bims-mitmed 2025-07-27 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–07–27
twenty-six papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease.
Molecule eases neurological symptoms of mitochondrial deficiency in coenzyme Q10.
Mutation of NDUFAF2 Linked to Mitochondrial Complex I Deficiency.
NDUFV1 mutation presenting as isolated progressive optic neuropathy: a unique manifestation of mitochondrial complex I deficiency.
The peculiar properties of mitochondrial carriers of the SLC25 family.
Mitochondrial Donation in a Reproductive Care Pathway for mtDNA Disease.
Identification of a pathogenic RNU4-2 variant in patients with mitochondrial disease: Broadening the spectrum of non-coding RNA gene variants in mitochondrial dysfunction.
Mitophagy modulation rescues single large-scale mitochondrial DNA deletion (SLSMD) disease symptoms in the C. elegans uaDf5 animal model.
NAD+-Boosters Improve Mitochondria Quality Control In Parkinson's Disease Models Via Mitochondrial UPR.
Maternal Circulatory NAD Precursor Levels and the Yolk Sac Determine NAD Deficiency-Driven Congenital Malformation Risk.
Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex.
Antisense oligonucleotide therapy for patients with Friedreich's ataxia carrying the c.165+5G>C splicing mutation.
In vivo prime editing rescues alternating hemiplegia of childhood in mice.
Immune aging impairs muscle regeneration via macrophage-derived anti-oxidant selenoprotein P.
SETDB1 ensures the continuity of embryonic to adult neural stem cells through metabolic alterations in the dentate gyrus.
Cell type-specific purifying selection of synonymous mitochondrial DNA variation.
LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.
Mitochondrial cardiomyopathies: pathogenesis, diagnosis, and treatment.
UCP2 MEDIATES MITOCHONDRIAL DYNAMICS TO INDUCE AgRP NEURONAL ACTIVITY.
Raised Leptin and Pappalysin2 cell-free RNAs are the hallmarks of pregnancies complicated by preeclampsia with fetal growth restriction.
The unexpected role of Na+ in mitochondrial bioenergetics, ROS production and homeostasis.
Microtubules coordinate mitochondria transport with myofibril morphogenesis during muscle development.
Protocol to generate species-specific astrocyte-conditioned medium for human organoid neuron maturation.
Third-trimester trophoblast stem cell function is impaired in fetal growth restriction.
Mosaic variants of neurodevelopmental and mitochondrial genes in postmortem paraventricular thalamus in bipolar disorder detected by deep exome sequencing.
Sirtuins in mitophagy: key gatekeepers of mitochondrial quality.

Clin Transl Med. 2025 Jul;15(7): e70404

PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease.

Swagat Pradhan, Takayuki Mito, Nahid A Khan, Sofiia Olander, Aleksandra Zhaivoron, Thomas G McWilliams, Anu Suomalainen.

   BACKGROUND: Mitochondria elicit various metabolic stress responses, the roles of which in diseases are poorly understood. Here, we explore how different muscles of one individual-extraocular muscles (EOMs) and quadriceps femoris (QFs) muscles-respond to mitochondrial disease. The aim is to explain why EOMs atrophy early in the disease, unlike other muscles.
METHODS: We used a mouse model for mitochondrial myopathy ("deletor"), which manifests progressive respiratory chain deficiency and human disease hallmarks in itsmuscles. Analyses included histology, ultrastructure, bulk and single-nuclear RNA-sequencing, metabolomics, and mitochondrial turnover assessed through in vivo mitophagy using transgenic mito-QC marker mice crossed to deletors.
RESULTS: In mitochondrial muscle disease, large QFs upregulate glucose uptake that drives anabolic glycolytic one-carbon metabolism and mitochondrial integrated stress response. EOMs, however, react in an opposite manner, inhibiting glucose and pyruvate oxidation by activating PDK4, a pyruvate dehydrogenase kinase and inhibitor. Instead, EOMs upregulate acetyl-CoA synthesis and fatty-acid oxidation pathways, and accumulate lipids. In QFs, Pdk4 transcription is not induced.- Amino acid levels are increased in QFs but are low in EOMs suggesting their catabolic use for energy metabolism. Mitophagy is stalled in both muscle types, in the most affected fibers.
CONCLUSIONS: Our evidence indicates that different muscles respond differently to mitochondrial disease even in one individual. While large muscles switch to anabolic mode and glycolysis, EOMs actively inhibit glucose usage. They upregulate lipid oxidation pathway, a non-optimal fuel choice in mitochondrial myopathy, leading to lipid accumulation and possibly increased reliance on amino acid oxidation. We propose that these consequences of non-optimal nutrient responses lead to EOMatrophy and progressive external ophthalmoplegia in patients. Our evidence highlights the importance of PDK4 and aberrant nutrient signaling underlying muscle atrophies.

Keywords:  integrated stress response; mitochondrial disease; mitochondrial myopathy; nutrient signaling; progressive external ophthalmoplegia; pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.1002/ctm2.70404
Nature. 2025 Jul 23.

Molecule eases neurological symptoms of mitochondrial deficiency in coenzyme Q10.



Keywords:  Brain; Diseases; Health care

DOI:  https://doi.org/10.1038/d41586-025-02289-0
Cureus. 2025 Jun;17(6): e86670

Mutation of NDUFAF2 Linked to Mitochondrial Complex I Deficiency.

Anwar R Alhamad, Aziza Mushiba, Huda Alkhawaja, AbdullabAli PeerZada, Shahad Bawazeer, Mohammed Saleh.

