bims-mecosi 2026-03-29 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–03–29
sixteen papers selected by
Verena Kohler, Umeå University

MCTP1 and MCTP2 promote ER-PM contact sites and regulate PI4P homeostasis and cell migration.
The role of mitochondria-associated membranes in tumorigenesis.
CAP1 deficiency protects podocytes in diabetic kidney disease by reducing mitochondria-associated endoplasmic reticulum membrane formation and mitochondrial fission.
MFN2-PERK Axis Regulates ER Stress in Parotid Glands of Aged Mice via MAMs.
Endoplasmic Reticulum-Mitochondrial Crosstalk in Calcium Regulation: Mechanistic Insights and Therapeutic Implications in Traumatic Brain Injury.
Disrupted SR-Mitochondria Coupling Drives Ischemia-Reperfusion Vulnerability in the Middle-Aged Rat Heart.
Sterol binding mechanism of a plant START-like domain: A new sterol transport paradigm via an amphiphilic cavity.
mtDNA-Depleted Mitochondria Form Sites of Contact with the Nucleus and Alter the Cellular Epigenome.
Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses.
5'tiRNA-32-LysCTT-11 Alleviates Sepsis-Induced Myocardial Injury by stabilizing Mfn2 and inhibiting mitochondrial dysfunction-mediated necroptosis.
Chronic cold exposure induces plasticity of mitochondrial calcium uptake in beige and brown fat of UCP1-deficient mice.
Protein domain characterization reveals human MIC60 tolerates loss of helical bundle domain.
Organelle-anchored translation factories: the roles of neuronal RBP condensates in organizing local protein synthesis in neurological diseases.
Heart-Specific and Conditional Deletion of the Immt Gene Reveals Its Role in Regulating Mitochondrial Structure and Total Heart Metabolism.
Stress-Encoded Mitochondrial Plasticity: ATF4 Control of Mega-Mitochondria and Nanotunnel Communication.
An ARVC-5 Drosophila knock-in model reveals new functions of Tmem43 in lipid homeostasis.

Mol Biol Cell. 2026 Mar 25. mbcE25090445

MCTP1 and MCTP2 promote ER-PM contact sites and regulate PI4P homeostasis and cell migration.

Suganthan Amirthagunanathan, Maxime Boutry, Vasudeva Tati, Dibyayan Maity, Caroline Chapman, Madhura R Pandkar, Brian Raught, Peter K Kim, Amit S Joshi.

Endoplasmic reticulum-plasma membrane (ER-PM) contact sites play important roles in maintaining lipid homeostasis at plasma membrane (PM), cellular calcium homeostasis and cell signaling. Here, we show that MCTP1 and MCTP2 are at ER subdomains that form membrane contact sites (MCS) with multiple organelles using proximity labelling assay. MCTPs are three C2 domain-containing transmembrane proteins. We show that upon overexpression, MCTPs promote ER-PM contact sites in C2 domain dependent manner. MCTP C2 domains bind to PI(4)P and PI(4,5)P2, phosphoinositides that are enriched in the PM. Furthermore, we show that deletion of MCTP1 or MCTP2 increases PI(4)P levels in the PM and promote cell migration. Thus, our study identifies MCTPs as multiple ER-organelle contact site proteins and establishes its role at ER-PM contact sites in regulating lipid homeostasis and cell migration.

DOI: https://doi.org/10.1091/mbc.E25-09-0445
Discov Oncol. 2026 Mar 26.

The role of mitochondria-associated membranes in tumorigenesis.

Yaqin Zhu, Guoyi Tang, Muya Tang, Baozhen Zhou, Jing Xu, Xiaoli Ma, Ziyu Li, Guichun Liu, Yu Han.

  The structural coupling between organelles is considered central to regulating cellular behavior. While each organelle performs specific functions, contact or structural coupling between them enables highly coordinated functionality. Mitochondria and the endoplasmic reticulum (ER) are vital organelles in eukaryotic cells, serving as the centers of oxidative metabolism and protein synthesis, respectively. Their homeostatic and coordinated interactions are essential for maintaining cellular activity. This review outlines the structure, function, research methodologies, and relationship with tumorigenesis of the mitochondria-associated membranes (MAMs). And discusses the potential of MAMs as therapeutic targets for cancer therapy and drug development.

