bims-mitmed 2025-08-03 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–08–03
thirty papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Opantimirs: A class of antagonizing microRNAs that upregulate Opa1 and improve mitochondrial and disuse myopathies.
Three-donor IVF prevents mitochondrial disease.
The genotype/phenotype conundrum of inherited mitochondrial disorders: Insights from a survey of mtDNA mutations associated with Leigh syndrome in complex I.
ATAD3 duplications bridge mitochondrial diseases and Aicardi-Goutières syndrome.
Therapies for Mitochondrial Disease: Past, Present, and Future.
Harnessing Mitochondrial Transplantation to Target Vascular Inflammation in Cardiovascular Health.
Mitochondrial Disorder: Kearns-Sayre Syndrome.
2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction.
An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Ménière's disease.
ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.
An emerging role of mitochondrial quality control in bone metabolism: from molecular mechanisms to targeted therapeutic interventions.
Maternal Nutrient Excess Induces Stress Signaling and Decreases Mitochondrial Number in Term Fetal Baboon Skeletal Muscle.
Small Molecule Oxybutynin Rescues Proliferative Capacity of Complex III-Defective Muscle Progenitor Cells.
Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway.
Role of impaired mitochondrial dynamics and mitophagy in cardiovascular diseases: Possible therapeutic approaches.
Mitochondrial protein aggregates recruit key chaperones and are sequestered in a fission/fusion-dependent process.
Evaluation of Mitochondrial Complex 1 Density with [18F]BCPP-EF in a Murine Model and Individuals with Friedreich Ataxia.
Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery.
Feasibility of Xenogeneic Mitochondrial Transplantation in Neuronal Systems: An Exploratory Study.
Gestational zearalenone causes fetal intrauterine growth restriction partially through deriving ROS-Drp1 mediated placental PANoptosis.
Sex-specific Impact of Selective Reduced Uterine Placental Perfusion Model of Preeclampsia on Fetal Cardiac Maturation and Mitochondrial Function.
CUMS stress facilitates hippocampal neural mitophagy through FIS1/MFF-mediated mitochondrial fragmentation.
Proteasomal dysfunction in the mouse forebrain induces mitochondrial DNA release, cGAS-STING signaling activation, and necroptosis.
SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40.
Protocol for assessing mitochondrial cholesterol transport and protein molten globule state in steroidogenic and nonsteroidogenic systems.
Structural basis for promoter recognition and transcription factor binding and release in human mitochondria.
Unraveling mitochondrial crosstalk: a new frontier in heart failure pathogenesis.
PDE4D Regulates Mitochondrial Homeostasis and Adult Hippocampal Neurogenesis via the cAMP/CREB Signaling Pathway in Chronic Stress-Induced Depressive-Like Behavior.
Micro magnetic resonance spectroscopy for noninvasive metabolic screening of mammalian embryos and oocytes.
Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex.

Cell Rep Med. 2025 Jul 16. pii: S2666-3791(25)00321-0. [Epub ahead of print] 102248

Opantimirs: A class of antagonizing microRNAs that upregulate Opa1 and improve mitochondrial and disuse myopathies.

Andre Djalalvandi, Keisuke Takeda, Francesca Grespi, Hualin Fan, Tiago Branco Fonseca, Leonardo Nogara, Saman Sharifi, Carlotta Barison, Martina Semenzato, Akiko Omori, Raffaele Cerutti, Davide Steffan, Lorenza Tsansizi, Valeria Balmaceda, Lukas Alan, Camilla Bean, Bert Blaauw, Carlo Viscomi, Luca Scorrano.

  Alterations in mitochondrial ultrastructure and reduced levels of the crista-shaping protein Opa1 are key features of mitochondrial myopathies and aging. We identify and characterize a biological therapy that improves mitochondrial and disuse myopathy models by boosting Opa1 levels. In silico analysis identifies microRNAs (miRNAs) 128-3p and 148/152-3p family as conserved modulators of OPA1 transcription and elevated in various muscle disorders. These miRNAs target the 3' UTR of murine and human OPA1, reducing its mRNA and protein levels, causing mitochondrial fragmentation and crista disorganization. Genetic experiments confirm that their mitochondrial effects rely on 3' UTR binding. In mitochondrial disease patient cells and murine models, elevated OPA1-specific miRNA levels are reduced by antagonistic miRNAs (Opantimirs), which restore mitochondrial ultrastructure, morphology, and function. In vivo, Opantimirs correct mitochondrial ultrastructure and fiber size in muscles of denervated and Cox15-ablated mice, improving strength in the latter. Thus, biopharmacological correction of the mitochondrial ultrastructure can ameliorate mitochondrial myopathies.

Keywords:  OPA1; antimiRs; cristae remodeling; disuse myopathies; miR-128-3p; miR-148/152-3p family; microRNAs; mitochondrial myopathies; mitochondrial ultrastructure

DOI:  https://doi.org/10.1016/j.xcrm.2025.102248
Nat Med. 2025 Jul 30.

Three-donor IVF prevents mitochondrial disease.

Karen O'Leary.



Keywords:  Genetics; Reproductive techniques ; Technology

DOI:  https://doi.org/10.1038/d41591-025-00047-3
Biochim Biophys Acta Mol Basis Dis. 2025 Jul 25. pii: S0925-4439(25)00344-8. [Epub ahead of print] 167996

The genotype/phenotype conundrum of inherited mitochondrial disorders: Insights from a survey of mtDNA mutations associated with Leigh syndrome in complex I.

Zeinab Alsadat Ahmadi, Ulrich Brandt.

  Mitochondrial disorders encompass a broad spectrum of genetic disorders impairing mitochondrial function. Considerable advancements have been made in the diagnosis and clinical management of these primary mitochondrial diseases. However, diagnosis and treatment have remained largely empirical, because the pathogenic mechanisms are still poorly understood by which any of the numerous known mutations lead to a specific phenotype in patients. To make inroads into this central challenge of mitochondrial medicine, we performed a focused survey of a cohort of published cases of Leigh syndrome caused by point mutations in subunits of respiratory chain complex I encoded by the mitochondrial genome. Leigh syndrome is one of the most severe mitochondrial disorders and is characterized by clinical and genetic manifestations predominantly affecting the central nervous system and the brain. We found that even basic correlations between a specific molecular defect and disease severity and progression are often obscured by the heterogeneity of the available diagnostic data. Still, our analysis showed that in order to understand the specific pathogenic impact it entails, for each mutation one has to carefully differentiate which functional domain of complex I is actually affected. It seems evident that much more comprehensive and differentiated studies of representative mutations as well as far more complete and standardized diagnostic data from patients should be obtained. This will be prerequisite for understanding and discriminating pathogenic mechanisms as a way to develop effective rational therapies for Leigh syndrome and other mitochondrial disorders.

