bims-mitmed 2025-09-14 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–09–14
24 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
Mending a mother's mitochondrial DNA.
Mitochondrial Transplantation Therapy: A Novel Approach in the Era of Organelle-Centered Regenerative Medicine.
Assessing a Mitochondrial Disease Treatment via a Novel Statistical Technique for Accelerometer Data.
OXPHOS complex deficiency in congenital myopathy: A systematic review.
Structural insights into DdCBE in action enable high-precision mitochondrial DNA editing.
Estradiol alleviates disease phenotypes caused by m.3635G > a mutations by activating mitochondrial biogenesis and PINK1-Parkin mediated mitophagy in iPSC-derived retinal pigment epithelium cells.
Preclinical and first-in-human evidence of 4-hydroxybenzoic acid for mitochondrial COQ2 deficiency.
ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation.
Sex-specific alterations in placental mitochondria, oxidative damage and apoptosis in mice of advanced maternal age.
Emerging strategies, applications and challenges of targeting NAD+ in the clinic.
Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.
Abundance of Maternal Mitochondrial Genome Is Dispensable up to the Mitochondrial Genome Activation in Post-Implantation Embryos.
Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
An iPSC-derived neuronal model reveals manganese's role in neuronal endocytosis, calcium flux and mitochondrial bioenergetics.
Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.
LONP1 Variants Are Associated With Clinically Diverse Phenotypes.
The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus.
Exposure to an environmentally relevant mixture of polychlorinated biphenyls affects mitochondrial bioenergetics and plasticity.
CRISPR/Cas9-mediated editing of COQ4 in induced pluripotent stem cells: A model for investigating COQ4-associated human coenzyme Q10 deficiency.
Matrix directs trophoblast differentiation in a bioprinted organoid model of early placental development.
Neuroimaging in Cerebellar Ataxias: A Diagnostic Approach.
SIRT2 and NAD+ Boosting Broadly Suppress Aging-Associated Inflammation.
Recessive variants in TWNK cause syndromic and non-syndromic post-synaptic auditory neuropathy through MtDNA replication defects.

EMBO J. 2025 Sep 08.

Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.

Amanda L Gunawan, Irene Liparulo, Andreas Stahl.

  A variety of stressors, including environmental insults, pathological conditions, and transition states, constantly challenge cells that, in turn, activate adaptive responses to maintain homeostasis. Mitochondria have pivotal roles in orchestrating these responses that influence not only cellular energy production but also broader physiological processes. Mitochondria contribute to stress adaptation through mechanisms including induction of the mitochondrial unfolded protein response (UPRmt) and the integrated stress response (ISR). These responses are essential for managing mitochondrial proteostasis and restoring cellular function, with each being tailored to specific stressors and cellular milieus. While excessive stress can lead to maladaptive responses, mitohormesis refers to the beneficial effects of low-level mitochondrial stress. Initially studied in invertebrates and cell cultures, recent research has expanded to mammalian models of mitohormesis. In this literature review, we describe the current landscape of mammalian mitohormesis research and identify mechanistic patterns that result in local, systemic, or interorgan mitohormesis. These investigations reveal the potential for targeting mitohormesis for therapeutic benefit and can transform the treatment of diseases commonly associated with mitochondrial stress in humans.

Keywords:  Integrated Stress Response; Mammalian Models; Mitochondrial Retrograde Signaling; Mitochondrial Unfolded Protein Response (UPRmt); Mitohormesis

DOI:  https://doi.org/10.1038/s44318-025-00549-3
Nat Med. 2025 Sep 12.

Mending a mother's mitochondrial DNA.

Mike May.

DOI: https://doi.org/10.1038/d41591-025-00056-2
Front Biosci (Landmark Ed). 2025 Aug 18. 30(8): 37006

Mitochondrial Transplantation Therapy: A Novel Approach in the Era of Organelle-Centered Regenerative Medicine.

Ha Rim Shin, Gaheon Lee, Kyung Hwa Kim.

  Mitochondria play crucial roles in maintaining health and influencing disease progression by acting as central regulators of cellular homeostasis and energy production. Dysfunctions in mitochondrial activity are increasingly recognized as key contributors to various pathologies, ultimately impacting healthspan and disease outcomes. However, traditional treatments often do not restore damaged mitochondria to a healthy state. Mitochondrial transplantation, a cellular organelle-based therapy in which mitochondria are introduced into a recipient, has emerged as a novel concept in next-generation therapeutics that overcomes the limitations of current cell-based treatments. This review highlights the unique properties of mitochondria as therapeutic agents, including their ability to restore cellular functions and treat a wide range of diseases. In this review, we focus on the unique role of mitochondria in the regulation of stem cell functions, including stem cell fate, self-renewal, and differentiation. Various perspectives have been explored to better understand mitochondrial transplantation therapy, which harnesses the capacity of mitochondria as living drugs in regenerative medicine, as an innovative strategy to bridge the gap between cell therapy and organelle-based treatments and overcome current clinical barriers.

Keywords:  mesenchymal stem cell; mitochondrial dysfunction; mitochondrial transplantation; organelle transplantation; regenerative medicine

DOI:  https://doi.org/10.31083/FBL37006
Ann Clin Transl Neurol. 2025 Sep 12.

Assessing a Mitochondrial Disease Treatment via a Novel Statistical Technique for Accelerometer Data.

Ian W McKeague, Kristin Engelstad, Yue Ge, Amber Tucker, Shufang Li, Jasim Uddin, Ziwei Zhao, John L P Thompson, Michio Hirano.

