bims-mitmed 2025-06-15 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–06–15
35 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific regulatory mechanisms.
Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.
Mitochondrial molecule has unexpected role in tissue healing.
Hepatic bioenergetics and metabolism in mitochondrial disease: insights from the Ndufs4 KO mouse model.
Mitochondrial Transplantation: A Novel Therapeutic Approach for Treating Diseases.
The trade-off between reproduction and resilience.
Mitochondrial PTRH2 controls the deubiquitinase TRABID to regulate mt-ND5 stability and metabolism.
Disruption of adaptive immunity does not attenuate disease in the Ndufs4(-/-) model of Leigh syndrome.
Long-Read Sequencing Identifies Mosaic Sequence Variations in Friedreich's Ataxia-GAA Repeats.
Advances in Management of Mitochondrial Myopathies.
Protocol to extract and measure ubiquinone and rhodoquinone in murine tissues.
AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.
Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
Metabolic adaptations direct cell fate during tissue regeneration.
Personalized, in vivo gene editing for a newborn.
Longitudinal plasma amino acids during pregnancy and neonatal anthropometry: findings from the NICHD Fetal Growth Studies-Singleton Cohort.
Construction of mitochondrial-targeted ferritin carrier: subunit-terminal fused mitochondrial presequences facilitate efficient delivery.
The Role of Placental Mitochondrial Dysfunction in Adverse Perinatal Outcomes: A Systematic Review.
Tmx2 Maintains Mitochondrial Function to Support Preimplantation Embryogenesis.
Conformation-specific synthetic intrabodies modulate mTOR signaling with subcellular spatial resolution.
Metabolic Pathway Tracing for NAD+ Synthesis and Consumption.
Anti-ageing effects of popular supplement taurine challenged.
In vivo epigenome editing with NovaIscB.
Charcot-Marie-Tooth disease type 1E: clinical natural history and molecular impact of PMP22 variants.
Safety and efficacy of leriglitazone in childhood cerebral adrenoleukodystrophy (NEXUS): an interim analysis of an open-label, phase 2/3 trial.
Disease spectrum and long-term prognosis of patients with BAG3-associated neuromuscular diseases in Europe.
Omaveloxolone, But Not Dimethyl Fumarate, Improves Cardiac Function in Friedreich's Ataxia Mice With Severe Cardiomyopathy.
Using RNA therapeutics to promote healthy aging.
Early life high fructose impairs microglial phagocytosis and neurodevelopment.
Association of placental mitochondrial DNA mutations on infant negative affectivity: modifying effects of maternal lifetime stress and infant sex.
Deleterious mitochondrial heteroplasmies exhibit increased longitudinal change in variant allele fraction.
At last: the mitochondrial pyruvate carrier structure revealed!
Nitric Oxide may Adversely Affect the Metabolism and Viability of Retinal Organoids Derived from Patients with Leber Hereditary Optic Neuropathy.
Mitochondrial metabolic rescue in post-COVID-19 syndrome: MR spectroscopy insights and precision nutritional therapeutics.

Cell. 2025 Jun 05. pii: S0092-8674(25)00570-7. [Epub ahead of print]

Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.

Daniel A Schmitz, Seiya Oura, Leijie Li, Yi Ding, Rashmi Dahiya, Emily Ballard, Carlos Pinzon-Arteaga, Masahiro Sakurai, Daiji Okamura, Leqian Yu, Peter Ly, Jun Wu.

  Mitochondrial abundance and genome are crucial for cellular function, with disruptions often associated with disease. However, methods to modulate these parameters for direct functional dissection remain limited. Here, we eliminate mitochondria from pluripotent stem cells (PSCs) by enforced mitophagy and show that PSCs survived for several days in culture without mitochondria. We then leverage enforced mitophagy to generate interspecies PSC fusions that harbor either human or non-human hominid (NHH) mitochondrial DNA (mtDNA). Comparative analyses indicate that human and NHH mtDNA are largely interchangeable in supporting pluripotency in these PSC fusions. However, species divergence between nuclear and mtDNA leads to subtle species-specific transcriptional and metabolic variations. By developing a transgenic enforced mitophagy approach, we further show that reducing mitochondrial abundance leads to delayed development in pre-implantation mouse embryos. Our study opens avenues for investigating the roles of mitochondria in development, disease, and interspecies biology.

Keywords:  cell fusion; great apes; interspecies composite; interspecies hybrid; metabolism; mitochondria; mitophagy; mtDNA; pluripotent stem cells

DOI:  https://doi.org/10.1016/j.cell.2025.05.020
Life Metab. 2025 Jun;4(3): loaf012

Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific regulatory mechanisms.

Jack Devine, Anna S Monzel, David Shire, Ayelet M Rosenberg, Alex Junker, Alan A Cohen, Martin Picard.

  Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors. This predicts that some individuals should have consistently high, while others show consistently low mitochondrial oxidative phosphorylation (OxPhos) capacity across organ systems. Here, we test this assumption using multi-tissue molecular and enzymatic assays in mice and humans. Across up to 22 mouse tissues, neither mitochondrial OxPhos capacity nor mitochondrial DNA (mtDNA) density was correlated between tissues (median r = -0.01 to 0.16), indicating that animals with high mitochondrial content or capacity in one tissue may have low content or capacity in other tissues. Similarly, RNA sequencing (RNAseq)-based indices of mitochondrial expression across 45 tissues from 948 women and men (genotype-tissue expression [GTEx]) showed only small to moderate coherence between some tissues, such as between brain regions (r = 0.26), but not between brain-body tissue pairs (r = 0.01). The mtDNA copy number (mtDNAcn) also lacked coherence across human tissues. Mechanistically, tissue-specific differences in mitochondrial gene expression were partially attributable to (i) tissue-specific activation of energy sensing pathways, including the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the integrated stress response (ISR), and other molecular regulators of mitochondrial biology, and (ii) proliferative activity across tissues. Finally, we identify subgroups of individuals with distinct mitochondrial distribution strategies that map onto distinct clinical phenotypes. These data raise the possibility that tissue-specific energy sensing pathways may contribute to idiosyncratic mitochondrial distribution patterns among individuals.

Keywords:  disease risk; energy sensing; gene regulation; inter-organ crosstalk; mitochondrial biogenesis; mitochondrion

DOI:  https://doi.org/10.1093/lifemeta/loaf012
Am J Hum Genet. 2025 Jun 03. pii: S0002-9297(25)00188-0. [Epub ahead of print]

Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.

Hana Antonicka, Woranontee Weraarpachai, Katherine M Szigety, Robert Kopajtich, James B Gibson, Johan L K Van Hove, Marisa W Friederich, Piervito Lopriore, Christiane Neuhofer, Roxanne A Van Hove, Michel A Cole, Richard Reisdorph, James T Peterson, Katherine J Dempsey, Rebecca D Ganetzky, Michelangelo Mancuso, Holger Prokisch, Eric A Shoubridge.

  Using exome sequencing, we identified compound heterozygous variants of unknown significance in FASTKD5, a gene that codes for a mitochondrial protein essential for processing mRNAs at non-canonical cleavage sites in the primary mitochondrial transcript, in three subjects with Leigh syndrome, a progressive neurodegenerative disease characterized by lesions in the brainstem and basal ganglia. Among the three subjects, we identified three missense variants and two frameshift variants leading to a premature stop codon. Analysis of fibroblasts from two subjects showed reduced steady-state levels of FASTKD5 protein by immunoblot, reduced translation of the cytochrome c oxidase subunit 1, impaired assembly of complex IV, and a consequent decrease in cytochrome c oxidase enzymatic activity. The extent of these deficiencies appeared to correlate with the severity of the clinical phenotype. Expression of a wild-type FASTKD5 cDNA, but not cDNAs expressing the missense mutations, rescued all the molecular defects in the subjects' fibroblasts, demonstrating that the alleles are pathogenic. Two of the three identified missense mutations resulted in near complete loss of function, while one was hypomorphic, resulting from impaired protein stability. These cases of mitochondrial disease associated with bi-allelic variants in FASTKD5 add to a growing list of primary genetic mutations causing Leigh syndrome associated with complex IV deficiency.