Keywords:  Complex I; Leigh syndrome; Mitochondrial disease; mtDNA

DOI:  https://doi.org/10.1016/j.bbadis.2025.167996
Dev Med Child Neurol. 2025 Jul 25.

ATAD3 duplications bridge mitochondrial diseases and Aicardi-Goutières syndrome.

DOI: https://doi.org/10.1111/dmcn.16446
J Inherit Metab Dis. 2025 Jul;48(4): e70065

Therapies for Mitochondrial Disease: Past, Present, and Future.

Megan Ball, Nicole J van Bergen, Alison G Compton, David R Thorburn, Shamima Rahman, John Christodoulou.

  Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA-encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre-molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA-based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

Keywords:  clinical trials; gene therapy; mitochondrial disease; small molecule therapy; treatment

DOI:  https://doi.org/10.1002/jimd.70065
JACC Basic Transl Sci. 2025 Jul 25. pii: S2452-302X(25)00283-9. [Epub ahead of print]10(8): 101331

Harnessing Mitochondrial Transplantation to Target Vascular Inflammation in Cardiovascular Health.

Natalia Matiuto, Brandon Applewhite, Nicola Habash, Ana Martins, Bowen Wang, Bin Jiang.

  Mitochondrial dysfunction is a key contributor to vascular inflammation in many cardiovascular diseases. This review explores mitochondrial transplantation as a promising strategy for addressing mitochondrial dysfunction and vascular inflammation. We discuss mitochondrial dysfunction across different vascular cell types and current clinical management strategies, highlighting the need for novel approaches that directly target mitochondrial health. We also present recent progress in mitochondrial transplantation across cardiac, neurovascular, and peripheral vascular applications in preclinical settings, as well as ongoing clinical trials. Important technical considerations, such as mitochondria sourcing, delivery routes, and storage, are discussed to facilitate future translation. By reinstating mitochondrial health and hence mitigating vascular inflammation, mitochondrial transplantation holds the potential to provide novel, targeted therapies for cardiovascular diseases, ultimately improving patient outcomes, reducing disease progression, and addressing unmet medical needs in vascular health. The translation of this technology into clinical practice could offer significant advances in the treatment of a wide range of cardiovascular conditions.

Keywords:  endothelial dysfunction; mitochondrial dysfunction; mitochondrial transfer; oxidative stress; vascular inflammation

DOI:  https://doi.org/10.1016/j.jacbts.2025.101331
Adv Exp Med Biol. 2025 ;1467 173-175

Mitochondrial Disorder: Kearns-Sayre Syndrome.

Benjamin Kuang-Chien Chiang, Stephen H Tsang, Alicia R P Aycinena, Tarun Sharma.

  Mitochondrial DNA (mtDNA) deletions can be identified, and rarely point mutation.

Keywords:  KSS; Kearns-Sayre syndrome; Mitochondrial disorder

DOI:  https://doi.org/10.1007/978-3-031-72230-1_30
Nat Metab. 2025 Aug 01.

2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction.

Harshita Kaul, Lea Isermann, Katharina Senft, Milica Popovic, Theodoros Georgomanolis, Linda Baumann, Pujyanathan Sivanesan, Andromachi Pouikli, Hendrik Nolte, Bojana Lucic, Ximena Hildebrandt, Katrin Seidel, Thorsten Gnad, Felix Gaedke, Ulrike Göbel, Franziska Peters, Maksym Cherevatenko, Joo Hyun Park, Astrid Schauss, Nieves Peltzer, Jens Claus Brüning, Jan-Wilhelm Kornfeld, Alexander Pfeifer, Thomas Langer, Marina Lusic, Sara A Wickström, Christian Frezza, Aleksandra Trifunovic.

Mitochondria have a crucial role in regulating cellular homeostasis in response to intrinsic and extrinsic cues by changing cellular metabolism to meet these challenges. However, the molecular underpinnings of this regulation and the complete spectrum of these physiological outcomes remain largely unexplored. In this study, we elucidate the mechanisms driving the whitening phenotype in brown adipose tissue (BAT) deficient in the mitochondrial matrix protease CLPP. Here we show that CLPP-deficient BAT shows aberrant accumulation of lipid droplets, which occurs independently of defects in oxygen consumption and fatty acid oxidation. Our results indicate that mitochondrial dysfunction due to CLPP deficiency leads to the build-up of the oncometabolite D-2-hydroxyglutarate (D-2HG), which in turn promotes lipid droplet enlargement. We further demonstrate that D-2HG influences gene expression and decreases nuclear stiffness by modifying epigenetic signatures. We propose that lipid accumulation and altered nuclear stiffness regulated through 2HG are stress responses to mitochondrial dysfunction in BAT.

DOI: https://doi.org/10.1038/s42255-025-01332-8
Cell Rep. 2025 Jul 25. pii: S2211-1247(25)00840-X. [Epub ahead of print]44(8): 116069

An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Ménière's disease.

Marcell Harhai, Mads M Foged, Christine Zarges, Juan C Landoni, Sylvain Chollet, Michele Simonelli, Emeline Recazens, Miriam Lisci, Nora Laban, Suliana Manley, Jan Riemer, Jose Antonio Lopez-Escamez, Anna Lysakowski, Alexis A Jourdain.

  Mitochondrial disorders (MDs) are among the most common inborn errors of metabolism, and dysfunction in oxidative phosphorylation (OXPHOS) is a hallmark. Their complex mode of inheritance and diverse clinical presentations render the diagnosis of MDs challenging, and, to date, most lack a cure. Here, we build on previous efforts to identify genes necessary for OXPHOS and report a highly complementary galactose-sensitized CRISPR-Cas9 "growth" screen, presenting an updated inventory of 481 OXPHOS genes, including 157 linked to MDs. We further focus on FAM136A, a gene associated with Ménière's disease, and demonstrate that it supports intermembrane space protein homeostasis and OXPHOS in cell lines, mice, and patients. Our study identifies a mitochondrial basis in familial Ménière's disease, provides a comprehensive resource of OXPHOS-related genes, and sheds light on the pathways involved in MDs, with the potential to guide future diagnostics and treatments for MDs.