   OBJECTIVE: Therapeutic development for mitochondrial diseases, rare genetic disorders with pathogenic defects of oxidative phosphorylation, is hindered by unsatisfactory outcome measures. To address this problem, we provide the first clinical application of a novel, bias-adjusted outcome measure of acceleration across a range of subjects' activities to assess nucleoside therapy for thymidine kinase 2 deficiency, an ultra-rare autosomal recessive mitochondrial disease.
METHODS: Data were collected from treated patients in an ongoing phase 2 clinical trial who served as their own controls. If there is a treatment effect, time-in-activity curves for these patients will increase over successive clinic visits. We used a combination of functional data analysis and longitudinal mixed-effects linear regression, adjusted for age and gender, to test for the effect of treatment length on time-in-activity.
RESULTS: For 14 patients with at least two assessments 6 months apart, we found a significant overall improvement of time-in-activity due to treatment. Improvement was especially significant at two individual activity levels within the range (0.14 and 2 g). In longitudinal analyses, using data on time-in-activity at these two levels for all clinic visits of 19 subjects, the effect of treatment length on time-in-activity was highly significant at both 0.14 g (0.04, CI 0.01-0.08, p = 0.023) and 2 g (0.01, 0.00-0.02, p = 0.013).
INTERPRETATION: This small-N exploratory analysis using a new accelerometer-based activity measure featuring powerful data reduction and adjustment for circadian rhythms and other biases finds that nucleoside therapy may increase activity levels in thymidine kinase 2 deficiency patients.

Keywords:  accelerometer; mitochondrial disease; outcome measure; thymidine kinase 2 deficiency

DOI:  https://doi.org/10.1002/acn3.70180
Eur J Clin Invest. 2025 Sep 11. e70114

OXPHOS complex deficiency in congenital myopathy: A systematic review.

Megan J du Preez, Maryke Schoonen, Monray E Williams, Michelle Bisschoff, Francois H van der Westhuizen.

   BACKGROUND: Congenital myopathies are inherited neuromuscular disorders characterized by early-onset muscle weakness and distinct histopathological features. Although mitochondrial involvement in congenital myopathy is well recognized in its pathophysiology, oxidative phosphorylation (OXPHOS) complex dysfunction, which is associated with primary mitochondrial diseases (MD), is not. This systematic review aimed to evaluate the prevalence and characteristics of reported OXPHOS complex dysfunction in genetically confirmed congenital myopathy cases.
METHODS: A systematic literature search was conducted in PubMed, Scopus and Web of Science. The search strategy was developed according to PRISMA guidelines. Two independent reviewers screened the studies for inclusion. Eligible studies reported genetically confirmed congenital myopathy cases or disease models and included diagnostic OXPHOS complex analyses via enzyme kinetic assays and/or protein/RNA expression.
RESULTS: Of 5841 studies screened, 23 publications (2009-2025) met the inclusion criteria, comprising 45 congenital myopathy cases. OXPHOS complex dysfunction was reported in 78% of these cases, including all human cases where OXPHOS enzymology was performed. Nine congenital myopathy-associated genes were involved in the cases, with RYR1 being the most frequent. No definitive genotype-phenotype relationship was established between specific genes and affected complexes.
CONCLUSIONS: OXPHOS complex dysfunction in congenital myopathy appears to be more prevalent than previously recognized, challenging the traditional view that associates such dysfunction exclusively with MD. This emerging evidence suggests that mitochondrial involvement in congenital myopathy is not incidental but may represent a meaningful aspect of its pathophysiology. The potential dysregulation of OXPHOS in congenital myopathy has implications for refining diagnostic frameworks for both congenital myopathy and MD.

Keywords:  congenital myopathy; good health and well‐being; mitochondrial disease; mitochondrial dysfunction; neuromuscular diseases diagnosis; oxidative phosphorylation

DOI:  https://doi.org/10.1111/eci.70114
Mol Cell. 2025 Sep 03. pii: S1097-2765(25)00701-4. [Epub ahead of print]

Structural insights into DdCBE in action enable high-precision mitochondrial DNA editing.

Jiangchao Xiang, Wenchao Xu, Jing Wu, Yaxin Luo, Chengyu Liu, Yaofeng Hou, Jia Chen, Bei Yang.

  DddA-derived cytosine base editor (DdCBE) couples transcription activator-like effector (TALE) arrays and the double-stranded DNA (dsDNA)-specific cytidine deaminase DddA to target mitochondrial DNA (mtDNA) for editing. However, structures of DdCBE in action are unavailable, impeding its mechanistic-based optimization for high-precision-demanding therapeutic applications. Here, we determined the cryo-electron microscopy (cryo-EM) structures of DdCBE targeting two native mitochondrial gene loci and combined editing data from systematically designed spacers to develop WinPred, a model that can predict DdCBE's editing outcome and guide its design to achieve high-precision editing. Furthermore, structure-guided engineering of DddA narrowed the editing window of DdCBE to 2-3 nt while minimizing its off-target (OT) editing to near-background levels, thereby generating accurate DdCBE (aDdCBE). Using aDdCBE, we precisely introduced a Leber hereditary optic neuropathy (LHON)-disease-related mutation into mtDNA and faithfully recapitulated the pathogenic conditions without interference from unintended bystander or OT mutations. Our work provides a mechanistic understanding of DdCBE and establishes WinPred and aDdCBE as useful tools for faithfully modeling or correcting disease-related mtDNA mutations.