  Mitochondrial complex I deficiency is an autosomal recessive disorder caused by homozygous mutations in the reduced form of nicotinamide adenine dinucleotide (NADH). It is characterized by a wide range of signs and symptoms that affect numerous human systems and organs. This disease causes neurological issues, including encephalopathy, recurrent epilepsy, intellectual disability, ataxia, and involuntary movements. The initial step of the mitochondrial respiratory chain, during which protons are transported across the inner mitochondrial membrane along with electron transfer from NADH to ubiquinone, is catalyzed by NADH: ubiquinone oxidoreductase. In this case report, we describe a patient presenting with severe, rapidly progressive neurological loss who harbored a novel mutation in NDUFAF2 identified using exome sequencing. At six months of age, her mother noticed delayed motor development. Thereafter, the patient developed metabolic acidosis and abnormal movements, mimicking seizures triggered by aspiration pneumonia, with elevated serum lactate levels. Genetic testing revealed a c.127G>A mutation in NDUFAF2, consistent with mitochondrial complex I deficiency. This case highlights the utility of exome sequencing as a powerful and cost-effective tool for diagnosing clinically heterogeneous disorders such as mitochondrial diseases. Mitochondrial complex I deficiency is an important differential diagnosis in patients with recurrent central hypoventilation. Our findings expand the mutational spectrum of this rare disease.

Keywords:  case report; episodic respiratory failure; mitochondrial complex i deficiency; ndufaf2; recurrent encephalopathy

DOI:  https://doi.org/10.7759/cureus.86670
BMJ Case Rep. 2025 Jul 18. pii: e266155. [Epub ahead of print]18(7):

NDUFV1 mutation presenting as isolated progressive optic neuropathy: a unique manifestation of mitochondrial complex I deficiency.

Parul Mittal, Samendra Karkhur, Vidhya Verma, Priti Singh.

  Mutations in the NDUFV1 gene, encoding a subunit of mitochondrial complex I, are typically associated with severe neurological disorders such as Leigh syndrome. We report a pre-teen girl with progressive bilateral optic atrophy and steady visual deterioration, without neurological findings or systemic involvement. Neuroimaging was unremarkable for white matter lesions or structural brain lesions. Whole-exome sequencing demonstrated a homozygous missense mutation (c.1156C>T, p. Arg386Cys) in NDUFV1, implying a nuclear-encoded complex I defect. Laboratory analysis revealed increased lactate levels, consistent with mitochondrial dysfunction. Despite treatment with coenzyme Q, riboflavin and idebenone, no significant visual improvement occurred. This case represents a novel phenotype of NDUFV1-associated disease isolated optic atrophy without systemic involvement expanding the clinical spectrum of NDUFV1 mutations. Recognising this unique mitochondrial optic neuropathy may aid early diagnosis and targeted management.

Keywords:  Genetics; Neuroimaging; Neuroopthalmology; Retina; Visual pathway

DOI:  https://doi.org/10.1136/bcr-2025-266155
Biochem J. 2025 Jul 23. pii: BCJ20253171. [Epub ahead of print]482(15):

The peculiar properties of mitochondrial carriers of the SLC25 family.

Edmund R S Kunji, Vasiliki Mavridou, Martin S King, Camila Cimadamore-Werthein, Stephany Jaiquel Baron, Scott A Jones, Alannah C King, Roger Springett, Deepak Chand, Shane M Palmer, Denis Lacabanne, Sotiria Tavoulari, Jonathan J Ruprecht.

  With 53 members, the SLC25 mitochondrial carriers form the largest solute carrier family in humans. They transport a wide variety of substrates across the mitochondrial inner membrane to generate chemical energy and to supply molecules and ions for growth and maintenance of cells. They are among the smallest transporters in nature, yet they translocate some of the largest molecules without proton leak. With one exception, they are monomeric and have an unusual three-fold pseudo-symmetric structure. These carriers also have a unique transport mechanism, which is facilitated by six structural elements, meaning that all transmembrane helices move separately, but in a co-ordinated way. In addition, there are three functional elements that are an integral part of the alternating access mechanism, which opens and closes the carrier to the mitochondrial matrix or the intermembrane space. The first is a matrix gate, comprising the matrix salt bridge network and glutamine braces on transmembrane helices H1, H3 and H5. The second is a cytoplasmic gate, containing the cytoplasmic salt bridge network and tyrosine braces on transmembrane helices H2, H4 and H6. The third functional element is a single central substrate-binding site, the access to which is controlled by the opening and closing of the two gates in an alternating way. The electrostatic properties of the binding site facilitate the exchange of charged substrates across the inner membrane in the presence of a high membrane potential. Here, we discuss the extraordinary features of mitochondrial carriers, providing new insights into one of the most complex and dynamic transport mechanisms in nature.

Keywords:  bioenergetics; mitochondria; oxidative phosphorylation; translocases; translocators; transport mechanism

DOI:  https://doi.org/10.1042/BCJ20253171
N Engl J Med. 2025 Jul 16.

Mitochondrial Donation in a Reproductive Care Pathway for mtDNA Disease.

Robert McFarland, Louise A Hyslop, Catherine Feeney, Rekha N Pillai, Emma L Blakely, Eilis Moody, Matthew Prior, Anita Devlin, Robert W Taylor, Mary Herbert, Meenakshi Choudhary, Jane A Stewart, Douglass M Turnbull.

Pathogenic variants in mitochondrial DNA (mtDNA) are a common cause of severe, often fatal, inherited metabolic disease. A reproductive care pathway was implemented to provide women carrying pathogenic mtDNA variants with reproductive options. A total of 22 women with pathogenic mtDNA variants have commenced or completed pronuclear transfer (and thus receipt of a mitochondrial donation), and there have been 8 live births. All 8 children were healthy at birth, with no or low levels of mtDNA heteroplasmy in blood. Hyperlipidemia and cardiac arrhythmia developed in a child whose mother had hyperlipidemia during pregnancy; both of the child's conditions responded to treatment. Infant myoclonic epilepsy developed in another child, with spontaneous remission. At the time of this report, all the children have made normal developmental progress. (Funded by the U.K. National Health Service and others.).