Keywords:  CLPB; CP: Metabolism; FAM136A; HAX1; Ménière; OXPHOS; functional genomics; intermembrane space; mitochondria; mitochondrial disease; proteostasis

DOI:  https://doi.org/10.1016/j.celrep.2025.116069
Cell Death Discov. 2025 Jul 29. 11(1): 349

ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.

Mudassar Ali, Anjali, Koyeli Mapa.

Mitochondria, the double membrane-bound organelles of endosymbiotic origin, are crucial centers for cellular energy production and several essential metabolic pathways. Recent studies reveal that mitochondria become dysfunctional following numerous cellular stresses, and during pathologies, demanding an extensive investigation of mitochondrial turnover mechanisms. Apart from the specific response pathways to tackle different stresses, mitophagy, or degradation of mitochondria by autophagy, is a critical quality control mechanism that clears irreversibly damaged mitochondria. Mitophagy is majorly executed either by receptor-mediated or PINK1-Parkin-dependent pathways. Here, we show that the human orthologue of yeast Vms1, ANKZF1, participates in PINK1-Parkin-mediated mitophagy. We show that ANKZF1 is extensively recruited to damaged mitochondria along with Parkin during mitochondrial proteotoxic stress induced by the expression of a single misfolded/aggregated protein or during uncoupler-induced membrane depolarization. Importantly, ANKZF1 recruitment to damaged mitochondria is significantly enhanced in the presence of Parkin, and ANKZF1 physically interacts with Parkin and LC3 during mitochondrial proteotoxic or depolarization stress. ANKZF1 harbors six putative LC3-interacting regions (LIRs), LIR4 present at residues 333-336, is particularly important for ANKZF1-LC3 interaction. Furthermore, we show that ANKZF1 knockout cells are compromised in clearing stress-damaged mitochondria by mitophagy, indicating an important role of ANKZF1 in mitochondrial turnover during stress. In summary, we show a new role of ANKZF1 in eliminating the stress-damaged mitochondria, reiterating the mito-protective role of Vms1/ANKZF1 during mitochondrial stresses. PINK1/Parkin signaling leads to polyubiquitination of outer mitochondrial membrane (OMM) proteins on stressed mitochondria. ANKZF1 functions as an adaptor protein, binding to polyubiquitinated OMM proteins via UBA domain and autophagosome receptor LC3 via LIR motif.

DOI: https://doi.org/10.1038/s41420-025-02638-y
Cell Mol Life Sci. 2025 Jul 29. 82(1): 291

An emerging role of mitochondrial quality control in bone metabolism: from molecular mechanisms to targeted therapeutic interventions.

Ziqi Qin, Xiting Zhu, Yifei Shen, Huiling Ling, Ngaifung Ruan, Wushuang Ye, Yang Xu, Xueqi Gan.

  The mitochondrial quality control system is the principal regulatory framework governing mitochondrial quantity, morphology, distribution, and functional integrity. This surveillance and regulatory machinery is essential for preserving cellular homeostasis and determining cellular differentiation. Mitochondria play a central role in maintaining the dynamic equilibrium between osteogenic differentiation and osteoclastic differentiation. Dysregulation of mitochondrial quality control can lead to disrupted mitochondrial homeostasis and functional impairments, disrupting the physiological processes of bone formation and bone resorption. However, comprehensive reviews elucidating the relationship between mitochondrial quality control and bone homeostasis are conspicuously lacking. This review systematically deconstructs the molecular architecture of mitochondrial quality control, elucidating the regulatory mechanism of each part (mitochondrial dynamics, mitophagy, mitochondrial biogenesis, mitochondrial redox) in bone-related cells. In addition, the mitochondrial quality control system in orchestrating cellular physiological activities is summarized to establish its indispensable in governing cellular homeostatic networks. Furthermore, the regulatory roles of the mitochondrial quality control system in bone-related cells and the balance between bone formation and resorption are reviewed. Finally, this review delineates the dysregulation of mitochondrial quality control in bone metabolic diseases and further advances mitochondrial quality control-targeted approaches for restoring mitochondria homeostasis, offering transformative strategies to treat bone metabolic diseases.

Keywords:  Bone metabolism; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Oxidative stress

DOI:  https://doi.org/10.1007/s00018-025-05802-w
Biology (Basel). 2025 Jul 17. pii: 868. [Epub ahead of print]14(7):

Maternal Nutrient Excess Induces Stress Signaling and Decreases Mitochondrial Number in Term Fetal Baboon Skeletal Muscle.

Xu Yan, Carolina Tocantins, Mei-Jun Zhu, Susana P Pereira, Min Du.

  Maternal obesity programs the fetus for increased risk of chronic disease development in early life and adulthood. We hypothesized that maternal nutrient excess leads to fetal inflammation and impairs offspring skeletal muscle mitochondrial biogenesis in non-human primates. At least 12 months before pregnancy, female baboons were fed a normal chow (CTR, 12% energy fat) or a maternal nutrient excess (MNE, 45% energy fat, and ad libitum fructose sodas) diet, with the latter to induce obesity. After 165 days of gestation (0.9 G), offspring baboons were delivered by cesarean section, and the soleus muscle was collected (CTR n = 16, MNE n = 5). At conception, MNE mothers presented increased body fat and weighed more than controls. The soleus muscle of MNE fetuses exhibited increased levels of stress signaling associated with inflammation (TLR4, TNFα, NF-kB p65, and p38), concomitant with reduced expression of key regulators of mitochondrial biogenesis, including PGC1α, both at the protein and transcript levels, as well as downregulation of PPARGC1B, PPARA, PPARB, CREB1, NOS3, SIRT1, SIRT3. Decreased transcript levels of NRF1 were observed alongside diminished mitochondrial DNA copy number, mitochondrial fusion elements (MFN1, MFN2), cytochrome C protein levels, and cytochrome C oxidase subunits I and II transcripts (cox1 and cox2). MNE coupled to MO-induced stress signaling in fetal baboon soleus muscle is associated with impaired mitochondrial biogenesis and lower mitochondrial content, resembling the changes observed in metabolic dysfunctions, such as diabetes. The observed fetal alterations may have important implications for postnatal development and metabolism, potentially increasing the risk of early-onset metabolic disorders and other non-communicable diseases.