Keywords:  DdCBE; DddA engineering; cryo-EM structure; editing precision; editing window; mitochondrial DNA; mitochondrial disease modeling

DOI:  https://doi.org/10.1016/j.molcel.2025.08.016
Cell Signal. 2025 Sep 08. pii: S0898-6568(25)00536-4. [Epub ahead of print]136 112121

Estradiol alleviates disease phenotypes caused by m.3635G > a mutations by activating mitochondrial biogenesis and PINK1-Parkin mediated mitophagy in iPSC-derived retinal pigment epithelium cells.

Chao Hu, Tianhong Su, Ying Zhang, Jing Yang, Xun Su, Zhikang Zhang, Xin Wang, Weiwei Zou, Dan Liang, Yajing Liu, Dongmei Ji, Yunxia Cao.

  Leber's hereditary optic neuropathy (LHON), a mitochondrial disorder marked by central vision loss, exhibits incomplete penetrance and male predominance. Since there are no adequate models for understanding the rapid vision loss associated with LHON, we generated induced pluripotent stem cells (iPSCs) from LHON patients carrying the pathogenic m.3635G > A mutation and differentiated them into retinal pigment epithelium (RPE) cells. The mutation disrupted mitochondrial dynamics, suppressing OPA1-mediated fusion and enhancing DRP1-dependent fission, resulting in decreased expression of ND1, ND5, NDUFB8, SDHB and COX2, impaired mitochondrial bioenergetic function, and cell proliferation. Additionally, the m.3635G > A mutation promoted intrinsic apoptosis, altered autophagic flux, evidenced by elevating levels in apoptotic proteins PARP1, caspase-3, and 9, reduced levels of autophagy protein LC3-II, and increased levels of substrate P62. Moreover, the m.3635G > A mutation inhibited PINK1-Parkin-dependent mitophagy. Based on sex-specific differences in hormone metabolism, we proposed that estrogen plays a protective role in women and showed that estrogen receptor α and β were downregulated in LHON. We demonstrated that estradiol improved cell viability by reducing apoptosis, inducing mitochondrial biogenesis through the PGC1α-NRF1/2-TFAM axis, and vigorously promoting PINK1-Parkin-dependent mitophagy in LHON iPSCs and iPSC-derived RPE cells. Our findings have highlighted the critical role of the m.3635G > A mutation in the pathogenetic process of LHON, and our observations support the hypothesis that estrogen is helpful in the preventive treatment of LHON.

Keywords:  Autophagy; Induced pluripotent stem cell; Leber's hereditary optic neuropathy (LHON); Mitochondrial disease; Mitophagy; mtDNA mutation

DOI:  https://doi.org/10.1016/j.cellsig.2025.112121
Brain. 2025 Sep 10. pii: awaf334. [Epub ahead of print]

Preclinical and first-in-human evidence of 4-hydroxybenzoic acid for mitochondrial COQ2 deficiency.

Felix Distelmaier, Julia Corral-Sarasa, Laura Jiménez-Sánchez, María Elena Díaz-Casado, Melanie Rohmann, Annette Seibt, Diran Herebian, Sander H J Smits, Juliane Münch, Ertan Mayatepek, Jörg Breitkreutz, Ralf A Husain, Sergio López-Herrador, Pilar González-García, Luis C López.

  Primary coenzyme Q (CoQ) deficiency is a mitochondrial disorder with variable clinical presentation and limited response to standard CoQ10 supplementation. Recent studies suggest that 4-hydroxybenzoic acid (4-HBA), a biosynthetic precursor of CoQ, may serve as a substrate enhancement treatment in cases caused by pathogenic variants in COQ2, a gene encoding a key enzyme in CoQ biosynthesis. However, it remains unclear whether 4-HBA is required throughout life to maintain health, whether it offers advantages over CoQ10 treatment, and whether these findings are translatable to humans. Here, we demonstrate that lifelong 4-HBA supplementation in a murine model carrying the pathogenic Coq2A252V variant is well tolerated and prevents the onset of mitochondrial encephalopathy. In contrast, withdrawal of 4-HBA leads to progressive neurological decline. Notably, while conventional CoQ10 supplementation transiently ameliorated cardiac dysfunction, it failed to prevent fatal neurological deterioration. Guided by these preclinical findings, we initiated a first-in-human individual therapeutic trial with 4-HBA in a 3-year-old boy with genetically confirmed primary CoQ10 deficiency due to compound heterozygous pathogenic COQ2 variants. The patient presented with a Leigh-like syndrome characterized by bilateral brain lesions, developmental delay, muscular hypotonia, failure to thrive, lactic acidosis, and steroid-resistant nephrotic syndrome. Despite high-dose oral CoQ10 supplementation, clinical response had been minimal. Prior to clinical application, patient-derived fibroblasts were treated in vitro with 4-HBA, resulting in a marked increase in endogenous CoQ10 levels. Following the initiation of oral 4-HBA treatment, the patient experienced rapid and sustained remission of proteinuria, improved renal hyperfiltration, and a gradual increase in serum CoQ10 concentrations. No adverse effects were observed during a six-month follow-up. Clinically, the patient showed notable improvements in motor skills, language acquisition, cognitive alertness, and overall development, accompanied by significant gains in growth and nutritional status. Clinical recovery was also reflected by improved scores on the Newcastle Paediatric Mitochondrial Disease Scale. These findings support 4-HBA as a promising targeted metabolic treatment for COQ2-related CoQ deficiency and highlight the need for further clinical investigation.