Keywords:  FASTKD5; Leigh syndrome; RNA processing; cytochrome c oxidase deficiency; mitochondrial DNA; mitochondrial disease; mitochondrial gene expression; mitochondrial translation; neurodegenerative disease

DOI:  https://doi.org/10.1016/j.ajhg.2025.05.007
Nature. 2025 Jun 11.

Mitochondrial molecule has unexpected role in tissue healing.

Ram P Chakrabarty, Navdeep S Chandel.



Keywords:  Biochemistry; Cell biology; Metabolism; Stem cells

DOI:  https://doi.org/10.1038/d41586-025-01583-1
Metabolomics. 2025 Jun 11. 21(4): 76

Hepatic bioenergetics and metabolism in mitochondrial disease: insights from the Ndufs4 KO mouse model.

Karin Terburgh, Nastassja Sweeney, Roan Louw.

   INTRODUCTION: Mitochondrial complex (CI) deficiency frequently manifests as a severe neurometabolic disorder called Leigh syndrome (LS). Research on the Ndufs4 knockout (KO) mouse model has identified neuronal vulnerability to CI deficiency as a major driver of the disease, yet its effects on hepatic function remain unclear. Considering the importance of the liver, and its interconnection with the brain, in regulating whole-body metabolic balance, further investigation into the effects of whole-body Ndufs4 KO on the liver is warranted.
OBJECTIVES: This study investigated liver bioenergetics and metabolism in Ndufs4 KO and WT mice at the late stage of LS.
METHODS: Bioenergetic investigations of liver mitochondria (n ≥ 3) included spectrophotometric respiratory chain enzyme (CI-IV) activity assays and high-resolution respirometry. Hypothesis-generating metabolomics of whole-liver extracts (n ≥ 19) utilised 1H-NMR, GC-TOFMS, and LC-MS/MS. Significant alterations were identified via t-tests and effect size calculations.
RESULTS: Ndufs4 KO livers displayed a significant ~ 86% reduction in CI activity and a ~ 43% decrease in CI contribution to CI + II-driven respiration. CII-driven respiration remained unaffected, providing the predominant electron flux in both genotypes. Metabolic profiling revealed widespread perturbations in Ndufs4 KO hepatic metabolism including glucose-, amino acid-, purine/pyrimidine metabolism and the TCA-cycle.
CONCLUSION: Despite severe CI deficiency, respiration in the Ndufs4 KO liver remains largely unaffected due to reliance on CII. Nonetheless, advanced LS significantly disrupts liver metabolism, with O-GlcNAcylation and mTOR signalling suggestsed as key areas for future investigation. Altogether, our findings underscore the importance of interorgan metabolic dynamics and the liver-brain axis in neurometabolic disorders like LS.

Keywords:   Ndufs4 knockout mice; Complex I deficiency; Leigh syndrome; Liver metabolism

DOI:  https://doi.org/10.1007/s11306-025-02275-7
MedComm (2020). 2025 Jun;6(6): e70253

Mitochondrial Transplantation: A Novel Therapeutic Approach for Treating Diseases.

Xinglu Miao, Pei Jiang, Zhaoping Wang, Weihua Kong, Lei Feng.

  Advances in mitochondrial biology have led to the development of mitochondrial transplantation as a novel and promising therapeutic strategy. This review provides a comprehensive analysis of the multifaceted roles of mitochondria in health and disease, highlighting their central functions in energy production, antioxidant defense, calcium signaling, apoptosis regulation, and mitochondrial homeostasis maintenance. We explore the mechanisms by which transplanted mitochondria exert their therapeutic effects, including restoring ATP production, attenuating oxidative stress, modulating inflammatory responses, reducing cellular apoptosis, promoting cell repair and regeneration, facilitating neural circuit reconstruction, and exhibiting antitumor properties. Key preclinical studies demonstrating the efficacy of mitochondrial transplantation across in vitro and in vivo disease models are discussed, along with the status of clinical trials. The review also critically compares mitochondrial transplantation with other mitochondria-targeted therapies, evaluating their relative advantages and limitations. Finally, we discuss the current challenges of translating this innovative therapy into clinical practice, such as mitochondrial isolation and purification, storage, targeted delivery, potential immune responses, and long-term safety and efficacy concerns. This review aims to stimulate further research and development in this promising field, paving the way for novel therapeutic interventions for various diseases.

Keywords:  disease therapy; mitochondria; mitochondrial transplantation; therapeutic strategy

DOI:  https://doi.org/10.1002/mco2.70253
Trends Endocrinol Metab. 2025 Jun 10. pii: S1043-2760(25)00102-X. [Epub ahead of print]

The trade-off between reproduction and resilience.

Liankui Zhou, Ying Liu.

  The mitochondrial unfolded protein response (UPRmt) is a transcriptional program that alleviates mitochondrial dysfunction by facilitating the recovery of the mitochondrial network. In Caenorhabditis elegans, reproductive maturity leads to suppression of the UPRmt, suggesting a trade-off between maintenance of stress resilience and fertility. Here, we examine emerging evidence suggesting that the reproduction-associated suppression of UPRmt is a representative example of the physiological costs of reproduction. We focus on the germline-to-soma intertissue signaling mechanisms recently identified in C. elegans, which modulate systemic physiological responses during reproduction. These findings not only illuminate the trade-offs between stress resistance and reproductive capacity but also underscore the broader implications of intertissue communication in coordinating resource allocation.

Keywords:  Caenorhabditis elegans; intertissue signaling networks; mitochondrial unfolded protein response; proteostasis regulation; reproduction-associated trade-offs

DOI:  https://doi.org/10.1016/j.tem.2025.05.003
PNAS Nexus. 2025 Jun;4(6): pgaf178

Mitochondrial PTRH2 controls the deubiquitinase TRABID to regulate mt-ND5 stability and metabolism.

Carlotta Giorgi, Femke J Aan, Natalija Glibetic, Daniela Ramaccini, Lorenzo Modesti, Veronica A M Vitto, Vanessa Montoya-Uribe, Austin Corpuz, Sonia Missiroli, Inês Simões, Yaiza Potes, Mariusz R Wieckowski, Joe W Ramos, Paolo Pinton, Michelle L Matter.

  The integrin effector, PTRH2, associates with mitochondria in adherent cells where its function has not been elucidated (Jan Y, et al. 2004. A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors. Cell. 116:751-762; Griffiths GS, et al. 2011. Bit-1 mediates integrin-dependent cell survival through activation of the NF{kappa}B pathway. J Biol Chem. 286:14713-14723). PTRH2 loss-of-function mutations cause multisystem disease in children through an unknown mechanism. We sought to determine the role of mitochondrial PTRH2. We used immunoprecipitation/mass spectrometric proteomics to identify PTRH2 interacting partners: TRABID (a deubiquitinase [DUB]) and respiratory complex I NADH: ubiquinone oxidoreductase core subunit 5 (mt-ND5). We show for the first time that mitochondrial PTRH2 regulates TRABID's ability to deubiquitylate mt-ND5. In cells lacking PTRH2 expression, mt-ND5 stability is significantly increased due to aberrant TRABID-mediated deubiquitylation of mt-ND5. This increase in mt-ND5 stability promotes complex I activity and ATP production, which under stress conditions leads to mitochondrial Ca2+ overload. Reexpression of mitochondrial PTRH2 blocks TRABID-mediated mt-ND5 deubiquitylation, resulting in mt-ND5 polyubiquitylation and proteasomal degradation. Inhibiting complex I or TRABID activity rescued PTRH2 loss-of-function mutant patient cells from mitochondrial Ca2+ overload under stress. Immunostaining analysis of ptrh2+/+ and ptrh2-/- mouse skeletal muscle revealed a negative relationship between PTRH2 and mt-ND5, confirming a regulatory role for PTRH2 in controlling mt-ND5 stability. Taken together, mitochondrial PTRH2 is a regulator of metabolic homeostasis that, when lost, promotes mitochondrial Ca2+ overload when cells are exposed to stress signals. Targeting mt-ND5 stability through PTRH2-mediated regulation of TRABID's DUB function provides a novel mechanistic approach to inhibit mitochondrial Ca2+ overload in diseases that occur due to dysregulated mitochondria.

Keywords:  PTRH2; TRABID; metabolism; mitochondrial Ca2+ overload; mt-ND5

DOI:  https://doi.org/10.1093/pnasnexus/pgaf178
PLoS One. 2025 ;20(6): e0324268

Disruption of adaptive immunity does not attenuate disease in the Ndufs4(-/-) model of Leigh syndrome.