Keywords:  cellular bioenergetics; developmental programming; fetal programming; maternal obesity; nutrient excess; skeletal muscle metabolism

DOI:  https://doi.org/10.3390/biology14070868
Am J Physiol Cell Physiol. 2025 Jul 31.

Small Molecule Oxybutynin Rescues Proliferative Capacity of Complex III-Defective Muscle Progenitor Cells.

Yue Qu, Kaydine Edwards, Muying Li, Matthew Williams, Yang Liu, Pei-Yin Tsai, Chloe Cheng, Jamie E Blum, Noel Acor, Tenzin Oshoe, Claire Walter, Venkatesh Thirumalaikumar, Anna E Thalacker-Mercer, Aleksandra Skirycz, Joeva Barrow.

  Mitochondrial disease encompasses a group of genetically inherited disorders hallmarked by an inability of the respiratory chain to produce sufficient ATP. These disorders present with multisystemic pathologies that predominantly impact highly energetic tissues such as skeletal muscle. There is no cure or effective treatment for mitochondrial disease. We have discovered a small molecule known as oxybutynin that can bypass Complex III mitochondrial dysfunction in primary murine and human skeletal muscle progenitor cells (MPCs). Oxybutynin administration improves MPC proliferative capacity, enhances cellular glycolytic function, and improves myotube formation. Mechanistically, results from our isothermal shift assay indicates that oxybutynin interacts with a suite of proteins involved in mRNA processing which then trigger the upregulation biological pathways to circumvent CIII mitochondrial dysfunction. Taken together, we provide evidence for the small molecule oxybutynin as a potential therapeutic candidate for the future treatment of CIII mitochondrial dysfunction.

Keywords:  Complex III; Mitochondrial Disease; Muscle Progenitor Cells; Oxybutynin; Uqcrfs1

DOI:  https://doi.org/10.1152/ajpcell.00141.2025
Commun Biol. 2025 Jul 29. 8(1): 1122

Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway.

Pin-Chao Liao, Tzu-Ying Lin, Catherine A Tsang, Chen-Jing Huang, Katherine Filpo, Istvan Boldogh, Liza A Pon.

The mitochondria-associated degradation pathway (MAD) mediates removal and elimination of damaged, unfolded mitochondrial proteins by the ubiquitin-proteasome system (UPS). Previous studies revealed that MAD is critical for mitochondrial protein quality control and that MAD function extends beyond mitochondrial outer membrane (MOM) to proteins within the organelle. Here, we reconstitute retrotranslocation of MAD substrates from the mitochondrial matrix across mitochondrial inner and outer membranes in cell-free systems. This retrotranslocation is ATP-dependent but membrane potential-independent. We also identify a role for the TOM complex, the protein import channel in the MOM, in this process. Inhibition of protein translocation across the Tom40p channel reduces the retrotranslocation of MAD substrates. Our studies support the model that the TOM complex is a bidirectional protein channel in the MOM: it mediates retrotranslocation of damaged mitochondrial proteins across the MOM in the MAD pathway for mitochondrial protein quality control in addition to its function in import of proteins into the organelle.

DOI: https://doi.org/10.1038/s42003-025-08549-z
Life Sci. 2025 Jul 30. pii: S0024-3205(25)00525-9. [Epub ahead of print] 123890

Role of impaired mitochondrial dynamics and mitophagy in cardiovascular diseases: Possible therapeutic approaches.

Sarmistha Sarkar, Aindrila Chattopadhyay, Debasish Bandyopadhyay.

  High mortality rates due to cardiovascular diseases (CVDs) fascinate the scientists worldwide in the past few decades to discover potent therapeutic strategies to save the victims. The myocardium being a highly active tissue, mitochondrial homeostasis and mitochondrial quality control system are crucial for maintaining optimal cardiac performance. Mitochondrial quality control mechanism is a finely tuned regulatory network encompassing mitochondrial biogenesis, mitochondrial dynamics and mitophagy and is an integral component of the mitochondrial response to stressor stimuli. Mitochondrial dynamics including the fusion and fission of mitochondrial membranes is regulated by an extensively conserved mechanism comprising a group of mitochondrial membrane proteins belonging to the dynamin family of GTPases. Emerging evidences indicate that defects in mitochondrial fusion or fission are intrinsically correlated with the pathophysiology of CVDs. Mitophagy is a kind of selective autophagy which removes damaged or redundant mitochondria. Experimental findings demonstrated that impairment of mitophagy in cardiomyocytes induces the accumulation of dysfunctional mitochondria, leading to the disruption of cellular homeostasis and consequently precipitating various CVDs. These findings speculate that pharmacological modulation of mitochondrial homeostasis including mitochondrial dynamics and mitophagy may represent a potential therapeutic approach in restoring cardiac physiology. This review summarizes the prevailing insight into the impact of disturbed mitochondrial dynamics and mitophagy in the pathogenesis of CVDs and also delineates the therapeutic potential of several relevant regulatory drugs that target mitochondrial function and quality control in alleviating mitochondrial impairment-related cardiac dysfunction.

Keywords:  Cardiomyocytes; Cardiovascular diseases; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy

DOI:  https://doi.org/10.1016/j.lfs.2025.123890
J Cell Sci. 2025 Jul 30. pii: jcs.263680. [Epub ahead of print]

Mitochondrial protein aggregates recruit key chaperones and are sequestered in a fission/fusion-dependent process.

Laura Ruland, Marc Sylvester, Lydia Maus, Hannes Beckert, Wolfgang Voos.