Keywords:  4-hydroxybenzoic acid; COQ2; coenzyme Q deficiency; mitochondrial diseases; pharmacological therapy; therapeutic trial

DOI:  https://doi.org/10.1093/brain/awaf334
Cell Rep. 2025 Sep 05. pii: S2211-1247(25)01001-0. [Epub ahead of print]44(9): 116230

ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation.

Matteo Bordi, Beatrice Testa, Claudia Compagnucci, Fiorella Colasuonno, Francesca Cipressa, Elisabetta Betterini, Andrea Mancini, Claudia Carsetti, Illari Salvatori, Caterina Ferraina, Ming Yang, Rossella De Cegli, Eugenio Del Prete, Chiara Veroni, Salvatore Rizza, Sofia Mauri, Elena Ziviani, Marina Macchiaiolo, Davide Vecchio, Filippo Maria Panfili, Teresa Rizza, Gerrit Weber, Rosalba Carrozzo, Alberto Ferri, Silvia Campello, Andrea Ballabio, Christian Frezza, Gianluca Cestra, Marco Tartaglia, Andrea Bartuli, Francesco Cecconi.

  Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues. We also identify defects in mitochondrial dynamics and transport linked to ERK2 and AKT suppression. Notably, overexpressing constitutively active ERK2 or supplementing purine intermediates partially rescues the mitochondrial phenotype. These findings suggest an alternative disease mechanism and highlight mitochondrial metabolism as a potential therapeutic target in ADSLd.

Keywords:  ADSL; CP: Metabolism; ERK; mitochondria; purine metabolism; rare genetic disease

DOI:  https://doi.org/10.1016/j.celrep.2025.116230
Reproduction. 2025 Oct 01. pii: e250160. [Epub ahead of print]170(4):

Sex-specific alterations in placental mitochondria, oxidative damage and apoptosis in mice of advanced maternal age.

Jessica Dalton-O'Reilly, Alexander E P Heazell, Susan Greenwood, Mark Dilworth, Michelle Desforges.

   In brief: Advanced maternal age (AMA) is associated with adverse pregnancy outcomes, particularly those associated with placental dysfunction. This study showed that in a mouse model of AMA, male but not female fetuses had increased placental apoptosis and lipid peroxidation, as well as increased mitochondrial content, suggesting that the placentas of male fetuses in AMA mothers adapt to be able to deliver sufficient energy to the fetus.
Abstract: Although advanced maternal age (AMA) increases the risk of fetal growth restriction (FGR) and stillbirth, the mechanisms leading to the placental dysfunction observed in AMA are unknown. Mitochondrial function declines and oxidative stress increases with age. Furthermore, FGR, of which placental dysfunction is a major cause, is associated with alterations in respiratory function of placental mitochondria. Therefore, this study aimed to examine placental mitochondrial function, oxidative stress, and apoptosis in AMA mice using respirometry and immunohistochemistry. Relative to young mice (12-16 weeks), AMA mice (36-42 weeks) demonstrated reduced weight in both female and male fetuses, but placental alterations occurred in a sex-specific manner. In AMA, lipid peroxidation and apoptosis were increased in the placental junctional zone (Jz) and labyrinth zone (Lz) of male but not female fetuses. Placental mitochondrial content was significantly increased in the Lz and Jz of male fetuses and the Lz of female fetuses in AMA. When normalised to sample mitochondrial content, complex I + II-linked respiration, electron transfer capacity, and complex IV activity were significantly reduced in the Jz of male fetuses and Lz of female fetuses in AMA. However, when normalised to protein content, no differences were observed in placentas of female fetuses; in the Lz of male fetuses, complex I-linked respiration was increased and complex IV activity was reduced. Collectively, these findings suggest that the observed increase in mitochondrial content could be an adaptation by the placenta to maintain appropriate bioenergetic capacity and that oxidative damage may contribute to placental dysfunction in male fetuses in AMA pregnancies.

Keywords:  apoptosis; fetal growth restriction; mitochondria; oxidative stress; placenta; pregnancy

DOI:  https://doi.org/10.1530/REP-25-0160
Nat Aging. 2025 Sep 09.

Emerging strategies, applications and challenges of targeting NAD+ in the clinic.

Jianying Zhang, He-Ling Wang, Sofie Lautrup, Hilde Loge Nilsen, Jonas T Treebak, Leiv Otto Watne, Geir Selbæk, Lindsay E Wu, Torbjørn Omland, Eija Pirinen, Tin Cho Cheung, Jun Wang, Mathias Ziegler, Ole-Bjørn Tysnes, Rubén Zapata-Pérez, Santina Bruzzone, Carles Canto, Michela Deleidi, Georges E Janssens, Riekelt H Houtkooper, Morten Scheibye-Knudsen, Masaya Koshizaka, Koutaro Yokote, Eric Verdin, Vilhelm A Bohr, Charalampos Tzoulis, David A Sinclair, Evandro Fei Fang.