Allison R Hanaford, Asheema Khanna, Vivian Truong, Katerina James, Ryan Liao, Yihan Chen, Michael Mulholland, Ernst-Bernhard Kayser, Kino Watanabe, Erin Shien Hsieh, Philip G Morgan, Surojit Sarkar, Vandana Kalia, Simon C Johnson.

Leigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease and characterized by neurological and metabolic abnormalities. The hallmark of the disease is the presence of progressive, bilateral, symmetric neurodegenerative lesions in the brainstem and/or basal ganglia. Recent studies in the Ndufs4(-/-) mouse model of LS indicate that disease is causally driven by the immune system. Both microglia and peripherally originating macrophages are enriched in the lesions of Ndufs4(-/-) mice and pharmacologic elimination of these cell types prevents disease indicating a crucial role for innate immune cells. Here, we investigated the role of the adaptive immune system in Ndufs4(-/-) disease pathogenesis. We crossed Ndufs4(-/-) mice with mice expressing a null form of interleukin 2 receptor gamma (Il2rg) and monitored disease onset and progression. Il2rg knockout (KO) mice have dramatically depleted numbers of B-, T-, the adaptive immune system's key cellular actors, and NK-cells. We observed no difference in neurological disease progression or overall survival between Ndufs4(-/-)/Il2rg(WT) and Ndufs4(-/-)/Il2rg(KO) mice, strongly suggesting that T cells, B cells, and NK cells do not play a significant role in CNS disease pathogenesis in Ndufs4(-/-) mice. Combined with previous studies indicating a causal role for macrophages, we conclude that LS CNS pathology is primarily driven by the monocyte/macrophage innate immune system.

DOI: https://doi.org/10.1371/journal.pone.0324268
Int J Mol Sci. 2025 May 22. pii: 4969. [Epub ahead of print]26(11):

Long-Read Sequencing Identifies Mosaic Sequence Variations in Friedreich's Ataxia-GAA Repeats.

Joohyun Park, Claudia Dufke, Zofia Fleszar, Michael Schlotterbek, Elena Buena-Atienza, Lara G Stühn, Caspar Gross, Marc Sturm, Stephan Ossowski, Ludger Schöls, Olaf Riess, Tobias B Haack.

  Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by ataxia, sensory loss and pyramidal signs. While the majority of FRDA cases are caused by biallelic GAA trinucleotide repeat expansions in intron 1 of FXN, there is a subset of patients harboring a heterozygous pathogenic small variant compound-heterozygous with a GAA repeat expansion. We report on the diagnostic journey of a 21-year-old patient who was clinically suspected of having FRDA at the age of 12 years. Genetic testing included fragment analysis, gene panel analysis and exome sequencing, which only detected one pathogenic heterozygous missense variant (c.389 G>T,p.Gly130Val) in FXN. Although conventional repeat analyses failed to detect GAA expansions in our patient, subsequent short-read genome sequencing (GS) indicated a potential GAA repeat expansion. This finding was confirmed by long-read GS, which in addition revealed a complex pattern of interruptions. Both large and small GAA expansions with divergent interruptions containing G, A, GA, GAG and/or GAAG sequences were present within one allele, indicating mosaic sequence variations. Our findings underscore the complexity of repeat expansions which can exhibit both interruptions and somatic instability. We also highlight the utility of long-read GS in unraveling intricate genetic profiles, ultimately contributing to more accurate diagnoses in clinical practice.

Keywords:  FRDA; Friedreich’s ataxia; Oxford Nanopore Technologies; long-read sequencing; repeat expansion

DOI:  https://doi.org/10.3390/ijms26114969
Int J Mol Sci. 2025 Jun 05. pii: 5411. [Epub ahead of print]26(11):

Advances in Management of Mitochondrial Myopathies.

Athanasios Bangeas, Vasiliki Poulidou, Ioannis Liampas, Chrysa Marogianni, Athina-Maria Aloizou, Zisis Tsouris, Markos Sgantzos, Marianthi Arnaoutoglou, Dimitrios P Bogdanos, Efthimios Dardiotis, Vasileios Siokas.

  Mitochondria, the energy factories of human organisms, can be the cause of a variety of genetic disorders called mitochondrial myopathies. Mitochondrial diseases arise from genetic alterations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) and can manifest with great heterogeneity, leading to multiorgan dysfunction. The purpose of this article is to concisely review the pathophysiology, genetics and main clinical features of mitochondrial myopathies, focusing mainly on the treatment and management of these disorders. Currently, a particular treatment for mitochondrial myopathies does not exist, while the available guidelines concerning management are based on experts' opinions. The therapeutic options currently applied largely aim at symptom relief and amelioration of patients' quality of life. The most commonly used regimens involve the administration of vitamins and cofactors, although hard evidence regarding their true benefit for patients is still lacking. Recent studies have demonstrated promising results for elamipretide; however, phase III clinical trials are still ongoing. Regarding patient management, a multidisciplinary approach with the collaboration of different specialties is required. Further clinical trials for the already applied treatment options, as well as on novel experimental therapies, are of utmost importance in order to improve patients' outcomes.

Keywords:  management; mitochondrial myopathies; treatment

DOI:  https://doi.org/10.3390/ijms26115411
STAR Protoc. 2025 Jun 12. pii: S2666-1667(25)00286-2. [Epub ahead of print]6(2): 103880

Protocol to extract and measure ubiquinone and rhodoquinone in murine tissues.

Madison Jerome, Jessica B Spinelli.

  Ubiquinone (UQ) and rhodoquinone (RQ) are electron carriers for the electron transport chain (ETC). Here, we present a protocol for measuring UQ and RQ in mitochondria purified from murine tissues. We describe steps for isolating mitochondria by centrifugation, isolating UQ and RQ by biphasic extraction, and normalizing samples to the protein content of the mitochondrial pellet. We then detail procedures for analyzing UQ and RQ by integrating peak areas for UQ-9 and RQ-9 (abundant in mice) or UQ-10 and RQ-10 (abundant in human). Thus, through enrichment of mitochondria, we establish a method to measure UQ and RQ in tissues. For complete details on the use and execution of this protocol, please refer to Valeros et al.1.

Keywords:  cell biology; metabolism; metabolomics

DOI:  https://doi.org/10.1016/j.xpro.2025.103880
Dev Cell. 2025 May 30. pii: S1534-5807(25)00319-3. [Epub ahead of print]

AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.

Yann Cormerais, Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Jong Shin, Benjamin Stefadu, Jean Personnaz, Sandra Schrötter, Jessica Freed, Angelica D'Amore, Emma R Martin, Catherine L Salussolia, Mustafa Sahin, Suchithra Menon, Vanessa Byles, Brendan D Manning.

  Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates diverse growth signals to regulate cell and tissue growth. How the molecular mechanisms regulating mTORC1 signaling-established through biochemical and cell biological studies-function under physiological states in specific mammalian tissues is undefined. Here, we characterize a genetic mouse model lacking the five phosphorylation sites on the tuberous sclerosis complex 2 (TSC2) protein through which the growth factor-stimulated protein kinase AKT can activate mTORC1 signaling in cell culture models. These phospho-mutant mice (TSC2-5A) are developmentally normal but exhibit reduced body weight and the weight of specific organs, such as the brain and skeletal muscle, associated with cell-intrinsic decreases in growth factor-stimulated mTORC1 signaling. The TSC2-5A mice demonstrate that TSC2 phosphorylation is a primary mechanism of mTORC1 regulation in response to exogenous signals in some, but not all, tissues and provide a genetic tool to study the physiological regulation of mTORC1.

Keywords:  PI3K; RHEB; feeding; insulin; lean mass; lysosome; microcephaly; myotubes; neurons; phosphoinositide 3-kinase

DOI:  https://doi.org/10.1016/j.devcel.2025.05.008
bioRxiv. 2025 May 29. pii: 2025.05.28.656437. [Epub ahead of print]

Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.

Yash Flora, Dhriti Shastri, K Adam Bohnert.