  The potential proteotoxicity of mitochondrial aggregates in yeast cells is reduced by a sequestration of affected polypeptides into a mitochondrial protein quality control compartment (IMiQ). Based on the expression of an aggregation-prone protein in the mitochondrial matrix, we determined the effect of organelle dynamics on aggregate sequestration. Fusion deficient cells were unable to accumulate the aggregates in the IMiQ, resulting in a stress-sensitive phenotype. In contrast, fission deficient cells could not separate the aggregate from the mitochondrial network. In these mitochondria, the aggregates were neutralized by the formation of a shell formed by mitochondrial chaperones. We also performed quantitative mass spectrometry to analyse the mitochondrial proteome and the extent of co-aggregation of mitochondrial proteins. While only minor changes of the total proteome were detected in response to aggregate accumulation, we found a recruitment of proteins of the respiratory chain complexes and of the protein quality control system (PQC). In particular members of the Hsp70 chaperone family were prominently associated with the aggregate. We conclude that this chaperone-dependent neutralization prevents a major co-aggregation of endogenous mitochondrial proteins.

Keywords:  Cell biology; Chaperone; Hsp70; Mitochondria; Protein aggregation; Proteostasis; Yeast

DOI:  https://doi.org/10.1242/jcs.263680
J Nucl Med. 2025 Jul 31. pii: jnumed.124.268698. [Epub ahead of print]

Evaluation of Mitochondrial Complex 1 Density with [18F]BCPP-EF in a Murine Model and Individuals with Friedreich Ataxia.

Laigao Chen, Gaia Rizzo, Christine Bulawa, Koene R A Van Dijk, Erica C Henning, Alain Martelli, Jeffrey Palmer, Avery McIntosh, Marko Pregel, Pengling Sun, Emmanuel Adewunmi, Mark Aldridge, Jackson Chan, Roger N Gunn, Mickael Huiban, Allan Listanco, Peter T Loudon, Sara Moz, Jan Passchier, Lauren Sauvage, Rachel Stewart, Lisa Wells, Eugenii A Rabiner, Lawrence R Charnas, Richard J Festenstein.

  Friedreich ataxia is caused by mutations in the frataxin gene, leading to neurodegeneration and premature death from cardiac dysfunction. Loss of frataxin impacts mitochondrial complex 1 (MC1) activity, suggesting MC1 may be a potential biomarker of frataxin levels and function. Biomarkers evaluated by noninvasive techniques are needed to monitor disease progression and treatment effects in people with Friedreich ataxia. Methods: PET with [18F]BCPP-EF, a ligand with high binding specificity for MC1, was used to measure cardiac and brain MC1 density in a mouse model of Friedreich ataxia and in healthy volunteers and participants with Friedreich ataxia. Results: An imaging protocol was developed in humans that included a 70-min brain scan immediately after administration of [18F]BCPP-EF followed by a 60-min cardiac scan 255 min after [18F]BCPP-EF administration. Cardiac [18F]BCPP-EF binding in participants with Friedreich ataxia was lower than that in healthy volunteers and in a mouse model of Friedreich ataxia versus wild-type mice (∼50% reduction in both). In the brain, no statistically significant difference in the [18F]BCPP-EF binding was detected between participants with Friedreich ataxia and healthy volunteers. Correlation analyses showed that blood frataxin and cardiac [18F]BCPP-EF levels decreased with increasing guanine-adenine-adenine expansion size (R = -0.82 and -0.78, respectively; both P < 0.05) but not in the precentral gyrus (R = 0.63; P < 0.05). Conclusion: MC1 density as measured using [18F]BCPP-EF-based PET may be a viable biomarker of mitochondrial deficit and frataxin levels in people with Friedreich ataxia.

Keywords:  Friedreich ataxia; PET; [18F]BCPP-EF; frataxin; mitochondrial complex 1

DOI:  https://doi.org/10.2967/jnumed.124.268698
Nat Cell Biol. 2025 Jul 25.

Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery.

Elias Adriaenssens, Stefan Schaar, Annan S I Cook, Jan F M Stuke, Justyna Sawa-Makarska, Thanh Ngoc Nguyen, Xuefeng Ren, Martina Schuschnig, Julia Romanov, Grace Khuu, Louise Uoselis, Michael Lazarou, Gerhard Hummer, James H Hurley, Sascha Martens.

Selective autophagy is a lysosomal degradation pathway that is critical for maintaining cellular homeostasis by disposing of harmful cellular material. Although the mechanisms by which soluble cargo receptors recruit the autophagy machinery are becoming increasingly clear, the principles governing how organelle-localized transmembrane cargo receptors initiate selective autophagy remain poorly understood. Here we demonstrate that the human transmembrane cargo receptors can initiate autophagosome biogenesis not only by recruiting the upstream FIP200/ULK1 complex but also via a WIPI-ATG13 complex. This latter pathway is employed by the BNIP3/NIX receptors to trigger mitophagy. Additionally, other transmembrane mitophagy receptors, including FUNDC1 and BCL2L13, exclusively use the FIP200/ULK1 complex, whereas FKBP8 and the ER-phagy receptor TEX264 are capable of utilizing both pathways to initiate autophagy. Our study defines the molecular rules for initiation by transmembrane cargo receptors, revealing remarkable flexibility in the assembly and activation of the autophagy machinery, with important implications for therapeutic interventions.

DOI: https://doi.org/10.1038/s41556-025-01712-y
Life (Basel). 2025 Jun 23. pii: 998. [Epub ahead of print]15(7):

Feasibility of Xenogeneic Mitochondrial Transplantation in Neuronal Systems: An Exploratory Study.

Eriko Nakamura, Tomoaki Aoki, Cyrus E Kuschner, Yusuke Endo, Jacob S Kazmi, Tai Yin, Ryosuke Takegawa, Lance B Becker, Kei Hayashida.

  Mitochondrial transplantation (MTx) has emerged as a potential therapeutic approach for diseases associated with mitochondrial dysfunction, yet its scalability and cross-species feasibility remain underexplored. This study aimed to evaluate the dose-dependent uptake and molecular effects of xenogeneic mitochondrial transplantation (xeno-MTx) using rat-derived mitochondria in mouse neuronal systems. HT-22 hippocampal neuronal cells and a murine model of cardiac arrest-induced global cerebral ischemia were used to assess mitochondrial uptake, gene expression, and mitochondrial DNA presence. Donor mitochondria were isolated from rat pectoralis muscle and labeled with MitoTracker dyes. Flow cytometry and confocal microscopy revealed a dose-dependent increase in donor mitochondrial uptake in vitro. Quantitative PCR demonstrated a corresponding increase in rat-specific mitochondrial DNA and upregulation of Mfn2 and Bak1, with no changes in other fusion, fission, or apoptotic genes. Inhibitor studies indicated that mitochondrial internalization may involve actin-dependent macropinocytosis and cholesterol-sensitive endocytic pathways. In vivo, rat mitochondrial DNA was detected in mouse brains post-xeno-MTx, confirming donor mitochondrial delivery to ischemic tissue. These findings support the feasibility of xeno-MTx and its dose-responsive biological effects in neuronal systems while underscoring the need for further research to determine long-term functional outcomes and clinical applicability.