Beyond their classical functions as redox cofactors, recent fundamental and clinical research has expanded our understanding of the diverse roles of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) in signaling pathways, epigenetic regulation and energy homeostasis. Moreover, NAD and NADP influence numerous diseases as well as the processes of aging, and are emerging as targets for clinical intervention. Here, we summarize safety, bioavailability and efficacy data from NAD+-related clinical trials, focusing on aging and neurodegenerative diseases. We discuss the established NAD+ precursors nicotinic acid and nicotinamide, newer compounds such as nicotinamide riboside and nicotinamide mononucleotide, and emerging precursors. We also discuss technological advances including in industrial-scale production and real-time detection, which are facilitating NAD+ research and clinical translation. Finally, we emphasize the need for further large-scale studies to determine optimal dose, administration routes and frequency, as well as long-term safety and interindividual variability in response.

DOI: https://doi.org/10.1038/s43587-025-00947-6
Nat Aging. 2025 Sep 10.

Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.

Yan Bai, Tengfei Ma, Shan Zhao, Shalan Li, Xin Wang, Jingyang Li, Wenhao Sun, Yang Yang, Fenglian Liu, Qian Shan, Zizhen Qin, Nan Liu, Jie Zhang, Fei Tian, Mei Duan, Shunkai Chen, Fan Lai, Qingfeng Chen, Xuna Wu, Chonglin Yang.

Membraneless organelles assembled by liquid-liquid phase separation interact with diverse membranous organelles to regulate distinct cellular processes. It remains unknown how membraneless organelles are engaged in mitochondrial homeostasis. Here we demonstrate that mitochondria-associated translation organelles (MATOs) mediate local synthesis of proteins required for structural and functional maintenance of mitochondria. In Caenorhabditis elegans, the RNA-binding protein LARP-1 (La-related protein 1) orchestrates coalescence of translation machinery and multiple RNA-binding proteins via liquid-liquid phase separation into MATOs that associate with mitochondria in a translocase of the outer membrane complex-dependent manner. LARP-1 deficiency markedly reduces mitochondrial protein levels, impairing cristae organization and ATP production. Specifically, we show that the membrane-shaping MICOS subunit IMMT-1(MIC60) and the ATP synthase β subunit ATP-2, both being important for cristae organization, are synthesized in LARP-1 MATOs. During aging and starvation, LARP-1 MATOs dissociate from mitochondria; however, mitochondrion-persistent LARP-1 MATOs protect mitochondrial health and greatly extend lifespan. These findings suggest an important mitochondrion-regulating mechanism in aging and stress.

DOI: https://doi.org/10.1038/s43587-025-00942-x
FASEB J. 2025 Sep 15. 39(17): e70986

Abundance of Maternal Mitochondrial Genome Is Dispensable up to the Mitochondrial Genome Activation in Post-Implantation Embryos.

Miki Shavit, Marie Vancová, Jan Jedlicka, Tomáš Bílý, Mushrek Mahrouk, Jan Cendelin, Kateřina Grygarova, Kristýna Popelková, Zdeněk Tůma, Gabriela Pribanova, Jitka Kuncová, Jan Nevoral.

  Mitochondria in the egg are suggested to be crucial for the onset of new life. However, there is ambiguous knowledge about the necessity for fertilization and early embryonic development. Therefore, we created a conditional Tfam knockout (TfamloxP/loxP; Zp3-Cre) to produce Tfamnull oocytes for investigation of the mitochondrial abundance in oocytes and early embryos. This created mtDNA-depleted eggs, although the abundance of mitochondria did not change. Despite decreased mitochondrial membrane potential, Tfamnull oocytes matured and were fertilized, which led to embryo formation. These Tfamnull eggs were developed into mtDNA-deficient blastocysts. Both TFAM and mtDNA appear to be dispensable for the success of embryo implantation. Tfam expression and mtDNA replication rescue the mtDNA-deficient embryo after implantation, enabling passage through a post-implantation bottleneck, and allowing survivor embryos to develop into healthy individuals. Our findings highlight the uncoupled relationship between mtDNA replication and mitochondrial abundance in the growing oocyte and show the importance of the oocyte bulk mtDNA for successful mitochondrial activation in post-implantation embryos.

Keywords:  embryo; fertilization; mitochondrial; mitochondrion; oocyte; transcription factor A

DOI:  https://doi.org/10.1096/fj.202501179R
Autophagy. 2025 Sep 13.

Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.

Antonis Roussos, Katerina Kitopoulou, Fivos Borbolis, Christina Ploumi, Despoina D Gianniou, Zhiquan Li, Haijun He, Eleni Tsakiri, Helena Borland, Ioannis K Kostakis, Martina Samiotaki, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.

  Mitochondrial dysfunction and impaired mitophagy are hallmarks of aging and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analyses reveal that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In C. elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.

Keywords:  Calcium; ER; cellular senescence; geroprotection; lysosome; mitochondria

DOI:  https://doi.org/10.1080/15548627.2025.2561073
iScience. 2025 Sep 19. 28(9): 113311

An iPSC-derived neuronal model reveals manganese's role in neuronal endocytosis, calcium flux and mitochondrial bioenergetics.

Dimitri Budinger, Sharmin Alhaque, Ramón González-Méndez, Chris Dadswell, Katy Barwick, Arianna Ferrini, Charlotte Roth, Conor J McCann, Karin Tuschl, Fatma Al Jasmi, Maha S Zaki, Julien H Park, Russell C Dale, Shekeeb Mohammad, John Christodoulou, Dale Moulding, Michael R Duchen, Serena Barral, Manju A Kurian.