Peroxisomes execute essential functions in cells, including detoxification and lipid oxidation. Despite their centrality to cell biology, the relevance of peroxisomes to aging remains understudied. We recently reported that peroxisomes are degraded en masse via pexophagy during early aging in the nematode Caenorhabditis elegans , and we found that downregulating the peroxisome-fission protein PRX-11/PEX11 prevents this age-dependent pexophagy and extends lifespan. Here, we further investigated how prx-11 inhibition promotes longevity. Remarkably, we found that reducing peroxisome degradation with age led to concurrent improvements in another organelle: mitochondria. Animals lacking prx-11 function showed tubular, youthful mitochondria in older ages, and these enhancements required multiple factors involved in mitochondrial tubulation and biogenesis, including FZO-1/Mitofusin, UNC-43 protein kinase, and DAF- 16/FOXO. Importantly, mutation of each of these factors negated lifespan extension in prx-11- defective animals, indicating that pexophagy inhibition promotes longevity only if mitochondrial health is co-maintained. Our data support a model in which peroxisomes and mitochondria track together with age and interdependently influence animal lifespan.

DOI: https://doi.org/10.1101/2025.05.28.656437
Nature. 2025 Jun 11.

Metabolic adaptations direct cell fate during tissue regeneration.

Almudena Chaves-Perez, Scott E Millman, Sudha Janaki-Raman, Yu-Jui Ho, Clemens Hinterleitner, Valentin J A Barthet, John P Morris, Francisco M Barriga, Jose Reyes, Aye Kyaw, H Amalia Pasolli, Dana Pe'er, Craig B Thompson, Lydia W S Finley, Justin R Cross, Scott W Lowe.

Although cell-fate specification is generally attributed to transcriptional regulation, emerging data also indicate a role for molecules linked with intermediary metabolism. For example, α-ketoglutarate (αKG), which fuels energy production and biosynthetic pathways in the tricarboxylic acid (TCA) cycle, is also a co-factor for chromatin-modifying enzymes1-3. Nevertheless, whether TCA-cycle metabolites regulate cell fate during tissue homeostasis and regeneration remains unclear. Here we show that TCA-cycle enzymes are expressed in the intestine in a heterogeneous manner, with components of the αKG dehydrogenase complex4-6 upregulated in the absorptive lineage and downregulated in the secretory lineage. Using genetically modified mouse models and organoids, we reveal that 2-oxoglutarate dehydrogenase (OGDH), the enzymatic subunit of the αKG dehydrogenase complex, has a dual, lineage-specific role. In the absorptive lineage, OGDH is upregulated by HNF4 transcription factors to maintain the bioenergetic and biosynthetic needs of enterocytes. In the secretory lineage, OGDH is downregulated through a process that, when modelled, increases the levels of αKG and stimulates the differentiation of secretory cells. Consistent with this, in mouse models of colitis with impaired differentiation and maturation of secretory cells, inhibition of OGDH or supplementation with αKG reversed these impairments and promoted tissue healing. Hence, OGDH dependency is lineage-specific, and its regulation helps to direct cell fate, offering insights for targeted therapies in regenerative medicine.

DOI: https://doi.org/10.1038/s41586-025-09097-6
Nat Med. 2025 Jun 06.

Personalized, in vivo gene editing for a newborn.

Karen O'Leary.



Keywords:  Gene therapy; Genetics; Paediatrics

DOI:  https://doi.org/10.1038/d41591-025-00037-5
BMC Med. 2025 Jun 09. 23(1): 343

Longitudinal plasma amino acids during pregnancy and neonatal anthropometry: findings from the NICHD Fetal Growth Studies-Singleton Cohort.

Claire Guivarch, Jing Wu, Ruijin Lu, Jagteshwar Grewal, Guoqi Yu, Ling-Jun Li, Jiaxi Yang, Wei Wei Pang, Dong D Wang, Natalie L Weir, Zhen Chen, Michael Y Tsai, Cuilin Zhang.

   BACKGROUND: Amino acids (AAs) during pregnancy are crucial for fetal growth. Prior studies measured AA concentrations at single time points in pregnancy, despite their fluctuations throughout pregnancy. We measured plasma AA profiles in blood samples longitudinally collected from early through late pregnancy and evaluated their associations with neonatal anthropometry.
METHODS: Concentrations of plasma aromatic AAs, branched-chain AAs, and AAs involved in one-carbon metabolism were assessed at 10-14, 15-26, 23-31, and 33-39 gestational weeks (GW) among 321 women from a case-control study from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton Cohort. Associations between AA concentrations in tertiles at each visit and neonatal anthropometric measures were assessed using weighted generalized estimating equations models, after adjusting for major confounders.
RESULTS: Women with higher concentrations of glutamine (3rd vs. 1st tertile) at 10-14 GW had offspring with greater birthweight z-score (β [95% CI] = 0.31 [0.06, 0.56], p-trend = 0.04) and birth length (1.35 cm [0.32, 2.37], p-trend = 0.04). Women with higher concentrations of aspartic acid (3rd vs. 1st tertile) at 23-31 GW, however, had offspring with smaller sum of skinfolds (- 3.9 mm [- 6.0, - 1.7], p-trend = 0.007). Similarly, women with higher concentrations of glycine (3rd vs. 1st tertile) at 10-14 GW had offspring with lower birthweight z-score (- 0.37 [- 0.65, - 0.08], p-trend = 0.04).
CONCLUSIONS: Plasma AA concentrations during pregnancy appear to play a crucial role in neonatal anthropometry. Associations were observed as early as 10 GW and varied by type of AAs and gestational age.
TRIAL REGISTRATION: Clinical Trial Registry number: NCT00912132.

Keywords:  Amino acids; Birth length; Birthweight; Neonatal anthropometry; Pregnancy; Sum of skinfolds

DOI:  https://doi.org/10.1186/s12916-025-04146-3
J Adv Res. 2025 Jun 09. pii: S2090-1232(25)00418-7. [Epub ahead of print]

Construction of mitochondrial-targeted ferritin carrier: subunit-terminal fused mitochondrial presequences facilitate efficient delivery.

Jia Zeng, Yitong Li, Xinning Fang, Han Yu, Mengyuan Xu, Xiangyu Zhao, Zhenghong Wu, Xiaole Qi.

   INTRODUCTION: Protein sorting within mitochondria is intricately linked to the amino acid sequence facilitating the transmembrane transport of proteins into this organelle. Leveraging the Mitochondrial Targeting Signal (MTS)-mediated protein sorting mechanism presents a promising strategy for directing therapeutic agents into the mitochondria.
OBJECTIVES: By fusing MTS to the subunit terminus of recombinant heavy chain ferritin (HFn), we aim to establish a highly effective mitochondrial targeting vector. This fusion is designed to enhance the ability to specifically direct and accumulate within mitochondria, and to precisely deliver Lonidamine (LND), a selective metabolic inhibitor, into these organelles, ultimately realizing potent anti-tumor activity.
METHODS: Utilizing gene engineering strategies, a plasmid encoding MTS-modified HFn (MTS-HFn) was transferred into E.coli to induce protein expression. At the cellular level, the mitochondrial targeting capacity of MTS-HFn was investigated. Subsequently, LND was encapsulated within MTS-HFn, and its tumoral accumulation and anti-tumor efficacy were studied in tumor-bearing models.
RESULTS: MTS-HFn demonstrated exceptional mitochondrial targeting, achieving a 2.7-fold higher accumulation in mitochondria compared to wild-type HFn. The targeting mechanism exploration unveiled that the positive charge of MTS drives aggregation of HFn around mitochondria, and mediates its entry into the mitochondrial matrix via the TOM/TIM complex. In vivo antitumor activity studies revealed that MTS-HFn preserved its inherent tumor targeting ability and significantly enhanced the tumor suppressive effect of LND, yielding an inhibition rate of 51.06%.
CONCLUSION: This vector inspired by natural mitochondrial protein sorting represents an optimal hierarchical delivery system for targeting both tumor and mitochondrial, offering a dependable alternative for precise treatment strategies in mitochondrial diseases.

Keywords:  Hierarchical delivery; Human ferritin nanocage; Mitochondria targeting; Mitochondrial targeting signal

DOI:  https://doi.org/10.1016/j.jare.2025.06.015
J Clin Med. 2025 May 29. pii: 3838. [Epub ahead of print]14(11):

The Role of Placental Mitochondrial Dysfunction in Adverse Perinatal Outcomes: A Systematic Review.