Keywords:  Cancer; ER; Mitochondria; Mitochondria-associated membranes (MAMs)

DOI:  https://doi.org/10.1007/s12672-026-04762-2
Free Radic Biol Med. 2026 Mar 19. pii: S0891-5849(26)00243-1. [Epub ahead of print]250 116-133

CAP1 deficiency protects podocytes in diabetic kidney disease by reducing mitochondria-associated endoplasmic reticulum membrane formation and mitochondrial fission.

Shuang Yao, Zongda Li, Huimin Ma, Xinying Yu, Tingting Hu, Zihan Wang, Rui Zhang, Haihai Liang, Jundong Jiao.

  The mitochondria-associated endoplasmic reticulum membrane (MAM) is crucial for mitochondrial homeostasis. Excessive mitochondrial fission has been recognized as an early pathological event in podocyte injury in diabetic kidney disease (DKD). Cyclase-associated protein 1 (CAP1), an actin-binding protein, has been implicated as a potential regulator of mitochondrial dynamics; however, its role in DKD remains unclear. This study revealed that increased MAM formation is associated with excessive mitochondrial fission in podocytes from DKD patients. Podocyte-specific CAP1 knockdown significantly ameliorated podocyte injury and albuminuria in diabetic mice, with the protective effect attributed to the inhibition of MAM formation and mitochondrial fission. Mechanistically, high glucose triggered the CAP1-induced actin depolymerization, which promoted the enrichment of inverted formin 2 (INF2) from the endoplasmic reticulum (ER) to the MAM. At the MAM interface, the protein interaction between CAP1 and the enriched INF2 was enhanced, thereby exacerbating mitochondrial fission and dysfunction, which ultimately led to podocyte injury. Our findings not only provide the first evidence for the pathogenic role of CAP1 in podocytes during DKD progression, but also elucidate a novel mechanism by which CAP1 modulates mitochondrial fission via the MAM.

Keywords:  Actin; Cyclase-associated protein 1; Diabetic kidney disease; Mitochondria-associated endoplasmic reticulum membrane; Mitochondrial fission

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.052
J Dent Res. 2026 Mar 28. 220345261427294

MFN2-PERK Axis Regulates ER Stress in Parotid Glands of Aged Mice via MAMs.

Y Chen, Y M Xu, L L Zhu, Z Y Shan, Z G Yao, H Zhao.

  With aging, the morphology and function of the parotid glands are impaired, and the current mechanism is unknown. The integrity of mitochondria-associated membranes (MAMs), the structure connecting mitochondria and the endoplasmic reticulum (ER), is compromised during aging. This study investigated the effects of aging on MAMs and ER stress in the parotid glands of mice. Here, aged mice presented abnormalities in gland morphology and mitochondrial morphology and reduced MAMs integrity. Protein kinase R-like endoplasmic reticulum kinase (PERK) signaling is the primary mediator of ER stress, which is activated in the parotid glands of aged mice. Furthermore, aging-induced MFN2 downregulation disrupts mitochondrial dynamics. In addition, aging reduces MAMs function by blocking the MFN2-PERK interaction. Treatment with 4-phenylbutyric acid (4-PBA) improved MAMs integrity, inhibited the PERK pathway, and reduced apoptosis. Like 4-PBA, GSK2606414, a pharmacological antagonist of PERK, regulates ER stress and MAMs. Collectively, our data highlight disruption of the MFN2-PERK axis-mediated ER-mitochondrion connection as a cause of aging-induced parotid gland dysfunction.