DOI: https://doi.org/10.1056/NEJMoa2503658
J Hum Genet. 2025 Jul 22.

Identification of a pathogenic RNU4-2 variant in patients with mitochondrial disease: Broadening the spectrum of non-coding RNA gene variants in mitochondrial dysfunction.

Kohta Nakamura, Yoshihito Kishita, Atsuko Imai-Okazaki, Taku Omata, Maki Nodera, Yukiko Yatsuka, Ayumu Sugiura, Naoyuki Matsumoto, Holger Prokisch, Hiroshi Matsumoto, Akira Ohtake, Kei Murayama, Yasushi Okazaki.

Mitochondrial diseases are characterized by impaired energy production due to mitochondrial dysfunction. Despite advances in sequencing technologies, many cases remain genetically undiagnosed. We report two cases of mitochondrial disease harboring identical de novo variant in the non-coding RNA gene RNU4-2, previously associated with neurodevelopmental disorders. Re-analysis of whole genome sequencing data from 357 patients ascertained as possibly having mitochondrial disease (see Methods: Supplementary Data S1) identified two cases with a pathogenic RNU4-2 variant (GRCh38: chr.12:120291839: T > TA; NR_003137.2: n.64_65insT). Both patients exhibited decreased oxygen consumption rates and clinical features including developmental delay, microcephaly, short stature. This study provides the first evidence linking RNU4-2 variant to mitochondrial disease, expanding the phenotypic spectrum associated with this gene. Our findings highlight the importance of re-analyzing genomic data and considering non-coding RNA gene variants in mitochondrial disease diagnostics, potentially improving the diagnosis of previously unsolved cases.

DOI: https://doi.org/10.1038/s10038-025-01356-8
bioRxiv. 2024 Oct 27. pii: 2024.10.27.620333. [Epub ahead of print]

Mitophagy modulation rescues single large-scale mitochondrial DNA deletion (SLSMD) disease symptoms in the C. elegans uaDf5 animal model.

Ryan M Mendel, Sofie Matsuno, Alex Lu, Marni J Falk, Suraiya Haroon.

S ingle large s cale m itochondrial DNA (mtDNA) d eletions (SLSMD) underlie a range of sporadic or maternally inherited primary mitochondrial diseases having significant morbidity and mortality, including Pearson syndrome, Kearns-Sayre Syndrome, or Chronic Progressive External Ophthalmoplegia. Therapeutic development has been hindered by limited existing knowledge on mtDNA quality control and a lack of SLSMD animal models. To address this challenge, we utilized the C. elegans heteroplasmic SLSMD strain, uaDf5, to objectively screen for potential therapies. As mitophagy modulation has been implicated in mtDNA homeostasis, we screened a library of mitophagy modulating compounds to determine their comparative effects to rescue mitochondrial unfolded protein (UPR mt ) stress induction in in uaDf5 SLSMD worms. Interestingly, Thiamine was discovered to be an effective positive control, significantly reducing mitochondrial stress in this model. Two lead therapeutic candidates from the mitophagy library screen were Hemin and Celastrol (Tripterin). Celastrol is a mitophagy activating anti-inflammatory and metabolic modifying natural product derived compound, that rescued multiple fitness outcomes (thrashing, development, survival) and reduced the mitochondrial stress in uaDf5 animals in a mitophagy-dependent fashion. This study highlights the utility of the uaDf5 worm model to enable preclinical identification of therapeutic candidate leads for SLSMD-based heteroplasmic mtDNA diseases and identifies possible therapeutic candidates that serve as mitophagy modulators to improve health and specifically reduce heteroplasmy levels in SLSMD diseases.

DOI: https://doi.org/10.1101/2024.10.27.620333
Adv Sci (Weinh). 2025 Jul 20. e08503

NAD+-Boosters Improve Mitochondria Quality Control In Parkinson's Disease Models Via Mitochondrial UPR.

Shuoting Zhou, Xi Xiong, Jialong Hou, Qi Duan, Yi Zheng, Tao Jiang, Jiani Huang, Haijun He, Jiaxue Xu, Keke Chen, Wenwen Wang, Jinlai Cai, Jingjing Qian, Huijun Chen, Weihong Song, XinShi Wang, Chenglong Xie.

  Serving as a pivotal hub for cellular metabolism and intracellular signaling, the mitochondrion has emerged as a crucial organelle whose dysfunction is linked to many human diseases, including neurodegenerative disorders, particularly Parkinson's disease (PD). However, whether mitochondrial quality control (MQC) can be targeted for therapeutic interventions remains uncertain. This study uses clinical samples, molecular biology techniques, pharmacological interventions, and genetic approaches to investigate the significance of NAD+ levels in cross-species models of PD. These results reveal that treatment of rotenone-incubated cells with NAD+ boosters (such as NMN, siCD38, and NAT) increases UPRmt/mitophagy-related MQC, reduces pro-inflammatory cytokine expression, inhibits apoptosis, and strengthen redox reactions. In vivo, NMN supplementation inhibits motor deficit and forestalls the neuropathological phenotypes of MPTP-induced PD mice, which are required for the atf4-related mitochondrial UPR pathway. Notably, bulk omics signatures and metabolomic profiling analyses of the striatum reveal NMN-induced transcriptional changes in genes and proteins involved in mitochondrial homeostasis. Thus, these findings demonstrate that the accelerated pathology in PD models is probably mediated by impaired MQC and that bolstering cellular NAD+ levels alleviates mitochondrial proteotoxic stress and mitigate PD phenotypes.

Keywords:  NAD+‐boosters; Parkinson's disease; mitochondria quality control; mitochondrial unfolded protein response; nicotinamide mononucleotide

DOI:  https://doi.org/10.1002/advs.202408503
FASEB J. 2025 Jul 31. 39(14): e70834

Maternal Circulatory NAD Precursor Levels and the Yolk Sac Determine NAD Deficiency-Driven Congenital Malformation Risk.

