochondrial dysfunction is a central driver of cellular senescence, a core hallmark of aging. While intrinsic mechanisms have been extensively reviewed, this article offers a novel paradigm by emphasizing the critical role of interorganellar communication in mitochondria-mediated senescence. We present a systematic dissection of the molecular mechanisms underlying functional crosstalk between mitochondria and key organelles, including the endoplasmic reticulum (ER), lysosomes, and peroxisomes. A particular focus is placed on established regulatory hubs such as mitochondria-associated ER membranes (MAMs), which orchestrate calcium signaling, lipid metabolism, and inflammatory responses. We further explore emerging pathways involving lysosomal mitochondrial coordination in nutrient sensing and mitophagy, and peroxisomal mitochondrial cooperation in redox balance and lipid homeostasis. By elucidating how defects in these dynamic networks propagate mitochondrial damage and execute senescence, this review establishes a unified framework for aging as integrated organelle network dysfunction. This synthesis advances fundamental aging biology and identifies novel molecular targets, providing a foundation for developing therapeutic strategies targeting organelle networks against age related pathologies.

Keywords:  Cellular senescence; Mitochondrial dysfunction; Molecular mechanism; Organelle

DOI:  https://doi.org/10.1016/j.exger.2025.112913
Behav Brain Funct. 2025 Sep 30. 21(1): 32

Copper loading may affect rat neurobehaviour by impairing mitochondria-associated endoplasmic reticulum membranes in hippocampal neurons.

Zhengzhe Sun, Shan Jin, Xiang Fang, Wenming Yang, Huaizhen Chen.

   BACKGROUND: To observe the effects of copper sulfate (CuSO4)-induced copper loading on neurobehaviour, mitochondria-associated endoplasmic reticulum membranes (MAMs) and related regulatory proteins in the hippocampal CA1 region of Sprague-Dawley (SD) rats.
METHODS: Forty SD male rats were randomly divided into control and copper loading groups of 20 rats each. The control group rats were fed with normal feed and water; rats in the copper loading group were fed high copper feed (containing 1g/kg of CuSO4) and CuSO4 deionized water (concentration of 0.185%). After 12 weeks of rearing, the morris water maze (MWM) task and novel object recognition (NOR) test were conducted to compare the neurobehavioral characteristics of the two groups of rats. Morphological changes of neuronal MAMs in the hippocampal CA1 region of copper-loaded rats were observed using a transmission electron microscope (TEM) and immunofluorescence double-labelling techniques. Western-blot analysis was used to detect the expression of MAMs proteins VDAC1, IP3R, GRP75 and Mfn2.
RESULTS: The results revealed that rats in the copper-loading group had significantly prolonged escape latency and reduced number of platform crossings in the MWM task (p < 0.01). The percentage of novel objects explored (also known as the Discrimination Ratio, DR) and the discrimination index (DI) were significantly reduced in the NOR test (p < 0.01). In addition, electron microscopy shows increased disruption of neuronal endoplasmic reticulum (ER)-mitochondrion coupling in the hippocampal CA1 region of rats in the copper-loading group (p < 0.05), and the percentage of MAMs in mitochondrial circumference decreased (p < 0.05), the colocalization coefficients between the ER and mitochondria was significantly reduced (p < 0.05). Moreover, the protein expression levels of VDAC1, IP3R, and GRP75 in rat hippocampal tissue were detected to be significantly increased (p < 0.01), while the protein expression level of Mfn2 was significantly decreased (p < 0.01).
CONCLUSIONS: In this study, it is speculated that the neurobehavioral changes in rats may be related to the increased expression levels of the MAMs proteins VDAC1, IP3R, and GRP75, the reduced expression level of Mfn2, and the disruption of the structural integrity of MAMs in the hippocampal CA1 region of rats caused by copper loading.

Keywords:  Copper loading; MAMs; Neurobehavior; Wilson’s disease

DOI:  https://doi.org/10.1186/s12993-025-00277-y
Front Fungal Biol. 2025 ;6 1640465

Roles of non-specific lipid transfer proteins in plant defense: structural and functional perspectives.

John E McLaughlin, Nilgun E Tumer.