Keywords:  aging; endoplasmic reticulum stress; mitochondria-associated membranes; mitofusin 2; oxidative stress; protein kinase R-like endoplasmic reticulum kinase

DOI:  https://doi.org/10.1177/00220345261427294
Mol Neurobiol. 2026 Mar 25. pii: 521. [Epub ahead of print]63(1):

Endoplasmic Reticulum-Mitochondrial Crosstalk in Calcium Regulation: Mechanistic Insights and Therapeutic Implications in Traumatic Brain Injury.

Harapriya Baral, Deepali Kumari, Vikrant Rahi, Ravinder K Kaundal.

  The endoplasmic reticulum (ER) and mitochondria are fundamental organelles that govern a wide array of cellular processes and maintain intracellular homeostasis through highly specialized and interconnected functions. Their intimate structural and functional coupling at mitochondria-associated membranes (MAMs) enables the regulated exchange of Ca2⁺, lipids, and metabolites, thereby coordinating key physiological processes. Accumulating evidence underscores the critical role of ER-mitochondrial communication in the maintenance of intracellular Ca2⁺ homeostasis. Traumatic brain injury (TBI), however, disrupts this finely tuned inter-organelle crosstalk, triggering a complex cascade of pathological events characterized by Ca2⁺ dysregulation, ER stress, impaired protein folding, mitochondrial dysfunction, and activation of cell death pathways. This review provides a comprehensive synthesis of current knowledge on MAM-mediated Ca2⁺ transport and delineates how its dysregulation exacerbates cellular stress responses following TBI. We examine the contribution of Ca2⁺ imbalance to ER stress signalling, protein misfolding, and the pathological shift toward excessive mitochondrial fission, culminating in compromised bioenergetics and loss of cellular integrity. Furthermore, we discuss Ca2⁺ dysregulation-driven cell death mechanisms in the injured brain and evaluate emerging therapeutic strategies to restore MAMs function and Ca2⁺ signalling. Collectively, the interplay between Ca2⁺ dysregulation, ER stress, and mitochondrial dysfunction emerges as a central axis underlying neuronal loss after TBI. Elucidating these mechanisms may inform the development of targeted interventions to mitigate secondary injury and preserve neuronal function following TBI.

Keywords:  Calcium dysregulation; ER-stress; MAMs; Mitochondrial dynamics; TBI; UPRs

DOI:  https://doi.org/10.1007/s12035-026-05818-8
Biomedicines. 2026 Feb 27. pii: 547. [Epub ahead of print]14(3):

Disrupted SR-Mitochondria Coupling Drives Ischemia-Reperfusion Vulnerability in the Middle-Aged Rat Heart.

Katarina Leskova Majdova, Maria Bencurova, Maria Kovalska, Peter Kaplan, Peter Racay, Zuzana Tatarkova.

  Background: Myocardial ischemia-reperfusion (IR) injury is associated with dysregulated Ca2+ handling and oxidative stress, particularly in the middle-aged heart. Sarcoplasmic reticulum (SR)-mitochondria communication via mitochondria-associated membranes (MAMs) is essential for coordinating Ca2+ transfer and redox signaling; however, its role in IR injury in the middle-aged myocardium remains incompletely understood. This study investigated changes in cardiac MAM protein composition and associated functional and oxidative parameters during ischemia and IR. Methods: Middle-aged rat hearts were subjected to global ischemia or IR using the Langendorff perfusion model. Mitochondrial, MAM, and homogenate fractions were analyzed using biochemical, proteomic, and functional assays to assess Ca2+-handling proteins, redox enzymes, lipid peroxidation markers, and mitochondrial antioxidant defenses. Results: Myocardial ischemia and IR disrupted SR-mitochondria communication in middle-aged hearts, leading to impaired Ca2+ handling, redox imbalance, and reduced contractile recovery. Ischemia induced significant MAM remodeling, characterized by reduced mitofusin 2 levels and increased enrichment of voltage-dependent anion channel 1. These changes were associated with disturbed mitochondrial Ca2+ signaling, impaired SR Ca2+ sequestration. Although mitochondrial antioxidant defenses, including MnSOD, were largely preserved, IR was associated with compartment-specific redox alterations within MAMs, as inferred from altered redox enzyme activity and enhanced lipid peroxidation. Conclusions: Disruption of SR-mitochondria coupling and MAM-associated redox regulation represents a key mechanism underlying increased vulnerability to IR injury in the middle-aged heart. Targeting MAM integrity and modulating Ca2+-redox cross-talk may improve cardiac resilience in elderly populations.