Kayleigh Bozon, Hartmut Cuny, Delicia Z Sheng, Alena Sipka, Antonia W Shand, Natasha Nassar, Sally L Dunwoodie.

  Nicotinamide adenine dinucleotide (NAD) is an essential cofactor in hundreds of cellular processes. Genetic disruption of NAD de novo synthesis causes congenital NAD deficiency disorder (CNDD), characterized by multiple congenital malformations or death in utero. Patient outcomes are highly variable, likely due to differences in the availability of maternal NAD precursors vitamin B3 and tryptophan to the embryo and its extraembryonic tissues. Here, maternal plasma and yolk sac NAD metabolomes, embryonic NAD levels, and pregnancy outcomes were quantified in a CNDD mouse model to determine how maternal circulatory NAD precursor provision affects pregnancy outcome and to identify metabolic markers of CNDD risk. Maternal levels of nicotinamide positively correlated with embryonic NAD levels, highlighting its central role for embryonic NAD metabolism. Levels of nicotinamide-derived excretion metabolites were the best predictors of adverse pregnancy outcome. NAD metabolomic analysis of pregnant women confirmed the relationship between dietary NAD precursor intake and circulatory nicotinamide and derived excretion product levels seen in mice, as women taking vitamin B3 supplements had elevated levels. Furthermore, mouse embryos with genetic disruption of NAD de novo synthesis (Haao-/-) were more susceptible to CNDD when maternal circulatory nicotinamide was limited, as their yolk sacs cannot generate NAD de novo from tryptophan. Metabolites originating from Haao-/- embryos were detectable in maternal plasma, showing that embryonic NAD metabolism also affects maternal circulation. Together, our findings elucidate the complex interplay between NAD metabolism of mother and conceptus and identify metabolic markers in maternal circulation that predict risk of NAD deficiency-related adverse pregnancy outcomes.

Keywords:  NAD; congenital malformation; embryonic development; metabolism; pregnancy

DOI:  https://doi.org/10.1096/fj.202500708RR
Nat Commun. 2025 Jul 21. 16(1): 6700

Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex.

Yingyuan Sun, Yaru Wang, Zheng Xing, Dongyu Li, Rong Wang, Baozhi Chen, Ning Zhou, Alyssa Ayala, Benjamin P Tu, Xiaofeng Qi.

The Mitochondrial Pyruvate Carrier (MPC) bridges cytosolic and mitochondrial metabolism by transporting pyruvate into mitochondria for ATP production and biosynthesis of various essential molecules. MPC functions as a heterodimer composed of MPC1 and MPC2 in most mammalian cells. Here, we present the cryogenic electron microscopy (cryo-EM) structures of the human MPC1-2 complex in the mitochondrial intermembrane space (IMS)-open state and the inhibitor-bound in the mitochondrial matrix-open state. Structural analysis shows that the transport channel of MPC is formed by the interaction of transmembrane helix (TM) 1 and TM2 of MPC1 with TM2 and TM1 of MPC2, respectively. UK5099, a potent MPC inhibitor, shares the same binding site with pyruvate at the matrix side of the transport channel, stabilizing MPC in its matrix-open conformation. Notably, a functional W82F mutation in MPC2 leads to the complex in an IMS-open conformation. Structural comparisons across different conformations, combined with yeast rescue assays, reveal the mechanisms of substrate binding and asymmetric conformational changes in MPC during pyruvate transport across the inner mitochondrial membrane (IMM) as well as the inhibitory mechanisms of MPC inhibitors.

DOI: https://doi.org/10.1038/s41467-025-61939-z
Mol Ther Nucleic Acids. 2025 Sep 09. 36(3): 102617

Antisense oligonucleotide therapy for patients with Friedreich's ataxia carrying the c.165+5G>C splicing mutation.

Pouiré Yameogo, Selina Aguilar, Thazha P Prakash, Frank Rigo, David R Lynch, Jill S Napierala, Marek Napierala.

  Friedreich's ataxia (FRDA) is a multisystem, progressive disease. 96% of patients carry biallelic GAA triplet expansion mutations in intron 1 of the frataxin gene (FXN). The remaining 4% have a pathogenic GAA expansion on one FXN allele and another mutation on the second allele. A point mutation, FXN c.165+5G>C, was identified in intron 1 of a patient with FRDA resulting in a significant decrease of FXN levels. Using patient fibroblasts, we demonstrated that the c.165+5G>C mutation affects canonical splicing of FXN, leading to the generation of an aberrant transcript. A library of antisense oligonucleotides (ASOs) was designed to target potential intronic splicing regulator motifs and tested in patient cells. Selected O-methoxyethyl (MOE)-ASOs increased FXN levels in c.165+5G>C patient cells without affecting FXN splicing in control cells. The leading MOE-ASO increased expression of a miniFXN gene carrying the c.165+5G>C point mutation by splicing repair. To increase efficacy, we simultaneously targeted the GAA-expanded allele in patient cells using a synthetic transcription factor (synthetic transcription elongation factor 1 [Syn-TEF1]). This ASO strategy may be therapeutically feasible for patients with FRDA with other point mutations that cause splicing defects. Success in developing treatments for disorders with only a few known cases will give hope to patients with FRDA carrying these rare point mutations.

Keywords:  Friedreich’s ataxia; MT: Oligonucleotides: Therapies and Applications; aberrant splicing; antisense oligonucleotides; compound heterozygous; frataxin point mutation; miniFXN gene

DOI:  https://doi.org/10.1016/j.omtn.2025.102617
Cell. 2025 Jul 15. pii: S0092-8674(25)00740-8. [Epub ahead of print]

In vivo prime editing rescues alternating hemiplegia of childhood in mice.