Keywords:  cardiac arrest; ischemia–reperfusion; mitochondria; mitochondrial transplantation; neuron

DOI:  https://doi.org/10.3390/life15070998
Ecotoxicol Environ Saf. 2025 Jul 24. pii: S0147-6513(25)00981-9. [Epub ahead of print]302 118636

Gestational zearalenone causes fetal intrauterine growth restriction partially through deriving ROS-Drp1 mediated placental PANoptosis.

Jie Ru Liu, Fang Nan Wu, Shuai Lin, Chen Chen, Yan Liu, Jing Wen Fan, Qiang Hong, Yuan Hua Chen.

  The ubiquity of zearalenone (ZEA) in cereal-based products and the aquatic environment raises growing concerns about health problems to humans and animals. Here, we explored the mechanism by which ZEA exposure during pregnancy induced fetal growth restriction (FGR). Interestingly, both fetal weights and crown-rump length were significant decreases when dams were administrated with ZEA. Consistently, the incidence of FGR is significantly increased in ZEA group in a dose-dependent manner. Moreover, mean placental weight and diameter was significantly reduced in ZEA group, suggesting that poor placental development may be involved in ZEA-induced FGR. The genome-wide expression profiles of mouse placentas were significantly different between two groups by RNA-sequencing. GO and KEGG analysis indicated significant enrichment of these differentially expressed genes in mitochondrial apoptotic signaling pathway, inflammatory cell apoptotic process, necroptosis, and regulation of mitochondrial membrane potential. Further study showed that mitochondrial quality control disorder and PANoptosis plays an important role in ZEA-induced poor placental development. Mdivi-1, an inhibitor of Drp-1, attenuated ZEA-induced mitochondrial quality control disorder and PANoptosis in mouse placentas and human placental trophoblasts. N-acetylcysteine (NAC), an antioxidant, abolished ZEA-induced mitochondrial quality control disorder and PANoptosis in mouse placentas and human placental trophoblasts. Importantly, Mdivi-1 and NAC rescued gestational ZEA exposure-induced poor placental development and FGR in mice. Our results indicate that ZEA exposure during pregnancy caused poor placental development and subsequently FGR may be via deriving ROS-Drp1 mediated placental PANoptosis.

Keywords:  Fetal growth restriction; Mitochondrial quality control disorder; PANoptosis; Placenta; Zearalenone

DOI:  https://doi.org/10.1016/j.ecoenv.2025.118636
Am J Physiol Regul Integr Comp Physiol. 2025 Aug 01.

Sex-specific Impact of Selective Reduced Uterine Placental Perfusion Model of Preeclampsia on Fetal Cardiac Maturation and Mitochondrial Function.

Paulami Chatterjee, Rebecca Molberg, Raven Kirschenman, Claudia D Holody, Anita Quon, Floor Spaans, Stephane L Bourque, Hélène Lemieux, Sandra T Davidge.

  Preeclampsia is a serious pregnancy complication and increases the risk of cardiovascular disease in offspring later in life. Cardiac development includes maturation of cardiomyocytes, a process that is intricately dependent on proper mitochondrial function. However, it remains unclear whether preeclampsia impairs mitochondrial function and alters cardiac maturation of fetal hearts during late gestation. Herein we induced selective reduced uterine placental perfusion (sRUPP), as a model of preeclampsia in rats, to investigate fetal cardiac myosin heavy chain (MYH) expression, reactive oxygen species (ROS) production, mitochondrial respiration, mitochondrial content and dynamics in male and female fetuses at gestational day (GD) 20 (term = GD 22). Litter size was reduced, while pup reabsorptions were increased in sRUPP compared to Sham controls. In only the male fetuses of sRUPP dams, cardiac MYH7/MYH6 ratio was reduced and MYH6 expression increased. Complex IV activity was elevated in sRUPP male fetuses, with no changes in mitochondrial citrate synthase or ATP synthase activities in either sex. However, ROS production increased in only sRUPP female fetuses. In male fetal hearts, sRUPP increased fusion protein MFN1 expression, tended to decrease fusion protein OPA1 expression, and decreased fission protein FIS1 expression. In contrast, MFN2 and OPA1 were reduced in sRUPP female fetuses. In conclusion, the sRUPP model of preeclampsia affected cardiac maturation and mitochondrial function in late gestation fetuses in a sex-specific manner. As prenatal strategies are being developed to improve pregnancy outcomes, sex-specific fetal effects should be taken into consideration.

Keywords:  cardiac maturation; fetus; mitochondrial dynamics; preeclampsia; sex differences

DOI:  https://doi.org/10.1152/ajpregu.00118.2025
J Neurophysiol. 2025 Aug 01.

CUMS stress facilitates hippocampal neural mitophagy through FIS1/MFF-mediated mitochondrial fragmentation.

Xiaoke Qiu, Shaoda Lai, Yingyi Zhang, Shengtao Huang, Han Li, Junsheng Liu, Yong Huang, Zhinan Zhang.

  The chronic unpredictable mild stress (CUMS) paradigm influences the neuronal count in the dentate gyrus (DG) region of the hippocampus, potentially linking to mitophagy induced by mitochondrial fragmentation. Fission mitochondrial 1 (FIS1)/mitochondrial fission factor (MFF) represents one of the mechanisms regulating mitochondrial fission and autophagy. Herein, we investigated the effects of CUMS on mitophagy and mitochondrial fragmentation in hippocampal DG neurons, along with their modulation of the mitochondrial fission pathway governed by FIS1/MFF. Our results demonstrated that CUMS stress augmented mitophagy in hippocampal DG neurons. Concurrently, it exacerbated the tendency towards mitochondrial fragmentation. The impact on the upstream regulatory pathway of mitochondrial fragmentation manifested as upregulation of FIS1 and downregulation of MFF, resulting in a net loss of mitochondrial content and a subsequent energy deficit. These findings suggest that CUMS stress, by modulating the FIS1/MFF balance, increase mitophagy stemming from mitochondrial fragmentation in hippocampal DG neurons.