Charalampos Voros, Sofoklis Stavros, Ioakeim Sapantzoglou, Despoina Mavrogianni, Maria Anastasia Daskalaki, Marianna Theodora, Panagiotis Antsaklis, Peter Drakakis, Dimitrios Loutradis, Georgios Daskalakis.

  Background: Mitochondria are essential for placental function as they regulate energy metabolism, oxidative balance, and apoptotic signaling. Increasing evidence suggests that placental mitochondrial dysfunction may play a role in the development of many poor perinatal outcomes, including preeclampsia, intrauterine growth restriction (IUGR), premature birth, and stillbirth. Nonetheless, no systematic review has thoroughly investigated this connection across human research. This study aims to consolidate evidence from human research concerning the link between placental mitochondrial dysfunction and negative birth outcomes. Methods: A systematic search of PubMed, Scopus, and Web of Science identified human research examining placental mitochondrial features (e.g., mtDNA copy number, ATP production, oxidative stress indicators) in connection with adverse pregnancy outcomes. Methodological variety resulted in narrative data extraction and synthesis. Results: Twenty-nine studies met the inclusion criteria. Mitochondrial dysfunction was consistently associated with PE, IUGR, FGR, and PTB. The most often observed outcomes included diminished mtDNA copy number, decreased ATP production, elevated reactive oxygen species (ROS), and disrupted mitochondrial dynamics, characterized by increased DRP1 and decreased MFN2. Early-onset preeclampsia and symmetric fetal growth restriction exhibited particularly severe mitochondrial abnormalities, indicating a primary placental origin of the condition. Conclusions: A significant factor contributing to adverse pregnancy outcomes is the dysfunction of placental mitochondria. The analogous molecular signatures across many disorders suggest promising avenues for developing targeted therapies aimed at improving maternal-fetal health and predictive biomarkers.

Keywords:  IUGR; mitochondrial dysfunction; oxidative stress; perinatal outcomes; placenta; preeclampsia; systematic review

DOI:  https://doi.org/10.3390/jcm14113838
FASEB J. 2025 Jun 15. 39(11): e70723

Tmx2 Maintains Mitochondrial Function to Support Preimplantation Embryogenesis.

Shangrong Zhang, Qing Liu, Siyu Wang, Xiaoyu Zhang, Dingmei Qin, Ruisong Bai, Ji Chen, Zijian Ma, Zhipeng Lin, Yuheng Bi, Huan Liu, Aoxue Sun, Zhongzhi Mo, Hongcheng Wang, Xiaoqing Wu, Yong Liu.

  Thioredoxin (TRX)-related transmembrane proteins (TMX), a subgroup of the protein disulfide isomerase (PDI) family, comprise a class of transmembrane proteins with diverse biological functions. Among these, TMX2 (PDIA12) remains one of the least characterized members. Recent studies have identified missense mutations in TMX2 associated with aberrant brain development and cerebellar malformations, highlighting its potential importance in developmental processes. Notably, Tmx2 mutant embryos exhibit developmental arrest at the E3.5 stage, suggesting a critical role in preimplantation embryogenesis. However, the precise molecular and cellular functions of Tmx2 in mammalian embryonic development remain largely unexplored. In this study, we provide novel insights into the essential role of Tmx2 during preimplantation embryonic development in mice. We demonstrate that TMX2 is specifically expressed in mouse embryos, with its subcellular localization closely associated with mitochondria during the two-cell to eight-cell stages. Knockdown of Tmx2 recapitulates the phenotypic defects observed in genetic mutants, revealing a pronounced impairment in blastomere proliferation, as confirmed by EdU incorporation assays. Furthermore, TUNEL assays indicate a significant increase in apoptotic signaling in Tmx2-deficient embryos, accompanied by elevated mRNA levels of the cell cycle inhibitors p21 and p53. Mechanistically, we show that Tmx2 knockdown disrupts mitochondrial function, leading to oxidative stress and impaired mitophagy and autophagy in developing embryos. These findings suggest that Tmx2 plays a pivotal role in maintaining mitochondrial integrity and cellular homeostasis during preimplantation embryogenesis. In summary, our study elucidates the critical role of Tmx2 in preimplantation embryonic development in mice, primarily through its regulation of mitochondrial function. These results advance our understanding of the molecular mechanisms governing preimplantation embryonic development and establish Tmx2 as a key regulator of mitochondrial dynamics and cellular survival during this critical developmental window.

Keywords:   Tmx2 ; autophagy; embryo development; mice; mitochondrial dysfunction

DOI:  https://doi.org/10.1096/fj.202500640R
Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2424679122

Conformation-specific synthetic intrabodies modulate mTOR signaling with subcellular spatial resolution.

Kelly M O'Leary, Tomasz Slezak, Anthony A Kossiakoff.

  Subcellular compartmentalization is integral to the spatial regulation of mechanistic target of rapamycin (mTOR) signaling. However, the biological outputs associated with location-specific mTOR signaling events are poorly understood and challenging to decouple. Here, we engineered synthetic intracellular antibodies (intrabodies) that are capable of modulating mTOR signaling with genetically programmable spatial resolution. Epitope-directed phage display was exploited to generate high affinity synthetic antibody fragments (Fabs) against the FKBP12-Rapamycin binding site of mTOR (mTORFRB). We determined high-resolution crystal structures of two unique Fabs that discriminate distinct conformational states of mTORFRB through recognition of its substrate recruitment interface. By leveraging these conformation-specific binders as intracellular probes, we uncovered the structural basis for an allosteric mechanism governing mTOR complex 1 (mTORC1) stability mediated by subtle structural adjustments within mTORFRB. Furthermore, our results demonstrated that synthetic binders emulate natural substrates by employing divergent yet complementary hydrophobic residues at defined positions, underscoring the broad molecular recognition capability of mTORFRB. Intracellular signaling studies showed differential time-dependent inhibition of S6 kinase 1 and Akt phosphorylation by genetically encoded intrabodies, thus supporting a mechanism of inhibition analogous to the natural product rapamycin. Finally, we implemented a feasible approach to selectively modulate mTOR signaling in the nucleus through spatially programmed intrabody expression. These findings establish intrabodies as versatile tools for dissecting the conformational regulation of mTORC1 and should be useful to explore how location-specific mTOR signaling influences disease progression.

Keywords:  allosteric; inhibition; intrabody; mTOR; spatial

DOI:  https://doi.org/10.1073/pnas.2424679122
Methods Mol Biol. 2025 ;2925 203-222

Metabolic Pathway Tracing for NAD+ Synthesis and Consumption.

Tumpa Dutta, Stephen J Gardell.

  NAD+ is an abundant cellular metabolite which plays vital roles in central metabolism while serving as a cofactor for oxidoreductases and cosubstrate for sirtuins and poly(ADP-ribose)polymerases (PARPs). Decreased tissue NAD+ levels have been linked to aging-associated metabolic decline and a host of chronic diseases. Cellular steady-state NAD+ levels are governed by contemporaneous synthetic and consumptive processes. Hence, lower NAD+ levels in aged tissues can arise from decreased synthesis or increased consumption. A static snapshot of the tissue levels of NAD+ is inadequate for assessing the highly dynamic pathway network which mediates NAD+ synthesis and consumption. Metabolic pathway tracing with stable isotope-labeled NAD+ precursors (e.g., nicotinamide (NAM), nicotinic acid (NA), tryptophan) and high-resolution mass spectrometry (HRMS) can unveil the individual contributions of synthesis and consumption to the steady-state NAD+ concentration. The metabolic fate of the NAD+ precursor can also be traced to metabolic products of NAD+ including NADH, NADP, and NADPH as well as intermediates in the various NAD+ biosynthetic pathways. Metabolic tracing of NAD+ synthesis and degradation as well as conversion of NAD+ to its downstream products is a highly versatile technique. It can be used to interrogate isolated cells, tissues slices, or specimens collected from preclinical or clinical in vivo studies (e.g., blood, urine, tissues). Bold claims about the pivotal role of NAD+ in human health and disease are typically fraught with uncertainty due to an incomplete understanding of NAD+ metabolism. Insight gleaned from metabolic pathway tracing can shed important new light on NAD+ metabolism and help to critically evaluate the intriguing link between cellular NAD+ levels and healthy aging.