Alexander A Sousa, Markus Terrey, Holt A Sakai, Christine Q Simmons, Elena Arystarkhova, Natalia S Morsci, Laura C Anderson, Jun Xie, Fabian Suri-Payer, Linda C Laux, Emmanuel Roze, Sylvie Forlani, Guangping Gao, Simon Frost, Nina Frost, Kathleen J Sweadner, Alfred L George, Cathleen M Lutz, David R Liu.

  Alternating hemiplegia of childhood (AHC) is a neurodevelopmental disorder with no disease-modifying treatment. Mutations in ATP1A3, encoding an Na+/K+ ATPase subunit, cause 70% of AHC cases. Here, we present prime editing (PE) and base editing (BE) strategies to correct ATP1A3 and Atp1a3 mutations in human cells and in two AHC mouse models. We used PE and BE to correct five prevalent ATP1A3 mutations with 43%-90% efficiency. AAV9-mediated in vivo PE corrects Atp1a3 D801N and E815K in the CNS of two AHC mouse models, yielding up to 48% DNA correction and 73% mRNA correction in bulk brain cortex. In vivo PE rescued clinically relevant phenotypes, including restoration of ATPase activity; amelioration of paroxysmal spells, motor defects, and cognition deficits; and dramatic extension of animal lifespan. This work suggests a potential one-time PE treatment for AHC and establishes the ability of PE to rescue a neurological disease in animals.

Keywords:  CRISPR-Cas9; alternating hemiplegia of childhood; genetic therapy; genome editing; neurological disorder; prime editing

DOI:  https://doi.org/10.1016/j.cell.2025.06.038
EMBO Rep. 2025 Jul 18.

Immune aging impairs muscle regeneration via macrophage-derived anti-oxidant selenoprotein P.

Dieu-Huong Hoang, Jessica Bouvière, Johanna Galvis, Pauline Moullé, Orane Mercier, Eugenia Migliavacca, Ananga Ghosh, Gaëtan Juban, Sophie Liot, Pascal Stuelsatz, Fabien Le Grand, Jérôme N Feige, Rémi Mounier, Bénédicte Chazaud.

  Muscle regeneration is impaired with aging, due to both intrinsic defects of muscle stem cells (MuSCs) and alterations of their niche. Here, we monitor the cells constituting the MuSC niche over time in young and old regenerating mouse muscle. Aging alters the expansion of all niche cells, with prominent phenotypes in macrophages that show impaired resolution of inflammation. RNA sequencing of FACS-isolated mononucleated cells uncovers specific profiles and kinetics of genes and molecular pathways in old versus young muscle cells, indicating that each cell type responds to aging in a specific manner. Moreover, we show that macrophages have an altered expression of Selenoprotein P (Sepp1). Macrophage-specific deletion of Sepp1 is sufficient to impair the acquisition of their restorative profile and causes inefficient skeletal muscle regeneration. When transplanted in aged mice, bone marrow from young WT mice, but not Sepp1-KOs, restores muscle regeneration. This work provides a unique resource to study MuSC niche aging, reveals that niche cell aging is asynchronous and establishes the antioxidant Selenoprotein P as a driver of age-related decline of muscle regeneration.

Keywords:  Aging; Macrophages; Selenoprotein P; Skeletal Muscle Regeneration

DOI:  https://doi.org/10.1038/s44319-025-00516-3
Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2424315122

SETDB1 ensures the continuity of embryonic to adult neural stem cells through metabolic alterations in the dentate gyrus.

Yunyun Huang, Yue Zhu, Yueyan Zhu, Yan Jiang, Yunli Xie.

  Embryonic neural progenitors give rise to adult neural stem cells (aNSCs), which share transcriptomic similarities with astrocytes while sustaining neurogenesis in the adult brain. How embryonic neural progenitors transit into aNSCs while preventing astrocyte fate to maintain the aNSC pool remains unclear. Here, we found that the Setdb1-mediated metabolic state is essential for the transition from embryonic neural progenitors to aNSCs. Loss of the histone methyltransferase SETDB1 during dentate gyrus development leads to increased astrocyte production at the expense of aNSCs and ultimately constraining neurogenesis. Single-cell RNA sequencing reveals a specific metabolic alteration following Setdb1 loss, notably implicating the cytochrome c oxidase, subunit 6b2 (Cox6b2)-a component of the mitochondrial complex-as a key target of SETDB1. COX6B2 modulates oxidative phosphorylation (OXPHOS) to control aNSC fate over astrocyte differentiation. Elevated Cox6b2 levels promote astrocyte fate during dentate gyrus development. Thus, our findings reveal a mechanism underlying the continuity of neural progenitors to generate aNSC enabling the production of new neurons in the adult brain, highlighting the potential therapeutic strategies for transforming astrocytes into neurons via aNSCs.

Keywords:  SETDB1; adult neural stem cell; adult neurogenesis; neural progenitor

DOI:  https://doi.org/10.1073/pnas.2424315122
Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2505704122

Cell type-specific purifying selection of synonymous mitochondrial DNA variation.

Caleb A Lareau, Patrick Maschmeyer, Yajie Yin, Jacob C Gutierrez, Ryan S Dhindsa, Anne-Sophie Gribling-Burrer, Sebastian Zielinski, Yu-Hsin Hsieh, Lena Nitsch, Veronika Dimitrova, Benan Nalbant, Frank A Buquicchio, Tsion Abay, Robert R Stickels, Jacob C Ulirsch, Patrick Yan, Fangyi Wang, Zhuang Miao, Katalin Sandor, Bence Daniel, Vincent Liu, Paul L Mendez, Petra Knaus, Manpreet Meyer, William J Greenleaf, Anshul Kundaje, Redmond P Smyth, Mathias Munschauer, Leif S Ludwig, Ansuman T Satpathy.