Keywords:  calcium homeostasis; lipid peroxidation; mitochondria-associated membranes; myocardial ischemia–reperfusion; redox signaling

DOI:  https://doi.org/10.3390/biomedicines14030547
FEBS J. 2026 Mar 24.

Sterol binding mechanism of a plant START-like domain: A new sterol transport paradigm via an amphiphilic cavity.

Hui-Juan Zhu, Ziyan Zhang, Jiachang Wang, Zhi-Xin Wang, Zhipu Luo, Bo Duan, Jia-Wei Wu.

  Redistribution of sterols among cellular compartments is crucial for the proper functions of different organelles, but how sterols are transported in plants is barely studied. Here, we identified that Arabidopsis C2 and GRAM domain-containing proteins C2GR1/2, a specialized subgroup of the lipid transfer proteins anchored at membrane contact sites (LAMs), transport sterols between membranes via their first START-like domains (SLD1s), while the SLD2 domains are inactive. Structural studies on C2GR2-SLD1/SLD2 elucidated that the sterol transport process involves the exchange of sterol and water, which requires the proper size and the amphiphilic nature of the cavity, as well as the conformational changes of the three Ω loops at the entrance. Importantly, the amphiphilicity of the cavity is shared by other SLD domains in yeast and mammals, a feature that was overlooked by previous studies. These findings not only advance our understanding of sterol transport in plants but also redefine the sterol transport paradigm for LAM proteins.

Keywords:  C2 and GRAM containing protein; START‐like domain; amphiphilic cavity; sterol transport; structural basis

DOI:  https://doi.org/10.1111/febs.70506
Contact (Thousand Oaks). 2026 Jan-Dec;9:9 25152564261428840

mtDNA-Depleted Mitochondria Form Sites of Contact with the Nucleus and Alter the Cellular Epigenome.

Richard Boulton-McDonald, Eva Sidlauskaite, Jiri Neuzil, Michelangelo Campanella.

  Mitochondrial sites of contact with the nucleus, hereafter referred to as Nucleus-Associated Mitochondria (NAM), are specialised domains that enable communication, influencing cellular function. Previous studies have shown that these contacts can be stabilised by protein scaffolds acting as tethers to promote retrograde signalling, particularly during apoptotic stress. This is facilitated via the mitochondrial protein TSPO. In this study, we have investigated a mitochondrial DNA (mtDNA)-depleted (ρ0) 4T1 cell model to further inform the role of NAM in retrograde communication between corrupted mitochondria and the nucleus. Our data report an increase in NAM frequency in mtDNA-depleted cells compared to the mtDNA-retaining parental 4T1 line. Using a combination of cellular assays, transmission electron microscopy, and epigenetic profiling, we have found that under conditions of mtDNA loss, mitochondria become enriched in TSPO, evading mitophagic clearance and are prone to forming stable contacts with the nucleus. This coincides with an extreme reduction in DNA methylation, as well as histone modifications associated with chromatin decondensation.

Keywords:  NAM; TSPO; VDAC; contact sites; mitochondria

DOI:  https://doi.org/10.1177/25152564261428840
bioRxiv. 2026 Mar 04. pii: 2026.03.03.709381. [Epub ahead of print]

Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses.

Sadia Ahmed, Namratha Javvaji, Katherine L Hammond, Kevin M Casin, John W Elrod, Paul M Holloway, Yvonne Couch, Jillian N Simon.