Keywords:  Mass isotopomer distribution profiling; Mass spectrometry; NAD+ consumption; NAD+ flux; NAD+ metabolism; NAD+ synthesis; Stable isotope tracing

DOI:  https://doi.org/10.1007/978-1-0716-4534-5_14
Nature. 2025 Jun 05.

Anti-ageing effects of popular supplement taurine challenged.

Humberto Basilio.



Keywords:  Ageing; Molecular biology

DOI:  https://doi.org/10.1038/d41586-025-01747-z
Nat Genet. 2025 Jun;57(6): 1325

In vivo epigenome editing with NovaIscB.

Wei Li.

DOI: https://doi.org/10.1038/s41588-025-02243-w
Brain. 2025 Jun 09. pii: awaf219. [Epub ahead of print]

Charcot-Marie-Tooth disease type 1E: clinical natural history and molecular impact of PMP22 variants.

Inherited Neuropathy Consortium

  Charcot-Marie-Tooth disease type 1E (CMT1E) is a rare, autosomal dominant peripheral neuropathy caused by missense variants, deletions, and truncations within the peripheral myelin protein-22 (PMP22) gene. CMT1E phenotypes vary depending on the specific variant, ranging from mild to severe, and there is little natural history and phenotypic progression data on individuals with CMT1E. Patients with CMT1E were evaluated during initial and follow-up visits at sites within the Inherited Neuropathy Consortium. Clinical characteristics were obtained from history, neurological exams, and nerve conduction studies. Clinical outcome measures were used to quantify baseline and longitudinal changes, including the Rasch-modified CMT Examination Score version 2 (CMTESv2-R) and the CMT Pediatric Scale (CMTPedS). The trafficking of PMP22 variants in transfected cells was correlated to disease severity. Twenty-four presumed disease-causing PMP22 variants were identified in 50 individuals from 35 families, including 19 missense variants, three in-frame deletions, and two truncations. Twenty-nine patients presented with delayed walking during childhood. At their baseline evaluation, the mean CMTESv2-R in 46 patients was 16 ± 7.72 (out of 32), and the mean CMTPedS from 17 patients was 28 ± 6.35 (out of 44). Six individuals presented with hearing loss, eleven with scoliosis, three with hip dysplasia, and one with both scoliosis and hip dysplasia. Twenty variants were localized within in transmembrane domains; 31 of 35 individuals with these variants had moderate to severe phenotypes. Three variants were found in the extracellular domain and were associated with milder phenotypes. Reduced expression of PMP22 at the cell surface, and the location of missense variants within in the transmembrane domain correlated with disease severity. Pathogenic PMP22 variants located within the transmembrane regions usually cause a moderate to severe clinical phenotype, beginning in early childhood, and have impaired trafficking to the plasma membrane.

Keywords:   PMP22 ; Charcot-Marie-Tooth type 1E (CMT1E); natural history

DOI:  https://doi.org/10.1093/brain/awaf219
EClinicalMedicine. 2025 Jun;84 103265

Safety and efficacy of leriglitazone in childhood cerebral adrenoleukodystrophy (NEXUS): an interim analysis of an open-label, phase 2/3 trial.

Ángeles García-Cazorla, Caroline Sevin, Juliana Ribeiro Constante, Elise Yazbeck, Hendrik Rosewich, Sandra Jimenez, Gloria Chia-Yi Chiang, Otto Rapalino, Paul Caruso, Daniel Balentine, Karl G Helmer, Seth Bennett, Marco Emanuele, Laura Rodriguez-Pascau, Pilar Pizcueta, Guillem Pina, Anna Vilà, Maria Rovira, Adriana Mantilla, Uwe Meya, Arun Mistry, María Pascual, Sílvia Pascual, Marc Martinell, Patricia L Musolino, Eric Mallack.

   Background: Cerebral adrenoleukodystrophy rapidly progresses in approximately 90% of untreated patients. Current treatment, haematopoietic stem-cell transplantation (HSCT), is associated with high morbidity and is not widely available. Lower risk treatments that can be administered immediately upon lesion identification are needed. Leriglitazone, a peroxisome proliferator-activated receptor gamma agonist, may slow disease progression.
Methods: NEXUS (NCT04528706), a 96-week, phase 2/3, open-label, multicentre study conducted between February 13, 2020 and April 2025, enrolled boys aged 2-12 years with X-linked adrenoleukodystrophy with white matter lesions. Participants received oral leriglitazone once-daily. The primary endpoint is the proportion of patients with arrested disease at week 96. This predefined interim analysis assessed the continuation criteria at week 24, defined as the proportion of patients with lesion growth deceleration or disease arrest (success: one-sided 95% CI >10%). Secondary endpoints were the change from baseline in neurologic function score (NFS), Loes score and gadolinium intensity score (GIS), the overall survival of patients remaining on leriglitazone, and the number of patients meeting study HSCT criteria.
Findings: Eleven patients were evaluable at week 24 and all met the continuation criteria. All remained clinically stable and showed lesion growth deceleration. Five (45%, 95% CI 16·7-76·6) had arrested disease. NFS, Loes score, and GIS stabilised by week 24 in most patients. Survival of patients who remained on leriglitazone was 100% (95% CI 69·2-100·0). Five patients met the study HSCT criteria owing to persistent gadolinium enhancement but had no significant lesion growth. Leriglitazone was well tolerated; 87 adverse events occurred and there were no treatment-related serious adverse events.
Interpretation: All evaluable patients met the continuation criteria. Clinical and radiological data suggest deceleration of disease progression compared with available natural history data, indicating that leriglitazone may be beneficial in boys with cerebral adrenoleukodystrophy. Additional follow-up will fully assess the safety and efficacy of leriglitazone in cerebral adrenoleukodystrophy.
Funding: Minoryx Therapeutics.

Keywords:  Cerebral adrenoleukodystrophy; PPARγ agonist; Paediatric adrenoleukodystrophy

DOI:  https://doi.org/10.1016/j.eclinm.2025.103265
Brain. 2025 Jun 10. pii: awaf223. [Epub ahead of print]

Disease spectrum and long-term prognosis of patients with BAG3-associated neuromuscular diseases in Europe.

Gorka Fernández-Eulate, Cyril Gitiaux, Simone Thiele, Heinz Jungbluth, Anna Potulska-Chromik, Chiara Marini-Bettolo, Jean Baptiste Davion, Germán Morís, Eduard Gallardo, Montsé Olivé, Carlos Pablo de Fuenmayor-Fernández de la Hoz, Frederique Audic, Arnaud Isapof, Maggie C Walter, Corrado Angelini, Enrico Bertini, Ulrike Schara-Schmidt, Kristl G Claeys, Maike F Dohrn, Mohamed Dembele, Frederic Fer, Guy Brochier, Teresinha Evangelista, Anna Kostera-Pruszczyk, Shahram Attarian, Volker Straub, Cristina Dominguez-Gonzalez, John Vissing, Pascale Richard, Corinne Metay, Diala Khraiche, Karim Wahbi, Tanya Stojkovic.