  Non-specific lipid transfer proteins (nsLTPs) are vital and versatile components of plant cellular systems. They are characterized by a conserved eight-cysteine motif and are increasingly recognized for their dual roles in direct defense and stress modulation. nsLTPs serve critical structural and signaling functions in plant immunity. In contrast, other lipid transfer proteins, which lack the conserved cysteine motif, are primarily localized at membrane contact sites, specialized inter-organelle junctions that act as central hubs for lipid trafficking and signaling. This review explores the diverse roles of nsLTPs from structural, functional, and evolutionary perspectives, and examines current classification methodologies for the plant nsLTP superfamily. Functionally, nsLTPs contribute to the formation of protective barriers by transporting cutin monomers and other lipids, while also possessing lipid-specific antimicrobial properties that disrupt pathogen membranes. They support redox balance by scavenging reactive oxygen species, thereby minimizing oxidative stress. Additionally, nsLTPs are involved in defense signaling by transporting lipid-derived molecules essential to systemic acquired resistance. Their structural adaptability enables binding to a wide range of lipid species, underpinning their involvement in cuticle integrity, immune responses, and abiotic stress tolerance. These attributes position nsLTPs as promising targets for engineering durable, broad-spectrum disease resistance in crops. However, significant knowledge gaps remain regarding their structure-function relationships, lipid transport mechanisms, and roles in defense signaling and pathogen resistance. Addressing these challenges through advanced molecular and genetic tools could unlock the potential of nsLTPs to enhance crop resilience and contribute significantly to global food security.

Keywords:  antimicrobial peptides (AMPs); genetic engineering; lipid biology; lipid signaling; lipidomics; non-specific lipid transfer proteins (nsLTPs); plant disease resistance; plant immunity

DOI:  https://doi.org/10.3389/ffunb.2025.1640465
Cell Biochem Funct. 2025 Oct;43(10): e70125

A Review of FUN14 Domain-Containing 1 Involvement in Mitochondrial Biological Processes and Mechanisms Across Various Systems.

Hailun He, Xin Zhang, Lidan Xiong, Xiao Qin.

  FUN14 domain-containing 1 (FUNDC1), an outer mitochondrial membrane protein, has emerged as a critical regulator of mitochondrial quality control and cellular homeostasis. Initially identified as a mitophagy receptor, FUNDC1 orchestrates hypoxia-induced mitophagy through phosphorylation-dependent interactions with LC3. Recent studies reveal its multifaceted roles in mitochondrial dynamics (fission/fusion), mitochondria-associated endoplasmic reticulum membranes (MAMs), and metabolic regulation, mediated by posttranslational modifications (phosphorylation, ubiquitination, acetylation). FUNDC1 dysfunction is implicated in cardiovascular diseases, neurodegeneration, cancer, and dermatological pathologies. It modulates oxidative stress primarily through impaired clearance of ROS-generating mitochondria via disrupted mitophagy, while also influencing apoptosis, pyroptosis, and inflammation via crosstalk with Bcl-2 family proteins, MOMP, mPTP, and cGAS-STING pathways. This review synthesizes FUNDC1's molecular mechanisms, highlighting its dual role as a protector (clearing damaged mitochondria) and potentiator of injury (excessive mitophagy). We also discuss therapeutic targeting of FUNDC1-dependent pathways in mitochondrial disorders.

Keywords:  FUNDC1; MAMs; metabolic diseases; mitochondrial dynamics; mitophagy

DOI:  https://doi.org/10.1002/cbf.70125
bioRxiv. 2025 Sep 26. pii: 2025.09.24.678188. [Epub ahead of print]

N-acetyl-phenylalanine induces hepatic steatosis in MASLD by disrupting ER-mitochondria calcium coupling and mitochondrial lipid oxidation.

Rémy Lefebvre, Théo Rousseaux, Nadia Bendridi, Stéphanie Chanon, Delphine Arquier, Alexandre Humbert, Nicolas Bertocchini, Bruno Pillot, Emmanuelle Meugnier, Aurélie Vieille-Marchiset, Margaux Nawrot, Claudie Pinteur, Sophie Ayciriex, Rohit Loomba, Jennifer Rieusset, Cyrielle Caussy.