Mitochondrial Ca 2+ uptake governs metabolism and cell fate, yet how signals from other organelles shape this remains incompletely defined. Although lysosomes are relatively small Ca 2+ stores, their strategic positioning at organelle contact sites suggests they may amplify Ca 2+ transfer within nanodomains. Here, we show that activation of the lysosomal Two-pore channel 2 (TPC2) initiates rapid mitochondrial Ca 2+ uptake through an endoplasmic reticulum-dependent relay requiring IP₃ receptors and the mitochondrial calcium uniporter channel. The extent of mitochondrial Ca 2+ accumulation scales with TPC2 activity without affecting global Ca 2+ responses, identifying TPC2 as a specific amplifier of lysosome-mitochondria Ca 2+ exchange. Moderate TPC2 activation transiently enhances oxidative phosphorylation, whereas sustained enhancement increases susceptibility to Ca 2+ -induced mitochondrial permeability transition. In stroke models, hyperactivation of TPC2 exacerbates injury, while acute pharmacological inhibition at reperfusion confers neuroprotection, including in human iPSC-derived neurons. Thus, lysosomal Ca 2+ release acts as an upstream regulator of mitochondrial energetic resilience under stress.

DOI: https://doi.org/10.64898/2026.03.03.709381
Shock. 2026 Mar 16.

5'tiRNA-32-LysCTT-11 Alleviates Sepsis-Induced Myocardial Injury by stabilizing Mfn2 and inhibiting mitochondrial dysfunction-mediated necroptosis.

Jing Li, Ludong Yuan, Xiaofang Lin, Dan Ni, Chuanhuan Deng, Yuxuan Liu, Manqing Luo, Pengfei Liang, Bimei Jiang.

   BACKGROUND: Transfer RNA-derived small RNAs (tsRNAs) represent a novel class of non-coding RNAs increasingly implicated in cardiovascular regulation. However, their roles in sepsis-induced cardiomyopathy (SICM) remain largely undefined. This study aimed to investigate the function and underlying mechanism of 5'tiRNA-32-LysCTT-11-a highly upregulated tsRNA in SICM-in modulating myocardial injury.
METHODS: A murine model of sepsis was established via cecal ligation and puncture (CLP), and myocardial injury was assessed by serum CK-MB/LDH levels, histology, and cardiac function via echocardiography. In vitro, H9C2 cardiomyocytes were exposed to conditioned media (CM) from lipopolysaccharide (LPS)-stimulated macrophages. The expression of 5'tiRNA-32-LysCTT-11 was measured by qRT-PCR. Functional assays including CCK-8, LDH release, PI staining, JC-1, ATP, ROS detection, and MitoTracker staining were performed. Necroptosis was evaluated via MLKL phosphorylation; Mitochondria-associated endoplasmic reticulum membranes (MAMs) formation was assessed by dual-label immunofluorescence and Pacs2 expression. Bioinformatics analysis identified Mitofusin 2 (Mfn2) as a putative target, validated by Western blot, mRNA stability assay (Actinomycin D), and rescue experiments.
FINDINGS: 5'tiRNA-32-LysCTT-11 was significantly upregulated in SICM. In vivo, its overexpression improved cardiac function and reduced injury biomarkers. In vitro, 5'tiRNA-32-LysCTT-11 mimics preserved mitochondrial integrity, reduced ROS and ATP depletion, suppressed MAM formation and necroptosis. Inhibitor transfection produced opposite effects. Mechanistically, 5'tiRNA-32-LysCTT-11 enhanced Mfn2 mRNA stability and protein expression. Silencing Mfn2 abrogated the protective effects, confirming its central role in the tsRNA's action.
INTERPRETATION: 5'tiRNA-32-LysCTT-11 exerts cardioprotective effects during sepsis by stabilizing Mfn2 mRNA, preserving mitochondrial function, limiting MAMs formation, and suppressing necroptosis. These findings uncover a novel regulatory mechanism and suggest 5'tiRNA-32-LysCTT-11 as a promising therapeutic target in SICM.