Keywords:  Depression; FIS1; MFF; mitochondria fragmentation; mitophagy

DOI:  https://doi.org/10.1152/jn.00523.2024
J Neuropathol Exp Neurol. 2025 Aug 01. pii: nlaf093. [Epub ahead of print]

Proteasomal dysfunction in the mouse forebrain induces mitochondrial DNA release, cGAS-STING signaling activation, and necroptosis.

Abena Dwamena, Yasin Asadi, Erin Gilstrap, Hongmin Wang.

  Impaired proteasome function is associated with various neurodegenerative disorders that are hallmarked by neuroinflammation and neurodegeneration, including Alzheimer disease (AD); however, the relationships between these phenomena remain unclear. By utilizing a neuron-specific Psmc1 conditional knockout (cKO) mouse model in which one of the 19S proteasome is disrupted, we studied the effect of impaired proteasome function on neuroinflammation and neuronal death in the brain. We discovered that disrupting the 19S proteasome led to increased release of mitochondrial double-stranded DNA into the cytosol, upregulated levels of cyclic GMP-AMP synthase (cGAS), stimulator of interferon gene (STING), phosphorylated TBK1, and IRF3, and the downstream pro-inflammatory mediators, including STAT1, NF-κB, IL-1β, IL-6, and TNFα in the cKO mouse brains as compared to control brains. Importantly, we also observed reduced brain weight and elevation in levels of factors involved in necroptosis, ie the mixed lineage kinase domain-like (MLKL) protein, phosphorylated MLKL, and receptor-interacting protein kinases (RIPK) 1 and 3 in the cKO mouse brains. Together, our data suggest that proteasome dysfunction activates the cGAS-STING pathway and induces neuroinflammation and necroptotic neuronal death.

Keywords:  cGAS-STING; necroptosis; neurodegenerative disease; neuroinflammation; proteasome; proteasome dysfunction

DOI:  https://doi.org/10.1093/jnen/nlaf093
Adv Sci (Weinh). 2025 Jul 29. e03408

SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40.

Liubing Hu, Jianshuang Li, Haolin Guo, Lei Su, Peina Dong, Juan Huang, Yanyan Liu, Xinjie Liu, Zhenhuan Luo, Wei Xiong, Zhenyu Ju, Qinghua Zhou, Hao Wang, Wenjun Wang.

  SUMOylation, a reversible post-translational modification, regulates various mitochondrial processes, including biogenesis, dynamics, mitophagy, and the mitochondrial unfolded protein response. Although SUMOylation is shown to be triggered by mitochondrial protein import failure in yeast, its impact on mammalian mitochondrial protein import remains unclear. Here, it is demonstrated that SENP6 knockdown-induced SUMOylation causes loss of mitochondrial proteostasis, which impairs mitochondrial morphology and function. Mechanistically, SENP6 knockdown dampens TOM complex assembly by SUMOylating TOM40, thereby hindering the mitochondrial protein import process, including TOM40 precursor, and ultimately disrupts mitochondrial homeostasis. Additionally, it is observed that CCCP treatment resulted in a decrease of SENP6 within mitochondria fraction, accompanied by increased TOM40 SUMOylation in the brains of 3×Tg-Alzheimer's disease (AD) mice or Aβ1-42 peptide-stimulated cells. Collectively, the results suggest that Aβ1-42 accumulation may enhance TOM40 SUMOylation by suppressing SENP6, thereby impairing mitochondrial homeostasis through protein import failure and potentially contributing to the pathological process of AD. This study elucidates the role of TOM40 SUMOylation/deSUMOylation in regulating the mitochondrial import process during mitochondrial stress.

Keywords:  Mitochondrial protein import; SENP6; SUMOylation; TOM complex; TOM40

DOI:  https://doi.org/10.1002/advs.202503408
STAR Protoc. 2025 Jul 25. pii: S2666-1667(25)00377-6. [Epub ahead of print]6(3): 103971

Protocol for assessing mitochondrial cholesterol transport and protein molten globule state in steroidogenic and nonsteroidogenic systems.

Himangshu S Bose, Mahuya Bose, Randy M Whittal.

  Steroid hormones are essential for the survival of all mammals for carbohydrate metabolism, stress management, and sexual reproduction. Here, we present a protocol for assessing mitochondrial cholesterol transport and protein molten globule state via measurement of pregnenolone or progesterone synthesis in steroidogenic and nonsteroidogenic cellular systems. We describe steps for cell culture, transfection, and measurement of steroidogenic activity from nonsteroidogenic cells. We then detail procedures for metabolic conversion. For complete details on the use and execution of this protocol, please refer to Bose,1 Bose et al.,2 Pawlak et al.,3 and Prasad et al.4.

Keywords:  Cell Biology; Health Sciences; Mass Spectrometry; Metabolism; Molecular Biology; Protein Biochemistry

DOI:  https://doi.org/10.1016/j.xpro.2025.103971
Mol Cell. 2025 Jul 22. pii: S1097-2765(25)00545-3. [Epub ahead of print]

Structural basis for promoter recognition and transcription factor binding and release in human mitochondria.

Karl Herbine, Ashok R Nayak, Angelica Zamudio-Ochoa, Dmitry Temiakov.

  Transcription in human mitochondria is driven by a core apparatus consisting of a Pol A family RNA polymerase (mtRNAP), the initiation factors TFAM and TFB2M, and the elongation factor TEFM. While earlier structures of initiation and elongation complexes provided valuable snapshots, they represent isolated stages of a highly dynamic and multistep process. Critical aspects of mitochondrial transcription-such as DNA recognition and melting, promoter escape, and the release of initiation factors-remain poorly understood. Here, we present a series of cryoelectron microscopy (cryo-EM) structures that capture the transcription complex as it transitions from the initial open promoter complex to the processive elongation complex through intermediate stages. Our data reveal new, previously unidentified determinants of promoter specificity: the sequential disengagement of mtRNAP from TFAM and the promoter, the release of TFB2M, and the recruitment of TEFM. Together, these findings provide a detailed molecular mechanism underlying transcription in human mitochondria.