Background & Aims: The gut-liver axis and hepatic ER-mitochondria miscommunication (at contact sites called MAMs) are involved in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). We investigated the role of circulating aromatic amino acids (AAA) derived from phenylalanine and tyrosine in MASLD potentially through MAM alterations.
Methods: We analyzed AAA metabolomic profiles in individuals with and without MASLD and validated findings in a biopsy-proven cohort. The pro-steatogenic effect of MASLD-associated AAAs was validated in vitro using lipid labeling, MAM structural/functional assays, and palmitate-induced respiration. In vivo effects were tested in mice fed with candidate AAAs, and MAM involvement was confirmed by expressing a specific organelle linker in vitro and in vivo .
Results: N-acetyl-phenylalanine (NAPA) was strongly associated with hepatic steatosis and correlated with specific gut microbes. In vitro , NAPA promoted lipid accumulation by impairing ER-mitochondria calcium exchange via a LAT1-dependent electrogenic mechanism, reducing mitochondrial lipid oxidation. Chronic NAPA administration in mice induced steatosis and MAM disruption. Notably, enhancing ER-mitochondria contacts with an organelle linker prevented NAPA-induced steatosis in vitro and in vivo . Additionally, other phenylalanine- and tyrosine-derived AAAs reproduced NAPA's effects, suggesting a class-dependent mechanism.
Conclusion: NAPA emerges as a MASLD-promoting metabolite, contributing to hepatic steatosis by disrupting ER-mitochondria calcium coupling and mitochondrial lipid oxidation.
Lay Summary: The gut-liver axis is a key component of the development of MASLD, and circulating gut-derived metabolites, notably AAAs derived from phenylalanine and tyrosine metabolism, have been associated with MASLD. However, the specific causal mechanisms of these AAA metabolites in MASLD development remain unexplored. Here, we identified NAPA, a gut microbiome linked metabolite elevated in MASLD patients, as a causal driver of hepatic steatosis both in vitro and in vivo. Mechanistically, NAPA alters ER-mitochondria calcium coupling leading to reduced mitochondrial lipid oxidation, highlighting a new mechanism with potential therapeutic implications.
HIGHLIGHTS: - Circulating NAPA levels are increased in MASLD patients and correlate with hepatic steatosis.- NAPA levels result from a complex host-microbiota interplay- NAPA induces lipid accumulation by dampening ER-mitochondria calcium coupling and mitochondrial lipid oxidation.- NAPA disrupts MAMs by a LAT1-mediated electrogenic mechanism.- Other Phe- and Tyr-mediated metabolites have the same pro-steatogenic effect than NAPA pointing to a class-dependent effect.

DOI: https://doi.org/10.1101/2025.09.24.678188
Cryobiology. 2025 Oct 02. pii: S0011-2240(25)00143-9. [Epub ahead of print]121 105337

Research on the role of endoplasmic reticulum-mitochondria interactions in maintaining calcium homeostasis in skeletal muscle fibers of hibernating Daurian ground squirrels.

Jie Zhang, Fangyang Pan, Yue He, Jing Zhao, Xiaozhuo Bai, Yanhong Wei, Yunfang Gao.

  The ability to maintain cytoplasmic Ca2+ homeostasis during the torpor-arousal cycle is a crucial strategy that enables hibernators to resist disuse-induced muscle atrophy during hibernation. However, whether ER-mitochondria interactions contribute to the regulation of cytoplasmic Ca2+ homeostasis in skeletal muscle fibers during hibernation remain unclear. Here, we systematically explored the expression of tethering proteins, Ca2+ axis-related proteins, and protein complexes involved in Ca2+ transport within the ER-mitochondria contact sites (ERMCS) of soleus (SOL) and extensor digitorum longus (EDL) muscles in Daurian ground squirrels (Spermophilus dauricus) during hibernation. Results demonstrated a significant increase in the expression of the tethering protein MFN2 and Ca2+ axis-related proteins GRP75 and VDAC1, as well as enhanced interactions within the Ca2+ axis complex in the SOL muscle in the inter-bout arousal (IBA) group, as compared to the late torpor (LT) group. In addition, these same indicators exhibited no significant alternation in the EDL muscle during the torpor-arousal cycle. These findings suggest that ER-mitochondria interactions may participate in maintaining Ca2+ homeostasis in the skeletal muscles during the torpor-arousal cycle, especially in slow-twitch muscle.

Keywords:  Ca(2+) axis complex; ER-Mitochondria interaction; ERMCS; Hibernation; Skeletal muscle

DOI:  https://doi.org/10.1016/j.cryobiol.2025.105337
Sci Adv. 2025 Oct 03. 11(40): eady9234

Mitochondrial ROS trigger interorganellular signaling and prime ER processes to establish enhanced plant immunity.

Yang Yang, Yan Zhao, Wei Zhao, Yingqi Zhang, Hongmei Wang, Murray Grant, Patrick Schäfer, Yuling Meng, Weixing Shan.

Reactive oxygen species (ROS) are key signaling molecules in plant development and immunity, but current understanding is primarily focused on apoplastic and chloroplastic ROS. Mitochondria are also a key source of intracellular ROS, yet their contribution to plant immunity is poorly characterized. Here, we studied mitochondrial ROS (mROS) function in plant-pathogen interactions, deploying genetically encoded sensors, assorted fluorescent markers, and genetic approaches to track mROS, specifically H2O2, dynamics and identify interorganelle contact sites. We unexpectedly found a mitochondria-endoplasmic reticulum (ER) ROS signal cascade functioning independently of apoplastic and chloroplastic ROS in plant immunity. mROS initiate immune responses induced by the oomycete pathogen Phytophthora parasitica and promote mitochondria-ER association. These enhanced mitochondria-ER membrane associations are required for transfer of mROS signals and initiation of extensive unfolded protein responses. We conclude that mROS transfer via mitochondria-ER membranes to the ER lumen is an underappreciated yet essential component in plant defense.