  De novo or autosomal dominant BAG3 gene variants cause a wide range of skeletal and cardiac muscle diseases encompassing Charcot-Marie-Tooth disease, myofibrillar myopathy, cardiomyopathy or a combination of them. Given the severity and rarity of BAG3-neuromuscular diseases (NMD), series of patients are lacking. Our aim was to characterize the clinical and genetic spectrum as well as the natural history of BAG3-NMD in Europe. In this multicentre retrospective study, we collected clinical, ancillary, and genetic data of patients with NMD and BAG3 variants, identified from European paediatric and adult neuromuscular reference centres from May to December 2023 following a call circulated through the European Reference Network EURO-NMD and other partners. Responses were received from 35 centres in 17 countries. Twenty-six patients (65.4% males, 34.6% females) with BAG3-NMD from 18 different families were included in the study. The c.626C>T p.(Pro209Leu) variant, carried by 16 patients, was the only recurrent variant and was associated with a homogeneous and severe phenotype, with predominantly lower-limb motor weakness (n=13, 81.25%) or heart failure (n=3, 18.75%) as the presenting feature, and a mean age at symptom onset of 7.8±3.4 years. Where available (n=13), electroneuromyography showed a polyneuropathy with demyelinating features and a frequently associated myopathy. Eleven (68.8%) patients had restrictive cardiomyopathy on initial assessment. Orthopaedic manifestations were common, with contractures (n=15, 93.8%), foot deformities (n=11, 84.6%), and scoliosis and/or rigid spine (n=12, 80%). At last follow-up (age 21.5±8.6 years), of the patients carrying the p.(Pro209Leu) variant, 10 (62.5%) had lost ambulation, 14 (93.3%) had respiratory insufficiency (11 requiring ventilation), and 12 (75%) had a restrictive cardiomyopathy, leading to heart failure and heart transplantation in five and four patients, respectively. Eight (50%) patients died prematurely at a mean age of 22.5±9.6 years, most frequently from sudden death (n=5). The other 10 patients carried three other BAG3 variants, and showed a milder disease course, with all patients remaining ambulatory, without cardiorespiratory manifestations at last follow-up. The p.(Arg309*) nonsense variant, known to cause isolated dilated cardiomyopathy, as well as the p.(Val505Glyfs*6) frameshift variant resulting in a premature stop codon, caused distal hereditary motor neuropathy. This is the largest study of patients with BAG3-NMD, delineating the frequency, specific presentation, and the natural history in patients with the recurrent BAG3 p.(Pro209Leu) missense variant, crucial for informing patient management in the context of a rapidly progressive disease. All other BAG3 variants were rare and caused milder clinical presentations.

Keywords:  BAG3; autophagy; cardiomyopathy; neuromyopathy

DOI:  https://doi.org/10.1093/brain/awaf223
J Am Heart Assoc. 2025 Jun 12. e038505

Omaveloxolone, But Not Dimethyl Fumarate, Improves Cardiac Function in Friedreich's Ataxia Mice With Severe Cardiomyopathy.

Lili Salinas, Francisco Figueroa, Claire B Montgomery, Phung N Thai, Nipavan Chiamvimonvat, Gino Cortopassi, Elena N Dedkova.

   BACKGROUND: Friedreich's ataxia (FA) is a genetic disorder caused by a severe decrease in FXN (frataxin) protein expression in mitochondria. The clinical manifestation of this disorder is a cerebellar ataxia; however, the common lethal component in FA is cardiomyopathy.
METHODS: A conditional Fxnflox/null::MCK-Cre knockout (FXN-cKO) mouse model was used to mimic the late-stage severe cardiomyopathy in FA. Nrf2 (nuclear factor erythroid 2-related factor 2) inducers, omaveloxolone and dimethyl fumarate (DMF), were independently tested in this mouse model to determine the effects on cardiac health and lifespan.
RESULTS: Omaveloxolone significantly improved cardiac contractile function and markers of heart failure in FA such as Nppb, Aldh1a3, and Gdf15. Despite improvement in cardiac function, omaveloxolone did not prevent premature death in FXN-cKO animals and notably accelerated death in FXN-cKO females. Omaveloxolone decreased oxidative stress and inflammatory marker IL1β (interleukin-1 beta), and stimulated Nqo1 gene expression above control level. DMF restored elevated HO-1 (Hmox) expression and significantly increased Sirt1 expression. Although both omaveloxolone and DMF restored decreased SERCA2 (Atp2a) and MCU (Mcu) expression and ameliorated elevated phosphorylation of CaMKIIδ at Thr286 site in FA hearts, DMF did not improve cardiac contractile function and survival. Furthermore, neither omaveloxolone or DMF decreased hypertrophy and fibrosis (Masson trichrome staining and Lgals3 expression) or rescued impaired mitochondrial function and integrative stress response in FXN-cKO hearts.
CONCLUSIONS: These data demonstrate that omaveloxolone significantly improved contractile function but not survival in FA hearts because cardiac fibrosis and wall stress persisted even with omaveloxolone treatment. More studies are warranted to determine the cause of premature death in omaveloxolone-treated FXN-cKO female mice.

Keywords:  Friedreich's ataxia; animal models of human disease; calcium signaling; cardiomyopathy; dimethyl fumarate; omaveloxolone

DOI:  https://doi.org/10.1161/JAHA.124.038505
Nat Aging. 2025 Jun 11.

Using RNA therapeutics to promote healthy aging.

Shuying Chen, Qian Chen, Xinru You, Zhuoming Zhou, Na Kong, Fabrisia Ambrosio, Yihai Cao, Reza Abdi, Wei Tao.

Aging is characterized by a gradual decline of cellular and physiological functions over time and an increased risk of different diseases. RNA therapeutics constitute an emerging approach to target the molecular mechanisms of aging and age-related diseases via rational design and have several advantages over traditional drug therapies, including high specificity, low toxicity and the potential for rapid development and production. Here, we discuss the latest developments in RNA therapeutics designed to promote healthy aging, including RNA activation, messenger RNA therapy, RNA interference, antisense oligonucleotides, aptamers and CRISPR-Cas-mediated RNA editing. We also review the latest preclinical and clinical studies of RNA technology for treating age-related diseases, including neurodegenerative, cardiovascular and musculoskeletal diseases. Finally, we discuss the challenges of RNA technology aimed at supporting healthy aging. We anticipate that the fusion of RNA therapeutics and aging biology will have an important effect on the development of new medicines and maximization of their efficacy.

DOI: https://doi.org/10.1038/s43587-025-00895-1
Nature. 2025 Jun 11.

Early life high fructose impairs microglial phagocytosis and neurodevelopment.

Zhaoquan Wang, Allie Lipshutz, Celia Martínez de la Torre, Alissa J Trzeciak, Zong-Lin Liu, Isabella C Miranda, Tomi Lazarov, Ana C Codo, Jesús E Romero-Pichardo, Achuth Nair, Tanya Schild, Waleska Saitz Rojas, Pedro H V Saavedra, Ann K Baako, Kelvin Fadojutimi, Michael S Downey, Frederic Geissmann, Giuseppe Faraco, Li Gan, Jon Iker Etchegaray, Christopher D Lucas, Marina Tanasova, Christopher N Parkhurst, Melody Y Zeng, Kayvan R Keshari, Justin S A Perry.

Despite the success of fructose as a low-cost food additive, epidemiological evidence suggests that high fructose consumption during pregnancy or adolescence is associated with disrupted neurodevelopment1-3. An essential step in appropriate mammalian neurodevelopment is the phagocytic elimination of newly formed neurons by microglia, the resident professional phagocyte of the central nervous system4. Whether high fructose consumption in early life affects microglial phagocytosis and whether this directly affects neurodevelopment remains unknown. Here we show that offspring born to female mice fed a high-fructose diet and neonates exposed to high fructose exhibit decreased phagocytic activity in vivo. Notably, deletion of the high-affinity fructose transporter GLUT5 (also known as SLC2A5) in neonatal microglia completely reversed microglia phagocytic dysfunction, suggesting that high fructose directly affects neonatal development by suppressing microglial phagocytosis. Mechanistically, we found that high-fructose treatment of mouse and human microglia suppresses phagocytosis capacity, which is rescued in GLUT5-deficient microglia. Additionally, we found that high fructose drives significant GLUT5-dependent fructose uptake and catabolism to fructose 6-phosphate, rewiring microglial metabolism towards a hypo-phagocytic state in part by enforcing mitochondrial localization of the enzyme hexokinase 2. Mice exposed to high fructose as neonates develop anxiety-like behaviour as adolescents-an effect that is rescued in GLUT5-deficient mice. Our findings provide a mechanistic explanation for the epidemiological observation that high-fructose exposure during early life is associated with increased prevalence of adolescent anxiety disorders.

DOI: https://doi.org/10.1038/s41586-025-09098-5
Biol Sex Differ. 2025 Jun 10. 16(1): 40

Association of placental mitochondrial DNA mutations on infant negative affectivity: modifying effects of maternal lifetime stress and infant sex.

Agathe M de Pins, Hsiao-Hsien Leon Hsu, Rosalind J Wright, Kelly J Brunst.