Keywords:  POLRMT; RNA polymerase; TEFM; TFAM; TFB2M; mitochondrial transcription; mtRNAP; promoter; transcription-replication switch

DOI:  https://doi.org/10.1016/j.molcel.2025.06.016
Front Cardiovasc Med. 2025 ;12 1641023

Unraveling mitochondrial crosstalk: a new frontier in heart failure pathogenesis.

Hongbo Chang, Pingge He, Weidi Liu, Hong Wu, Zhentao Wang.

  Mitochondria play a central role in energy production and signal transduction in cardiomyocytes. Their dysfunction is a key contributor to the development and progression of heart failure (HF). Beyond energy metabolism, mitochondria regulate calcium homeostasis, autophagy, protein synthesis, lipid metabolism, and gene expression through close interactions with other organelles. Disruption of these interactions has been linked to HF pathophysiology.This review focuses on the dynamic communication between mitochondria and five major organelles-the endoplasmic reticulum, lysosomes, ribosomes, lipid droplets, and the nucleus. We outline how these interactions maintain cardiac homeostasis and describe how their dysfunction contributes to HF. We also highlight emerging therapeutic strategies targeting these organelle networks.

Keywords:  calcium signaling; heart failure; metabolic regulation; mitochondria-organelle interaction; proteostasis; therapeutic target

DOI:  https://doi.org/10.3389/fcvm.2025.1641023
FASEB J. 2025 Aug 15. 39(15): e70882

PDE4D Regulates Mitochondrial Homeostasis and Adult Hippocampal Neurogenesis via the cAMP/CREB Signaling Pathway in Chronic Stress-Induced Depressive-Like Behavior.

Wei Zhao, Ziqi Wang, Xiaofei Chen, Shuang Zhao, Fangjiao Zong, Hanting Zhang.

  Phosphodiesterase 4D (PDE4D), a major enzyme responsible for cAMP degradation in the hippocampus, has been implicated in mood regulation. Although PDE4D inhibition exerts antidepressant effects, the underlying mechanisms remain poorly understood. Here, we explored the role of PDE4D in chronic stress-induced depressive-like behaviors, mitochondrial dysfunction, and impaired adult hippocampal neurogenesis (AHN). Using a chronic restraint stress (CRS) model, we found that PDE4D expression was significantly upregulated in the hippocampal dentate gyrus (DG) of CRS mice, leading to suppressed CREB signaling, mitochondrial dysfunction, and impaired AHN. PDE4D knockout (PDE4D-KO) restored mitochondrial quality by enhancing mitochondrial biogenesis, normalizing mitophagy, and improving oxidative phosphorylation (OXPHOS) via the nucleus and mitochondria cAMP/CREB signaling, ultimately promoting AHN and alleviating depression-like symptoms. These findings define PDE4D as a key regulator of mitochondrial homeostasis and AHN, suggesting that targeting PDE4D in the hippocampal DG may represent a novel treatment mechanism for depression.

Keywords:  adult hippocampal neurogenesis; chronic stress; depression; mitochondrion; pde4d

DOI:  https://doi.org/10.1096/fj.202501537R
Proc Natl Acad Sci U S A. 2025 Aug 05. 122(31): e2424459122

Micro magnetic resonance spectroscopy for noninvasive metabolic screening of mammalian embryos and oocytes.

Giulia Sivelli, Arthur Barakat, Kathryn B Marable, Guillaume Gruet, Serena L Bitetti, Barry Behr, Valentina Lodde, Alberto Maria Luciano, Carolina Herrera, Michelle Blom, Marco Grisi.

  Analyzing cellular health and metabolism without compromising cell integrity is a major challenge. We present a noninvasive technique using micro magnetic resonance spectroscopy (micro MRS) for nondestructive metabolic fingerprinting at the single-cell scale. This is an application of micro MRS to bovine preimplantation embryos (~8 cells) and oocytes (single cell), with measurements performed on a total of over 150 samples. Among various applications, this method holds significant potential for assisted reproductive technologies (ART), where metabolic assessments of preimplantation embryos could improve treatment outcomes. Early results indicate that classification models using micro MRS data effectively distinguish embryos with high developmental potential and show correlation with oocytes maturity. Furthermore, a multigenerational safety study in a mouse model revealed no adverse effects from embryo exposure to static magnetic field. These findings indicate that micro MRS is a promising, safe tool for assessing embryo metabolism, potentially improving the efficiency and outcomes of ART.

Keywords:  Magnetic Resonance Spectroscopy; metabolic fingerprinting; micro MRS; non-invasive embryo screening; single-cell MRS

DOI:  https://doi.org/10.1073/pnas.2424459122
Nat Struct Mol Biol. 2025 Jul 25.

Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex.

Rachel M Jansen, Clément Maghe, Karla Tapia, Selina Wu, Serim Yang, Xuefeng Ren, Roberto Zoncu, James H Hurley.

Mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient-responsive master regulator of metabolism. Amino acids control the recruitment and activation of mTORC1 at the lysosome through the nucleotide loading state of the heterodimeric Rag GTPases. Under low nutrients, including arginine, the GTPase-activating protein complex GATOR1 promotes GTP hydrolysis on RagA/B, inactivating mTORC1. GATOR1 is regulated by the cage-like GATOR2 complex and cytosolic amino acid sensors. To understand how the arginine sensor CASTOR1 binds to GATOR2 to disinhibit GATOR1 under low cytosolic arginine, we determined the cryo-electron microscopy structure of human GATOR2 bound to CASTOR1 in the absence of arginine. Two MIOS WD40 domain β-propellers of the GATOR2 cage engage with both subunits of a single CASTOR1 homodimer. Each propeller binds to a negatively charged MIOS-binding interface on CASTOR1 that is distal to the arginine pocket. The structure shows how arginine-triggered loop ordering in CASTOR1 blocks the MIOS-binding interface, switches off its binding to GATOR2 and, thus, communicates to downstream mTORC1 activation.

DOI: https://doi.org/10.1038/s41594-025-01635-0