  Manganese (Mn) is an essential trace metal required for normal biological function, yet it also poses neurotoxic risks when dysregulated. Maintaining proper intracellular and extracellular Mn levels is critical, as Mn imbalance has been implicated in a spectrum of human diseases-including inherited Mn transport disorders, acquired manganism, and more prevalent neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Despite these associations, the cellular mechanisms driving Mn-induced neuropathology remain poorly understood. To investigate this, we developed an induced pluripotent stem cell (iPSC)-derived midbrain neuronal model using patient lines with mutations in SLC39A14, SLC39A8, and SLC30A10. Through integrated transcriptomic and functional analyses, we found that Mn dyshomeostasis disrupts essential neuronal pathways, including mitochondrial bioenergetics, calcium signaling, endocytosis, glycosylation, and stress responses-leading to early neurodegeneration. This humanized model advances our understanding of Mn's impact on neuronal health and disease and highlights potential molecular targets for future therapeutic interventions in Mn-related neurological disorders.

Keywords:  Cell biology; Molecular biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2025.113311
Nat Metab. 2025 Sep 09.

Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.

Ran Liu, Zihan Zhang, Aye K Kyaw, Kariona A Grabińska, Hardik Shah, Hongying Shen.

The essential cofactor coenzyme A (CoASH) and its thioester derivatives (acyl-CoAs) have pivotal roles in cellular metabolism. However, the mechanism by which different acyl-CoAs are accurately partitioned into different subcellular compartments to support site-specific reactions, and the physiological impact of such compartmentalization, remain poorly understood. Here, we report an optimized liquid chromatography-mass spectrometry-based pan-chain acyl-CoA extraction and profiling method that enables a robust detection of 33 cellular and 23 mitochondrial acyl-CoAs from cultured human cells. We reveal that SLC25A16 and SLC25A42 are critical for mitochondrial import of free CoASH. This CoASH import process supports an enriched mitochondrial CoA pool and CoA-dependent pathways in the matrix, including the high-flux TCA cycle and fatty acid oxidation. Despite a small fraction of the mitochondria-localized CoA synthase COASY, de novo CoA biosynthesis is primarily cytosolic and supports cytosolic lipid anabolism. This mitochondrial acyl-CoA compartmentalization enables a spatial regulation of anabolic and energy-related catabolic processes, which promises to shed light on pathophysiology in the inborn errors of CoA metabolism.

DOI: https://doi.org/10.1038/s42255-025-01358-y
Clin Genet. 2025 Sep 10.

LONP1 Variants Are Associated With Clinically Diverse Phenotypes.

Undiagnosed Diseases Network

  LONP1 encodes a mitochondrial protease essential for protein quality control and metabolism. Variants in LONP1 are associated with a diverse and expanding spectrum of disorders, including Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies syndrome (CODAS), congenital diaphragmatic hernia (CDH), and neurodevelopmental disorders (NDD), with some individuals exhibiting features of mitochondrial encephalopathy. We report 16 novel LONP1 variants identified in 16 individuals (11 with NDD, 5 with CDH), further expanding the clinical spectrum. Structural mapping of disease-associated missense variants revealed phenotype-specific clustering, with CODAS variants enriched in the proteolytic chamber and NDD variants more broadly distributed. CODAS is caused by biallelic variants and CDH by monoallelic variants, both of which are predicted to act through loss-of-function mechanisms. Both monoallelic and biallelic variants are associated with LONP1-related NDD, suggesting complex mechanisms such as dominant-negative effects. Our findings broaden the phenotypic and genetic spectrum of LONP1-associated disorders and highlight the essential role of LONP1 in mitochondrial function and development.

Keywords:  CODAS; LONP1; congenital diaphragmatic hernia; mitochondrial encephalopathy; neurodevelopmental disorder

DOI:  https://doi.org/10.1111/cge.70057
Neurobiol Dis. 2025 Sep 04. pii: S0969-9961(25)00301-8. [Epub ahead of print]215 107084

The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus.

L Daniel Estrella, Xiaoke Xu, Collin White, Jane E Manganaro, Lexi Sheldon, Trey Farmer, Kelly L Stauch.

  Amongst the major histopathological hallmarks in Alzheimer's disease are intracellular neurofibrillary tangles consisting of hyperphosphorylated and aggregated Tau, synaptic dysfunction, and synapse loss. We have previously shown evidence of synaptic mitochondrial dysfunction in a mouse model of Tauopathy that overexpresses human Tau (hTau). Here, we questioned whether the levels or activity of Parkin, an E3 ubiquitin ligase involved in mitophagy, can influence Tau-induced synaptic mitochondrial dysfunction. Here, we generated novel mouse strains by crossing hTau mice with either Parkin knockout mice or mice expressing mutant Parkin (ParkinW402A, shown to lead to constitutively active Parkin in vitro). We found that Parkin levels are increased in synaptic mitochondria isolates from hTau compared to WT mice, suggesting increased mitophagy; while ParkinW402A surprisingly led to decreased levels of Parkin in hTau mice. Furthermore, we showed that absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction; however, ParkinW402A did not show functional rescuing effects. When compared to WT, proteomic analyses of synaptosomes demonstrated that hTau mice display protein changes that predict alterations to pathways related to mitochondrial metabolism, synaptic long-term potentiation, and synaptic calcium homeostasis. Both the absence of Parkin and expression of ParkinW402A led to distinct changes in the hTau mouse synaptic proteome. Finally, we showed that Parkin-null hTau mice have higher levels of phosphorylated Tau in the hippocampal Dentate Gyrus, with no observable changes in hTau mice expressing ParkinW402A. The data presented here illustrate the protective role that Parkin plays under Tau-induced mitochondrial and proteomic alterations, particularly at the synaptic level.