DOI: https://doi.org/10.1126/sciadv.ady9234
Int J Mol Med. 2025 Dec;pii: 213. [Epub ahead of print]56(6):

Changes in the endoplasmic reticulum‑mitochondria communication in dermal fibroblasts from early‑stage bipolar disorder patients: Skin‑brain axis as a new route to understand the pathophysiology of mental illness?

Ana Catarina Pereira, Ana Patrícia Marques, Rosa Resende, Laura Serrano-Cuñarro, Margarida Caldeira, Tânia Fernandes, Mariana Batista, António Macedo, Joana Barbosa De Melo, Nuno Madeira, Cláudia Cavadas, Maria Teresa Cruz, Cláudia Fragão Pereira.

  Compromised cellular resilience in bipolar disorder (BD) has been associated with structural brain changes and cognitive deficits caused by perturbation of redox status, endoplasmic reticulum (ER) stress and innate immunity. These crucial cellular events are regulated by the ER‑mitochondria close contacts at mitochondria‑associated membranes (MAM) through Ca2+ transfer and lipids exchange between these organelles. The present study aimed to investigate the structural and functional alterations in MAM during BD early stages using patient‑ and control‑derived cellular models, namely dermal fibroblasts. Morphological alterations in close ER‑mitochondria contacts at MAM occur in BD cells and correlate with functional changes, as shown by lipid droplets accumulation. The MAM dysfunction in BD cells parallels changes in Ca2+ homeostasis, namely inhibition of store‑operated Ca2+ entry (SOCE), ER Ca2+ depletion and attenuation of ER‑mitochondria Ca2+ transfer, as well as enhanced ER and oxidative stress and NOD‑like receptor family pyrin domain‑containing 3 (NLRP3) inflammasome activation leading to sterile inflammation. The absence of inflammasome activation upon lipopolysaccharide exposure supports the compromised ability of BD cells (fibroblasts as well as monocytes) to deal with stressful conditions. In conclusion, MAM disruption is highlighted as a potential pathophysiological mechanism driving impaired cellular resilience in BD. Skin fibroblasts are a particularly attractive cellular model for studying mental illnesses, such as BD, due to the shared developmental origin of epidermal and neural tissues. The ectodermal origins of the skin‑brain axis have been proposed as a novel route for understanding brain development, neurodevelopmental conditions and behavior modulation.

Keywords:  bipolar disorder; endoplasmic reticulum; mitochondria; mitochondria-associated membranes; skin fibroblasts

DOI:  https://doi.org/10.3892/ijmm.2025.5654
Theranostics. 2025 ;15(18): 9601-9622

GPX1-driven selenium nanoplatform reprograms MAMs-mediated organelle crosstalk to reverse inflammatory adipose expansion in thyroid eye disease.

Yao Tan, Feng Zhang, Jiamin Cao, Lemeng Feng, Bingyu Xie, Limo Gao, Xiangdong Chen, Zuyun Yan, Wei Xiong.

  Background: Thyroid eye disease (TED) is a multifactorial autoimmune disorder with limited therapeutic options due to the complexity of its oxidative, metabolic, and inflammatory networks. This study aims to develop a selenium-based nanoplatform that targets mitochondria-ER interactions to reverse inflammatory adipose expansion in TED. Methods: We designed a dual-responsive selenium nanoparticle (Se@LNT) modified with lentinan, capable of ROS/pH-triggered release. Human primary orbital fibroblasts, bioinformatic analysis of public datasets, and TED mouse models were used to investigate the therapeutic mechanism. Results: Se@LNT undergoes intracellular metabolic conversion into selenocysteine, which enhances GPX1 activity and promotes redox balance. It exerts triple regulatory effects by stabilizing mitochondrial membranes to reduce mtDNA leakage, downregulating GRP75 to normalize MAMs contact and calcium flux, and suppressing PERK-eIF2α-ATF4 signaling to relieve ER stress. Transcriptomic profiling reveals multi-target modulation of immune-stromal interactions. In vivo, Se@LNT achieves orbital targeting, rapid hepatic-renal clearance, and significant reduction of adipose expansion with immune remodeling. Conclusions: Se@LNT offers the first MAMs-targeted nanotherapy for TED by reprogramming organelle crosstalk, restoring metabolic-immune homeostasis, and modifying disease progression at the subcellular level.

Keywords:  endoplasmic reticulum stress; lentinan-modified selenium nanoparticles; mitochondria-associated membranes; oxidative stress; thyroid eye disease

DOI:  https://doi.org/10.7150/thno.117582