Keywords:  5’tiRNA-32-LysCTT-11; Cardiomyocytes; Mfn2; Mitochondria; Necroptosis; Sepsis-induced cardiomyopathy

DOI:  https://doi.org/10.1097/SHK.0000000000002821
bioRxiv. 2026 Mar 18. pii: 2026.03.16.712209. [Epub ahead of print]

Chronic cold exposure induces plasticity of mitochondrial calcium uptake in beige and brown fat of UCP1-deficient mice.

Casandra G Chamorro, Sachin Pathuri, Rebeca Acin-Perez, Michael Chhan, Madeleine G Milner, Natalia Ermolova, Anthony E Jones, Ajit S Divakaruni, Linsey Stiles, Andrea L Hevener, Zhenqi Zhou, Orian S Shirihai, Yuriy Kirichok, Ambre M Bertholet.

Brown adipose tissue (BAT) is a unique tissue with mitochondria specialized for thermogenesis via the BAT-specific uncoupling protein 1 (UCP1). Ucp1 -/- mice cannot tolerate acute exposure to cold, illustrating the necessity of UCP1 for efficient mitochondrial thermogenesis. However, these mice adapt to low temperatures through a gradual acclimation process, suggesting a high degree of mitochondrial plasticity in brown and beige fat cells. This phenomenon, which remains to be fully elucidated, indicates the potential for these mitochondria to implement effective thermogenic mechanisms in the absence of uncoupling protein 1 (UCP1). Here, we investigated mitochondrial remodeling in beige and brown fat of Ucp1 -/- mice to determine how they fulfill their thermogenic role. Upon gradual acclimation to a cold environment, Ucp 1 -/- mice exhibited body metabolic parameters and temperatures in the interscapular region similar to those of wild-type mice of BAT, highlighting effective thermogenesis. Interestingly, mitochondrial patch-clamp analysis and a mitochondrial Ca 2+ swelling assay revealed a dramatic increase in Ca 2+ uptake depending on the mitochondrial calcium uniporter (MCU) in BAT mitochondria from Ucp1 -/- mice when robust thermogenesis was required. Mitochondrial remodeling was accompanied by markedly increased tethering between mitochondria and the endoplasmic reticulum (ER) in Ucp1 -/- mice, confirming a significant restructuring of the contact sites between the ER and mitochondria, likely to adapt to a new Ca 2+ homeostasis. Respiratory complexes also underwent significant reorganization, which partly led to a reduction in their assembly. Levels of ATP synthase and its F1 subcomplex increased, suggesting a major source of ATP consumption and energy expenditure. We propose a new role for MCU as a key regulator of mitochondrial plasticity, enabling efficient thermogenesis in beige and brown adipose tissues in the absence of UCP1.

DOI: https://doi.org/10.64898/2026.03.16.712209
bioRxiv. 2026 Mar 22. pii: 2026.03.19.713006. [Epub ahead of print]

Protein domain characterization reveals human MIC60 tolerates loss of helical bundle domain.

Stephanie M Rockfield, Krishnan Venkataraman, Chih-Hsuan Wu, Randall Wakefield, Alan Wu, Amit Budhraja, Ricardo Rodriguez-Enriquez, Ali Khalighifar, Camenzind G Robinson, Cai Li, Alexandre F Carisey, Joseph Thomas Opferman.

The mitochondrial contact site and cristae organizing system (MICOS) is essential for cristae junction formation and inner mitochondrial membrane architecture. To define how MICOS integrity is established and maintained, we generated conditional deletion models of Immt (encoding MIC60), a core MICOS subunit, in tissue-specific settings and in cultured cells. Liver-specific deletion of Immt in mice induced profound defects in mitochondrial ultrastructure and function, establishing MIC60 as essential for mitochondrial integrity. Notably, despite the severity of the defects, we did not detect increased apoptosis in liver tissue or in cells. To directly link MIC60 structure to its function, we performed a systemic structure-function analysis of human MIC60 using domain-specific deletion mutants expressed in Immt-deleted cells. We identified that the transmembrane, coiled-coil, and mitofilin domains are required for MICOS assembly, mitochondrial morphology, and respiratory function. Unexpectedly, deletion of the predicted helical bundle (a region spanning 229 amino acids) substantially restored mitochondrial structure and function, nearly matching full-length MIC60. A mutation (K299E) associated with human disease within this domain similarly preserved most MIC60-dependent functions. Together, these results establish MIC60 as a non-redundant regulator of mitochondrial architecture while revealing that a large predicted structural domain is largely dispensable for MIC60s core functions, refining current models of MICOS organization and uncovering unexpected modularity within MIC60.