Keywords:  Alzheimer's disease; Mitophagy; Parkin; ParkinW402A; Phosphorylated Tau; Synapse; Synaptic mitochondria; Tauopathy

DOI:  https://doi.org/10.1016/j.nbd.2025.107084
Redox Biol. 2025 Sep 05. pii: S2213-2317(25)00375-1. [Epub ahead of print]87 103862

Exposure to an environmentally relevant mixture of polychlorinated biphenyls affects mitochondrial bioenergetics and plasticity.

Maria Carolina Peixoto-Rodrigues, Vladimir Pedro Peralva Borges-Martins, José Raphael Monteiro-Neto, Bruno Vicente, Lucas José Guimarães, Clara Fernandes-Carvalho, Antonio Galina, Victor Midlej, Michal Toborek, Rachel Ann Hauser-Davis, Daniel Adesse.

  Adaptations of cells to environmental insults typically require tightly regulated processes to preserve the organismal steady state, particularly in metabolically active cells such as neural cells. Polychlorinated biphenyls (PCBs) are persistent organic pollutants widely recognized for their neurotoxic potential. Due to their lipophilic nature, these compounds readily accumulate in the brain, where they can disrupt neuronal homeostasis. Herein, we examined the effects of exposure to an environmentally relevant PCB mixture on mitochondrial dynamics, ultrastructure, and function in the mouse neuroblastoma Neuro2a cell line. Ultrastructural examinations indicated evident signs of mitochondrial damage, including swelling, cristae disruption, and increased frequency of autophagic structures. Quantification of mitochondrial networks confirmed a shift from tubular to fragmented morphologies, accompanied with the modulation of the gene expression of genes involved in mitochondrial fusion and fission. Specifically, mitofusin 2 protein levels were increased at 24 and 48 h of treatment, and OPA1 at 48 h, whereas Drp1, phosphorylated at Ser616 was increased at 24 h. Markers of mitophagy PINK1 and Parkin were elevated at 72 and 48 h of exposure, respectively, whereas Atg5 and Atg7, markers of autophagy were increased at 24 h. We observed a decrease in mitochondrial membrane potential and increase in mtDNA levels in PCB-treated cultures at 24 h. Oxidative stress was also implicated by overexpression and increased enzymatic activity of superoxide dismutase 1 (SOD1). Functional tests revealed a transient impairment of mitochondrial respiration and ATP synthesis, which was later restored, pointing to the recruitment of compensatory mechanisms. Together, these results indicate that PCB exposure activates an integrated stress response with oxidative imbalance, mitochondrial bioenergetics, remodeling, and autophagy features, revealing the neural cell vulnerability and plasticity to environmental insult.

Keywords:  Central nervous system; Mitochondrial plasticity; Pollutants; Polychlorinated biphenyls

DOI:  https://doi.org/10.1016/j.redox.2025.103862
Stem Cell Res. 2025 Sep 01. pii: S1873-5061(25)00175-8. [Epub ahead of print]88 103825

CRISPR/Cas9-mediated editing of COQ4 in induced pluripotent stem cells: A model for investigating COQ4-associated human coenzyme Q10 deficiency.

Sonja Herbrich, Haribaskar Ramachandran, Annette Seibt, Isabella Tolle, Annika Zink, Alessandro Prigione, Andrea Rossi, Felix Distelmaier.

Pathogenic variants in the gene COQ4 cause primary coenzyme Q10 deficiency, which is associated with symptoms ranging from early epileptic encephalopathy up to adult-onset ataxia-spasticity spectrum disease. We genetically modified commercially available wild-type iPS cells by using a CRISPR/Cas9 approach to create heterozygous and homozygous isogenic cell lines carrying the disease-causing COQ4 variants c.458C > T, p.Ala153Val and c.437T > G, p.Phe146Cys, respectively. All iPSCs lines exhibited a normal cell morphology, expression of pluripotency markers, and the ability to differentiate into the three primary germ layers. The COQ4-deficient cell lines will provide a helpful tool to investigate the disease mechanism and to develop therapeutic strategies.

DOI: https://doi.org/10.1016/j.scr.2025.103825
Nat Commun. 2025 Sep 12. 16(1): 8267

Matrix directs trophoblast differentiation in a bioprinted organoid model of early placental development.

Claire Richards, Hao Chen, Matthew O'Rourke, Ashley Bannister, Grace Owen, Alexander Volkerling, Arnab Ghosh, Catherine A Gorrie, David Gallego-Ortega, Amy L Bottomley, Matthew P Padula, Kristine C McGrath, Louise Cole, Philip M Hansbro, Lana McClements.

Trophoblast organoids can provide crucial insights into mechanisms of placentation, however their potential is limited by highly variable extracellular matrices unable to reflect in vivo tissues. Here, we present a bioprinted placental organoid model, generated using the first trimester trophoblast cell line, ACH-3P, and a synthetic polyethylene glycol (PEG) matrix. Bioprinted or Matrigel-embedded organoids differentiate spontaneously from cytotrophoblasts into two major subtypes: extravillous trophoblasts (EVTs) and syncytiotrophoblasts (STBs). Bioprinted organoids are driven towards EVT differentiation and show close similarity with early human placenta or primary trophoblast organoids. Inflammation inhibits proliferation and STBs within bioprinted organoids, which aspirin or metformin (0.5 mM) cannot rescue. We reverse the inside-out architecture of ACH-3P organoids by suspension culture with STBs forming on the outer layer of organoids, reflecting placental tissue. Our bioprinted methodology is applicable to trophoblast stem cells. We present a high-throughput, automated, and tuneable trophoblast organoid model that reproducibly mimics the placental microenvironment in health and disease.