  While somatic variants are well-characterized drivers of tumor evolution, their influence on cellular fitness in nonmalignant contexts remains understudied. We identified a mosaic synonymous variant (m.7076A > G) in the mitochondrial DNA (mtDNA)-encoded cytochrome c-oxidase subunit 1 (MT-CO1, p.Gly391=), present at homoplasmy in 47% of immune cells from a healthy donor. Single-cell multiomics revealed strong, lineage-specific selection against the m.7076G allele in CD8+ effector memory T cells, but not other T cell subsets, mirroring patterns of purifying selection of pathogenic mtDNA alleles. The limited anticodon diversity of mitochondrial tRNAs forces m.7076G translation to rely on wobble pairing, unlike the Watson-Crick-Franklin pairing used for m.7076A. Mitochondrial ribosome profiling confirmed stalled translation of the m.7076G allele. Functional analyses demonstrated that the elevated translational and metabolic demands of short-lived effector T cells (SLECs) amplify dependence on MT-CO1, driving this selective pressure. These findings suggest that synonymous variants can alter codon syntax, impacting mitochondrial physiology in a cell type-specific manner.

Keywords:  immunology; mitochondria; selection; single-cell

DOI:  https://doi.org/10.1073/pnas.2505704122
Nat Metab. 2025 Jul 21.

LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.

Jin Li, Yamei Deng, Marie Gasser, Jie Zhu, Emily M Walker, Vaibhav Sidarala, Emma C Reck, Dre L Hubers, Mabelle B Pasmooij, Chun-Shik Shin, Khushdeep Bandesh, Eftyhmios Motakis, Siddhi Nargund, Romy Kursawe, Venkatesha Basrur, Alexey I Nesvizhskii, Michael L Stitzel, David C Chan, Guy A Rutter, Scott A Soleimanpour.

Protein misfolding is a contributor to the development of type 2 diabetes (T2D), but the specific role of impaired proteostasis is unclear. Here we show a robust accumulation of misfolded proteins in the mitochondria of human pancreatic islets from patients with T2D and elucidate its impact on β cell viability through the mitochondrial matrix protease LONP1. Quantitative proteomics studies of protein aggregates reveal that islets from donors with T2D have a signature resembling mitochondrial rather than endoplasmic reticulum protein misfolding. Loss of LONP1, a vital component of the mitochondrial proteostatic machinery, with reduced expression in the β cells of donors with T2D, yields mitochondrial protein misfolding and reduced respiratory function, leading to β cell apoptosis and hyperglycaemia. LONP1 gain of function ameliorates mitochondrial protein misfolding and restores human β cell survival after glucolipotoxicity via a protease-independent effect requiring LONP1-mitochondrial HSP70 chaperone activity. Thus, LONP1 promotes β cell survival and prevents hyperglycaemia by facilitating mitochondrial protein folding. These observations provide insights into the nature of proteotoxicity that promotes β cell loss during the pathogenesis of T2D, which could be considered as future therapeutic targets.

DOI: https://doi.org/10.1038/s42255-025-01333-7
Eur Heart J. 2025 Jul 24. pii: ehaf491. [Epub ahead of print]

Mitochondrial cardiomyopathies: pathogenesis, diagnosis, and treatment.

Christoph Maack, Jan Dudek, Edoardo Bertero, Emmanouil Tampakakis, Hilary J Vernon.

  Mitochondrial cardiomyopathies are a heterogeneous group of disorders caused by dysfunction of mitochondrial energy production due to genetic mutations affecting mitochondrial or nuclear DNA. Mitochondrial cardiomyopathies can include a wide range of cardiac manifestations and are frequently associated with other multisystemic symptoms, including skeletal myopathy, neurological deficits, and metabolic disturbances. Advances in genetic testing have improved diagnostic accuracy, but early identification remains challenging due to the variable clinical presentation and clinical overlap with other cardiomyopathies. Therapeutic strategies are still evolving, with current management focusing on symptom control and mitigation of mitochondrial dysfunction. This review aims to provide a comprehensive overview of the pathophysiology, clinical features, diagnostic approaches, and treatment options for mitochondrial cardiomyopathies, highlighting the ongoing need for research into effective therapies and improved patient outcomes.

Keywords:  Bioenergetics; Heart failure; Mitochondrial cardiomyopathy; mtDNA

DOI:  https://doi.org/10.1093/eurheartj/ehaf491
Mol Metab. 2025 Jul 17. pii: S2212-8778(25)00122-X. [Epub ahead of print] 102215

UCP2 MEDIATES MITOCHONDRIAL DYNAMICS TO INDUCE AgRP NEURONAL ACTIVITY.

Sungho Jin, Nal Ae Yoon, Zhong-Wu Liu, Ciro Menale, Jung Dae Kim, Nadia Diano, Sabrina Diano.

OBJECTIVE: The hypothalamic agouti-related protein (AgRP)- expressing neurons regulate feeding and whole-body energy homeostasis. A growing body of evidence indicates that changes in mitochondrial dynamics, such as fission and fusion, play a crucial role in regulating AgRP neuronal activity. However, the mechanisms underlying this process remain to be elucidated. Here, we showed a role of mitochondrial UCP2-mediated mitochondrial dynamics in AgRP neurons in regulating AgRP neuronal activity and fasting-induced feeding behavior.
METHODS: We analyzed mitochondrial morphology, expression of activated dynamin-related protein 1 (DRP1), and mRNA expression levels of uncoupling protein 2 (Ucp2) in AgRP neurons of mice that were either in fed or fasted states. We then generated a mouse model in which Ucp2 was selectively deleted from adult AgRP neurons to assess the role of this mitochondrial protein in feeding behavior and whole-body energy metabolism.
RESULTS: We show fasting-induced AgRP neuronal activation is associated with UCP2-mediated mitochondrial fission and mitochondrial fatty acid utilization in AgRP neurons. In line with this, mice lacking UCP2 in AgRP neurons (Ucp2AgRPKO) show attenuated fasting- or ghrelin-induced AgRP neuronal activation and feeding behaviors and exhibited a significant decrease in body weight and fat mass accompanied by a significant increase in energy expenditure.
CONCLUSIONS: Altogether, our data revealed that UCP2-mediated mitochondrial dynamics and fatty acids oxidation in the hypothalamic AgRP neurons is necessary for AgRP neuronal function and fasting-induced food intake.