DOI: https://doi.org/10.64898/2026.03.19.713006
Protein Cell. 2026 Mar 25. pii: pwag026. [Epub ahead of print]

Organelle-anchored translation factories: the roles of neuronal RBP condensates in organizing local protein synthesis in neurological diseases.

Semin Park, Hari Lim, Jin-A Lee.

  Neurons face a fundamental proteostasis challenge: synapses and axons located far from the soma must rapidly remodel their proteome during activity, stress, and development. While local protein synthesis has long been recognized as essential for meeting these demands, classical models largely focused on ribonucleoprotein (RNP) granules as autonomous carriers of translationally silent mRNAs, treating membranous organelles as parallel logistics or metabolic systems. Recent work overturns this view, revealing that endosomes, lysosomes, axonal endoplasmic reticulum, mitochondria, and their contact sites actively function as mobile translation platforms. In this review, we propose an RBP-centered framework in which phase-separated condensates physically tether specific mRNA cohorts to organelle surfaces, coupling mRNA transport, translational control, and organelle dynamics into a unified network. By organizing recent discoveries into functional modules-long-range transport, localized translation, and stress buffering-this neuron-focused framework identifies organelle-anchored translation factories as a unifying principle of synaptic proteostasis and a broadly applicable design paradigm for highly polarized cells.

Keywords:  RNA-binding proteins; neuronal local translation; organelle-anchored translation; ribonucleoprotein granules

DOI:  https://doi.org/10.1093/procel/pwag026
Cells. 2026 Mar 12. pii: 505. [Epub ahead of print]15(6):

Heart-Specific and Conditional Deletion of the Immt Gene Reveals Its Role in Regulating Mitochondrial Structure and Total Heart Metabolism.

Yasuhide Kuwabara, Caitlin Keezer, Suh-Chin J Lin, Akanksha Rajput, Jeffery D Molkentin.

  Mitochondria comprise ~1/3rd of the volume of an adult ventricular cardiomyocyte. The gene Immt encodes the Mic60/Mitofilin protein that is hypothesized to organize the mitochondrial contact site and cristae organization system (MICOS) complex that generates mitochondrial cristae junctions between the inner and outer membranes. To investigate the function of the Immt gene in the mouse heart, we generated and characterized mice in which this gene was specifically deleted in the mouse heart using a loxP-targeted allele (Immtfl/fl) and either the constitutive heart-specific Myh6-Cre transgene or the conditional Myh6-MerCreMer transgene, each of which showed lethality in several weeks. Hearts from these mice showed progressive hypertrophic cardiomyopathy and failure with lost contractility and lung edema. At the ultrastructural level, hearts from these mice showed extreme abnormalities in mitochondrial architecture characterized by lost cristae junctions, stacking of the inner mitochondrial membranes, mitophagy and areas with complete absence of mitochondria. Analysis of mitochondria showed loss of the MICOS complex of proteins as well as loss of mitochondrial membrane potential (Δψ) and increased expression of mitophagy proteins and mitochondrial biogenesis transcription factors. Hearts from these mice also showed widespread cardiomyocyte necrosis and induction of the universal mitochondrial stress response at the mRNA level, as well as major alterations in cardiac metabolites, suggesting greater use of glucose, ketones and amino acids. We conclude that the Immt gene is required for cardiac mitochondrial structure and function, although the ensuing mitochondrial stress response provides molecular clues as to how the heart can compensate metabolically and maintain viability for weeks after mitochondria are absent or unfunctional.