  Neuropsychiatric and behavioral disorders impact over 15% of U.S. children, with sex differences in manifestation. Prenatal exposure to psychosocial stress predicts adverse neurodevelopmental outcomes, particularly during gestation. Mechanisms remain poorly understood. Research links prenatal stress exposures with placental mitochondrial DNA (mtDNA) mutational load, suggesting that disrupted mitochondrial placental function may play a role. We conceptualize that placental mitochondrial biomarkers reflect environmentally-induced oxidation that may contribute to mechanisms influencing neurodevelopment. Furthermore, as maternal stress can impact female and male children differently, this may in part explain sex differences in early childhood neurobehavioral outcomes. This study explores the association between placental mtDNA mutational load and negative affectivity in infants, and whether these associations are modified by maternal lifetime stress and fetal sex. Placenta samples (N = 394) were collected at delivery and whole mtDNA sequencing was performed to identify gene-specific mutational loads. Mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R) when children were 6.69 ± 1.61 months of age and the Negative Affectivity factor was derived. Multivariable regression analyses were performed to model Negative Affectivity in relation to placental mtDNA mutational load, first adjusting for child sex and maternal age, self-reported race, and education. Lastly, we examined effect modification by maternal stress and fetal sex using cross-product terms and contrast statements. Results showed that higher mutational load in the MT_CYB region was positively associated with increased negative affectivity. Notably, interactions between mtDNA regions (MT_DLOOP and MT_ND), child sex, and maternal stress revealed that girls with higher mutational loads in these regions were at greater risk for increased negative affectivity, particularly under high maternal stress. These findings suggest that placental mtDNA mutational load could serve as a biomarker for neurodevelopmental risk, with sex-specific vulnerabilities influenced by maternal stress. This study underscores the importance of considering both environmental factors and sex differences in understanding early neurodevelopmental trajectories, and the potential of the placenta as a tool for early detection and intervention. Further research is needed to validate these findings and explore their implications for long-term child development. Highlights Increased mutational load in the cytochrome B region of placental mtDNA is associated with higher infant negative affectivity. Girls exhibited greater sensitivity to mutations in the mitochondrial D-loop and NADH dehydrogenase regions, showing stronger links to negative affectivity compared to boys. Higher maternal lifetime stress amplified the impact of mitochondrial NADH dehydrogenase mutational load on negative affectivity in girls, highlighting gene-environment interactions. Findings underscore the placenta's role in integrating environmental and genetic factors that influence early temperament, and its potential role as a future biomarker. This is the first study connecting placental mitochondrial DNA mutations with infant temperament in a diverse population, revealing sex-specific and stress-modulated effects.

Keywords:  Maternal stress; Mitochondria; Negative affectivity; Neurodevelopment; Placenta

DOI:  https://doi.org/10.1186/s13293-025-00717-4
iScience. 2025 Jun 20. 28(6): 112590

Deleterious mitochondrial heteroplasmies exhibit increased longitudinal change in variant allele fraction.

Lieke M Kuiper, Wen Shi, Joost A M Verlouw, Yun Soo Hong, Pascal Arp, Daniela Puiu, Linda Broer, Jiaqi Xie, Charles Newcomb, Stephen S Rich, Kent D Taylor, Jerome I Rotter, Joel S Bader, Eliseo Guallar, Joyce B J van Meurs, Dan E Arking.

  A common feature of human aging is the acquisition of somatic mutations, and mitochondria are particularly prone to mutation, leading to a state of mitochondrial DNA heteroplasmy. Cross-sectional studies have demonstrated that detection of heteroplasmy increases with participant age, a phenomenon that has been attributed to genetic drift. In this large-scale longitudinal study, we measured heteroplasmy in two prospective cohorts (combined n = 1404) at two time points (mean time between visits, 8.6 years), demonstrating that deleterious heteroplasmies were more likely to increase in variant allele fraction (VAF). We further demonstrated that increase in VAF was associated with increased risk of overall mortality. These results challenge the claim that somatic mtDNA mutations arise mainly due to genetic drift, instead suggesting a role for positive selection for a subset of predicted deleterious mutations at the cellular level, despite a negative impact of these mutations on overall mortality.

Keywords:  Cell biology; Genetics

DOI:  https://doi.org/10.1016/j.isci.2025.112590
Trends Pharmacol Sci. 2025 Jun 10. pii: S0165-6147(25)00100-2. [Epub ahead of print]

At last: the mitochondrial pyruvate carrier structure revealed!

Brian N Finck, Christy M Hadfield, Kyle S McCommis.

  Mitochondrial pyruvate carrier (MPC) inhibitors have shown promise as therapeutics for treating several chronic diseases. However, the structure of MPC and the molecular mechanisms by which it interacts with inhibitors have remained unclear, impeding rational drug design. Multiple groups have now independently resolved the structure of the MPC heterodimer.

Keywords:  MPC; cryoEM; mitochondria; pyruvate

DOI:  https://doi.org/10.1016/j.tips.2025.05.010
Am J Pathol. 2025 Jun 09. pii: S0002-9440(25)00188-9. [Epub ahead of print]

Nitric Oxide may Adversely Affect the Metabolism and Viability of Retinal Organoids Derived from Patients with Leber Hereditary Optic Neuropathy.

Fumio Takano, Megumi Kitamura, Kaori Ueda, Makoto Nakamura.

  Leber hereditary optic neuropathy (LHON) is a bilateral optic neuropathy associated with mitochondrial DNA (mtDNA) mutations characterized by parapapillary telangiectasia during the acute phase. However, its precise mechanism remains unclear. This study evaluated the effects of nitric oxide (NO) on retinal organoids (ROs) generated from induced pluripotent stem (iPS) cells derived from patients with LHON. Established iPS cells from three patients with the m.11778G>A mutation (patient group) and three healthy individuals (control group) were differentiated into ROs. Changes in cell death ratios, mtDNA copy number, and metabolite profiles in the ROs following exposure to sodium nitroprusside (SNP), which was an NO donor, were compared between the two groups. At baseline, terminal d-UTP nick end labeling (TUNEL)-positive cell ratios did not differ significantly, whereas the mtDNA copy number was significantly higher in the patient group. SNP exposure significantly increased the proportion of TUNEL-positive cells in the patient group but did not affect the mtDNA copy number. Relative concentrations of metabolites, including taurine and GABA, initially reduced in the patient group, increased following SNP exposure. These findings suggest that NO may promote retinal cell death and disrupt metabolite profiles in ROs derived from patients with LHON.

Keywords:  Leber hereditary optic neuropathy; induced pluripotent stem cell; nitric oxide; retinal organoid

DOI:  https://doi.org/10.1016/j.ajpath.2025.05.006
Front Immunol. 2025 ;16 1597370

Mitochondrial metabolic rescue in post-COVID-19 syndrome: MR spectroscopy insights and precision nutritional therapeutics.

Li-Zhen Chen, Qi Cai, Peng-Fei Zheng.

  Post-COVID-19 Condition (PCC), impacting 30-90% of survivors, is characterized by persistent fatigue and metabolic dysfunction, often linked to underlying mitochondrial impairment. This review examines current evidence on mitochondrial-targeted nutrition therapies, with a focus on magnetic resonance spectroscopy (MRS) as a tool for assessing metabolic recovery. Key findings highlight reduced adenosine triphosphate (ATP) production, heightened oxidative stress, and disrupted mitochondrial biogenesis- metabolic abnormalities that closely mirror those seen in chronic fatigue syndromes. While mitochondrial dysfunction is recognized as central, debate continues on whether systemic inflammation or direct viral damage primarily drives these abnormalities. Current evidence supports nutrients, such as, CoQ10, NAC, and creatine for restoring energy metabolism and reducing oxidative stress. MRS biomarkers (τPCr, Qmax), offer valuable tools for monitoring personalized intervention. However, several limitations persist, including variability in nutritional protocols, inconsistencies in MRS methodologies, and limited consideration of microbiome-psychosocial interactions. Most clinical trials focus on short-term outcomes, lacking data on long-term efficacy or stratification based on mitochondrial dysfunction severity. Future research priorities include multi-omics investigations into mitochondrial-epigenetic interactions, the development of targeted antioxidants, and exploration of engineered microbial metabolites. Standardizing MRS protocols, validating composite endpoints, and optimizing nutrient delivery systems require interdisciplinary collaboration. This review advocates for a precision medicine approach, combining MRS-based metabolic profiling with personalized nutritional strategies, to address the multifactorial nature of PCC and advance clinical translation.

Keywords:  magnetic resonance spectroscopy; mitochondrial dysfunction; nutrition; post-COVID-19 condition; precision medicine

DOI:  https://doi.org/10.3389/fimmu.2025.1597370