DOI: https://doi.org/10.1016/j.molmet.2025.102215
Nat Commun. 2025 Jul 18. 16(1): 6614

Raised Leptin and Pappalysin2 cell-free RNAs are the hallmarks of pregnancies complicated by preeclampsia with fetal growth restriction.

Sungsam Gong, Carlo Randise-Hinchliff, Suzanne Rohrback, Jing Yin Weng, Komal Singh, Sarah Shultzaberger, Ulla Sovio, Emma Cook, Fiona Kaper, Gordon C S Smith, D Stephen Charnock-Jones.

Preeclampsia (PE) and fetal growth restriction (FGR) complicate 5-10% of pregnancies and are major causes of maternal and fetal morbidity and mortality. Here we demonstrate that measuring circulating cell-free RNAs (cfRNAs) from maternal plasma can accurately predict pregnancies complicated by the combination of PE and FGR. We investigated 751 maternal plasma samples from 195 pregnant women (39 cases; 156 non-cases). We developed machine learning models from our discovery cohort (15 cases; 60 non-cases) and evaluated their predictive performances internally (24 cases; 96 controls) and externally (40 cases; 73 non-cases). We found circulating leptin (LEP) and pappalysin2 (PAPPA2) cfRNAs are the strongest cfRNA predictors of complicated pregnancies, each with an area under the receiver operating characteristic curve (AUC) of ~0.82. Using an external validation dataset of women with established PE, the combination of LEP and PAPPA2 had an AUC ~0.951. Our findings show that cfRNAs can predict complications of human pregnancy.

DOI: https://doi.org/10.1038/s41467-025-61931-7
Arch Biochem Biophys. 2025 Jul 17. pii: S0003-9861(25)00257-7. [Epub ahead of print]772 110544

The unexpected role of Na+ in mitochondrial bioenergetics, ROS production and homeostasis.

Pablo Hernansanz-Agustín.

  In the last few years, mitochondrial Na+ has emerged as an important player for cellular adaptation and bioenergetics. Previously, the role of Na+ was confined to the co-maintenance of plasma membrane potential. Now, it has expanded, particularly in the mitochondria, after its discovery as a second messenger. During acute hypoxia, Na+ enters in the mitochondrial matrix, interacts with phospholipids, regulating the inner mitochondrial membrane fluidity and reactive oxygen species (ROS) production by the mitochondrial electron transport chain. In addition, we have recently shown that, in normal conditions, Na+ also have deep implications in bioenergetics. It forms a gradient across the inner mitochondrial membrane which accounts for up to half of the ΔΨmt. This gradient is built up by the activity of the mitochondrial Na+-specific Na+/H+ exchanger (NHE), which partially dissipates the H+ gradient (ΔpH) to generate the Na+ gradient (ΔNa+). Interestingly, the molecular identity of this exchanger is complex I (CI). These roles of mitochondrial Na+ allow the control over mitochondrial Ca2+ content and open a novel relationship with physiology and disease. Overall, this review focuses on how mitochondrial Na+ regulates bioenergetics, mitochondrial ion handling and ROS levels, as well as its consequences for cell life and death.

Keywords:  Bioenergetics; Ca(2+); Mitochondria; Na(+); Reactive oxygen species; ion handling

DOI:  https://doi.org/10.1016/j.abb.2025.110544
Dev Cell. 2025 Jul 15. pii: S1534-5807(25)00411-3. [Epub ahead of print]

Microtubules coordinate mitochondria transport with myofibril morphogenesis during muscle development.

Jerome Avellaneda, Duarte Candeias, Ana da Rosa Soares, Edgar R Gomes, Nuno Miguel Luis, Frank Schnorrer.

  Muscle cells contain numerous energy-producing mitochondria and contractile myofibrils, whose myosin motors need ATP to generate force. Thus, myofibrils and mitochondria are in intimate contact in mature muscles. However, how their morphogenesis is coordinated during development remains largely unknown. Here, we used in vivo imaging to investigate myofibril and mitochondria network dynamics in developing Drosophila flight muscles. We found that mitochondria intercalate from the surface of actin bundles to their interior, and concomitantly, actin filaments condense to individual myofibrils. This ensures that mitochondria locate in proximity to every myofibril. Notably, antiparallel microtubules bundle with the assembling myofibrils, suggesting a key role in myofibril orientation. Indeed, microtubule severing affects myofibril orientation, whereas kinesin knockdown specifically blocks mitochondria intercalation. Importantly, mitochondria intercalation and their kinesin-dependent microtubule-based transport are conserved in mammalian muscle. Together, these data identify a key role for microtubules in coordinating mitochondria and myofibril morphogenesis to build functional muscles.

Keywords:  Drosophila; development; kinesin; live imaging; microtubules; mitochondria; mouse; muscle; myofibrillogenesis; sarcomere

DOI:  https://doi.org/10.1016/j.devcel.2025.06.033
STAR Protoc. 2025 Jul 23. pii: S2666-1667(25)00371-5. [Epub ahead of print]6(3): 103965

Protocol to generate species-specific astrocyte-conditioned medium for human organoid neuron maturation.

Honghui Zheng, Wenxin Xu, Feifei Yu, Jiani Xu, Mingyue Jiang, Ning Ma, Zhicheng Shao, Shaohua Ma.