Keywords:  cardiac hypertrophy; cardiomyocyte; metabolism; mitochondria; mitophagy

DOI:  https://doi.org/10.3390/cells15060505
bioRxiv. 2026 Mar 04. pii: 2026.03.04.709625. [Epub ahead of print]

Stress-Encoded Mitochondrial Plasticity: ATF4 Control of Mega-Mitochondria and Nanotunnel Communication.

Amber Crabtree, Suraj Thapliyal, Mohd Mabood Khan, Edgar Garza Lopez, Andrea Marshall, Calixto Pablo Hernandez Perez, Oleg Kovtun, Jenny C Schafer, Dea Pulatani, Yuho Kim, Sepiso K Masenga, Annet Kirabo, Jeremiah Afolabi, Melanie McReynolds, Renata O Pereira, Prasanna Venkhatesh, Prasanna Katti, Brian Glancy, Antentor Hinton.

Mitochondrial structural plasticity is a critical adaptive response to cellular stress, yet the transcriptional networks governing the formation of specialized mitochondrial architectures remain poorly defined. Here, we identified and demonstrated that activating transcription factor 4 (ATF4), the master regulator of the integrated stress response, directly regulates mitochondrial morphological remodeling through a novel ATF4-NRF1/Nrf2-MFN2 signaling axis. Using serial block-face scanning electron microscopy and three-dimensional reconstruction in Drosophila flight muscle, primary myotubes, and human skeletal muscle, we show that overexpression of ATF4 promotes significant mitochondrial elongation, increased cristae concentration, enhanced mitochondrial-endoplasmic reticulum contact site (MERC) formation, and the initiation of Mitochondrial Nanotunnels. In contrast, loss of ATF4 results in mitochondrial fragmentation and impaired aerobic capacity. Chromatin immunoprecipitation sequencing reveals direct ATF4 binding at the promoters of the genes encoding NRF1 and Nrf2, which in turn regulate MFN2 expression. Small-molecule inhibition studies further establish that activation of this hierarchical pathway is both necessary and sufficient for stress-induced mitochondrial structural adaptation. Together, these findings position ATF4 as a master regulator of mitochondrial architectural plasticity, providing a direct mechanistic link between cellular stress signaling and organelle remodeling.

DOI: https://doi.org/10.64898/2026.03.04.709625
Biol Open. 2026 Mar 24. pii: bio.062326. [Epub ahead of print]

An ARVC-5 Drosophila knock-in model reveals new functions of Tmem43 in lipid homeostasis.

Kai Jürgens, Lena Menzel, Nora Klinke, Lisa Schäper, Sandra Ratnavadivel, Stefan Walter, Hendrik Milting, Heiko Meyer, Achim Paululat.

  Arrhythmogenic right ventricular cardiomyopathy type 5 is caused by the missense mutation S358L in the gene TMEM43 in humans. To date, the molecular mechanisms underlying the disease remain poorly understood. We established a CRISPR/Cas9 knock-in Drosophila model carrying the orthologous Tmem43p.S333L mutation to investigate these mechanisms in vivo. The resulting flies were viable but displayed reduced lifespan, smaller body size, lipid droplet accumulation, and mitochondrial defects. Proteomic and lipidomic profiling revealed a dosage-dependent misregulation of the energy metabolism, concomitant with reduced fatty acid synthesis and ß-oxidation rates, altered peroxisomal pathways, and changes in membrane phospholipid composition. Notably, phosphatidylethanolamine (PE) and phosphatidylinositol (PI) levels were elevated, while triacylglycerols were reduced. Ultrastructural analyses confirmed mitochondrial degradation in the muscle tissue of corresponding mutants. These findings establish Tmem43p.S333L knock-in flies as a robust in vivo model of ARVC-5, and support a role for TMEM43 in linking lipid homeostasis to mitochondrial energy metabolism and integrity. Mutation-derived impairments in these processes result in cardiomyopathy.

Keywords:  ARVC5; Cardiomyopathy; Drosophila; ER-mitochondrial contact site; Mitochondria

DOI:  https://doi.org/10.1242/bio.062326