DOI: https://doi.org/10.1038/s41467-025-62996-0
Cerebellum. 2025 Sep 13. 24(6): 154

Neuroimaging in Cerebellar Ataxias: A Diagnostic Approach.

Alex Tiburtino Meira, Thiago Cardoso Vale, Sophia C G da Costa, Claudie Gauvreau, Camila Callegari Piccinin, Hélio A G Teive, Marcondes C França, Nicolas Dupré, Orlando G Barsottini, José Luiz Pedroso.

  Ataxias are a group of neurologic disorders, with heterogeneous clinical and genetic presentation and with a challenging diagnostic approach that navigates through the neuroimage field. Typical clinical features of ataxias include variable degrees of cerebellar ataxia, as a pure clinical picture or associated with other neurologic or extra neurological symptoms (cognitive impairment, epilepsy, other movement disorders, abnormal ocular movements, systemic symptoms). Neuroimaging plays an important role in the characterization of patients with ataxia. Despite the development of genetics and neuroimaging, some cases remain with no diagnosis. This review proposes a didactic investigation approach for ataxias based on three main magnetic resonance imaging features: a) ataxias without cerebellar atrophy; b) ataxias with pure cerebellar atrophy or olivopontocerebellar atrophy; and c) ataxias with specific imaging features. A comprehensive review of peer-reviewed articles on neuroimaging in diseases associated with cerebellar ataxia was conducted through a search in PubMed and SciELO. For each topic, we discuss the possible diagnosis and suggest a guided investigation. The classification of cerebellar ataxias into distinct categories-based on the presence or absence of cerebellar atrophy and specific neuroradiological features-profoundly enhances the diagnostic approach to these complex disorders.

Keywords:  Cerebellar ataxia; Cerebellum; Neurogenetics; Neuroimage

DOI:  https://doi.org/10.1007/s12311-025-01908-w
Aging Cell. 2025 Sep;24(9): e70162

SIRT2 and NAD+ Boosting Broadly Suppress Aging-Associated Inflammation.

Marine Barthez, Zehan Song, Yufan Feng, Yifei Wang, Chih-Ling Wang, Danica Chen.

Aging leads to chronic inflammation that is linked to aging-associated conditions and diseases. Multiple immune pathways become activated during aging, posing a challenge to effectively reduce aging-associated inflammation. SIRT2, an NAD+-dependent deacetylase, suppresses several immune pathways that become activated during aging and may represent an attractive target to broadly dampen aging-associated inflammation. Here, we show that SIRT2 deficiency leads to increased inflammation governed by multiple immune pathways and tissue function decline at an old age, while NAD+ boosting with 78c suppresses aging-associated inflammation and improves tissue function. These findings highlight SIRT2 as a master regulator of aging-associated inflammation and support NAD+ boosting as an effective strategy to counteract aging-associated inflammation and tissue function decline.

DOI: https://doi.org/10.1111/acel.70162
Hum Genet. 2025 Sep 08.

Recessive variants in TWNK cause syndromic and non-syndromic post-synaptic auditory neuropathy through MtDNA replication defects.

Xue Gao, Ying Ma, Wei-Qian Wang, Guo-Jian Wang, Kun Yang, Jin-Cao Xu, Sha-Sha Huang, Xiang Wang, Li-Min Hu, Xi Wang, Qiu-Quan Wang, Zhen-Dong Wang, Ming-Yu Han, Pu Dai, Yong-Yi Yuan.

Recessive variants in TWNK cause syndromes arising from mitochondrial DNA (mtDNA) depletion. Hearing loss is the most prevalent manifestation in individuals with these disorders. However, the clinical and pathophysiological features have not been fully elucidated. In this study, we collected five cases of hearing loss carrying bi-allelic TWNK variants from three unrelated Chinese families and identified two cases with isolated auditory neuropathy (AN) and three cases segregating with Perrault syndrome, characterized by AN, global developmental delay, and ovarian dysgenesis in females. All patients with cochlear implantation (CI) show poor speech discrimination outcomes, suggesting that the defect involves post-synaptic sites. In the mouse inner ear, Twinkle was immunolocalized to inner phalangeal cells and spiral ganglion neurons. Additionally, the broad expression pattern of Twinkle was observed in the auditory cortex, which to some extent explains the poor rehabilitation outcomes following CI. At the cellular level, Twinkle is localized at the mtDNA membrane, and the p.(Arg609AlaTer6) variant prevents the protein from reaching the mtDNA while the p.(Arg65Trp) variant exhibits a similar localization to the wild type, indicating a second mechanism of action. RT-PCR results indicated that the canonical transcript was abundant in the inner ear, while the shorter transcript was more abundant in the brain. Our findings revealed that bi-allelic TWNK variants lead to AN, which can be either syndromic or non-syndromic, with the molecular pathogenesis involving defects in mtDNA replication at post-synaptic sites. Patients with TWNK-associated conditions are not ideal candidates for CI and gene therapy may offer a solution for hearingrehabilitation.

DOI: https://doi.org/10.1007/s00439-025-02774-6