  Brain organoids have emerged as promising models for neuroscience research; however, their utility is often limited by inadequate maturation. Here, we present a protocol for enhancing the maturation of human 2D and 3D neural cultures using astrocyte-conditioned medium (ACM). We outline the steps for isolating primary mouse astrocytes, culturing both mouse and human astrocytes, and preparing ACM. Additionally, we provide detailed procedures for quality control and downstream applications of ACM derived from different species. For complete details on the use and execution of this protocol, please refer to Zheng et al.1.

Keywords:  Biotechnology and bioengineering; Cell Biology; Cell Differentiation; Cell culture; Developmental biology; Neuroscience; Organoids; Stem Cells

DOI:  https://doi.org/10.1016/j.xpro.2025.103965
Exp Cell Res. 2025 Jul 22. pii: S0014-4827(25)00284-8. [Epub ahead of print] 114684

Third-trimester trophoblast stem cell function is impaired in fetal growth restriction.

Cherry Sun, Teena Kjb Gamage, Jasper Perry, Vicky Fan, Lawrence W Chamley, Joanna L James.

  Trophoblasts are epithelial cells critical for placental development and function, ensuring healthy fetal growth. We have previously isolated trophoblast stem cells (TSC) from first trimester placentae using the side-population technique, showing that they persist to term for the first time, and are depleted in fetal growth restriction (FGR) - a serious condition of pregnancy where placental exchange function is impaired. However, the functional role of TSC in pregnancy pathologies has not previously been directly examined. Here, we first demonstrate that third-trimester side-population trophoblasts represent a TSC population that can differentiate into mature trophoblast lineages in a similar manner to their first trimester counterparts, and then combine transcriptomic and functional studies to demonstrate deficits in proliferation, differentiation, and susceptibility to cell death in FGR. Together, such stem cell level defects may have profound impacts on all downstream trophoblast lineages, potentially explaining why placentation is impaired in FGR.

Keywords:  Placenta; fetal growth restriction; side-population trophoblasts; trophoblast stem cells

DOI:  https://doi.org/10.1016/j.yexcr.2025.114684
Psychiatry Clin Neurosci. 2025 Jul 22.

Mosaic variants of neurodevelopmental and mitochondrial genes in postmortem paraventricular thalamus in bipolar disorder detected by deep exome sequencing.

Masaki Nishioka, Zen-Ichi Tanei, Yuko Saito, Maho Morishima, Mizuki Hino, Kanako Mori, Atsuko Nagaoka, Risa Shishido, Rie Saito, Hideaki Kitamura, Akito Nagakura, Araki Kimura, Shuji Iritani, Kenichi Oshima, Akiyoshi Kakita, Yasuto Kunii, Shigeo Murayama, Tadafumi Kato.

   AIM: The genetic architecture of bipolar disorder (BD) remains incompletely understood despite extensive genomic studies. Postzygotic mosaic variants have emerged as promising contributors to BD; however, the landscape of such variants in the BD brain has yet to be elucidated.
METHODS: We analyzed mosaic variants in the paraventricular thalamic region (PVR) from 18 Japanese BD cases and 11 controls using deep whole-exome sequencing. Candidate variants were validated via targeted amplicon sequencing. To explore their biological implications, we performed gene ontology analysis by integrating the brain-derived mosaic variants identified in this study with mosaic variants previously detected in peripheral tissues.
RESULTS: We identified 99 exonic and 13 mitochondrial heteroplasmic variants in the PVR. There was a significant enrichment of deleterious mosaic variants in constrained genes (P = 0.0402) and of non-synonymous mosaic variants in neurodevelopmental genes, particularly those involved in the positive regulation of neuron projection development (false discovery rate = 2.32 × 10-3). These genes also formed a significantly enriched protein-protein interaction network (P = 0.0106). Notably, we detected one mitochondrial variant known to be pathogenic for mitochondrial disease and two predicted pathogenic mitochondrial tRNA variants in BD cases, but none in controls.
CONCLUSION: Despite the modest sample size and potential confounding factors such as age and cancer status, our direct analysis of brain tissue supports previous findings of an enrichment of mosaic variants in neurodevelopmental and mitochondrial tRNA genes. These results advance our understanding of the genetic underpinnings of BD.

Keywords:  bipolar disorder; deep exome sequencing; mitochondria; mosaic variant; postmortem brain

DOI:  https://doi.org/10.1111/pcn.13871
Mol Cell Biochem. 2025 Jul 24.

Sirtuins in mitophagy: key gatekeepers of mitochondrial quality.

Francisco Alejandro Lagunas-Rangel.

  Mitochondria are highly dynamic organelles essential for cellular energy production. However, they are also a primary source of reactive oxygen species, making them particularly vulnerable to oxidative damage. To preserve mitochondrial integrity, cells employ quality control mechanisms such as mitophagy, a selective form of autophagy that targets damaged or dysfunctional mitochondria for degradation. Among the key regulators of mitophagy are the sirtuins, a family of NAD+-dependent deacetylases. SIRT1, SIRT3, and SIRT6 generally promote mitophagy, whereas SIRT2, SIRT4, SIRT5, and SIRT7 often act as negative regulators. Sirtuin-mediated regulation of mitophagy is critical for maintaining cellular homeostasis and is implicated in a variety of physiological and pathological conditions. The aim of this review is to provide an overview focused on describing how sirtuins influence the mitophagy process. It highlights the different molecular mechanisms by which individual members of the sirtuin family modulate mitophagy, either by promoting or suppressing it, depending on the context. In addition, the review explores the relevance of sirtuin-regulated mitophagy in health and disease, emphasizing some conditions under which altered sirtuin activity could be harnessed for therapeutic benefit.

Keywords:  FOXO transcription factors; Mitochondria; PINK1-PARKIN pathway; Receptor-mediated mitophagy; Ubiquitin-mediated mitophagy

DOI:  https://doi.org/10.1007/s11010-025-05358-0