bims-mitmed 2025-05-04 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–05–04
nineteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience.
Ramping up mitochondrial DNA replication.
Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.
Mitochondria Transfer in Mesenchymal Stem Cells: Unraveling the Mechanism and Therapeutic Potential.
Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline.
Dysfunctional Mitochondria Characterize Amyotrophic Lateral Sclerosis Patients' Cells Carrying the p.G376D TARDBP Pathogenetic Substitution.
NAD augmentation as a disease-modifying strategy for neurodegeneration.
Combining In Vivo 2-Photon Imaging with Photoactivatable Fluorescent Labeling Shows Low Rates of Mitochondrial Dynamics in Skeletal Muscle.
Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
Modulation of Lonp1 Activity by Small Compounds.
TSC-mTORC1 Pathway in Postnatal V-SVZ Neurodevelopment.
Altering metabolism programs cell identity via NAD+-dependent deacetylation.
Regional differences in progenitor metabolism shape brain growth during development.
Generation of two human induced pluripotent stem cell lines from Allan-Herndon-Dudley syndrome (AHDS) patients with SLC16A2:G401R or SLC16A2: H192R mutation.
mTOR controls ependymal cell differentiation by targeting the alternative cell cycle and centrosomal proteins.
Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.
Uncovering Mitochondrial Defects Induced by Chemicals: A Case Study of Low-Dose Medium-Chain Chlorinated Paraffin Exposure.

Cell Metab. 2025 Apr 24. pii: S1550-4131(25)00212-8. [Epub ahead of print]

NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.

Sabina Chubanava, Iuliia Karavaeva, Amy M Ehrlich, Roger M Justicia, Astrid L Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N Rodrigues, Jesper F Havelund, Farina L Schlabs, Steen Larsen, Caio Y Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Zachary Gerhart-Hines, Thomas Moritz, Juleen R Zierath, Kei Sakamoto, Thomas E Jensen, Nils J Færgeman, Gareth G Lavery, Atul S Deshmukh, Jonas T Treebak.

  Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD+ abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.

Keywords:  NAD metabolism; NAD(+) biosynthesis; NAMPT; aging; epigenetic clock; exercise; mitochondrial supercomplexes; nicotinamide; reactive oxygen species; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2025.04.002
Am J Hum Genet. 2025 Apr 23. pii: S0002-9297(25)00144-2. [Epub ahead of print]

Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience.

Solve-RD Consortium

  The diagnosis of mitochondrial DNA (mtDNA) diseases remains challenging with next-generation sequencing, where bioinformatic analysis is usually more focused on the nuclear genome. We developed a workflow for the evaluation of mtDNA diseases and applied it in a large European rare disease cohort (Solve-RD). A semi-automated bioinformatic pipeline with MToolBox was used to filter the unsolved Solve-RD cohort for rare mtDNA variants after validating this pipeline on exome datasets of 42 individuals previously diagnosed with mtDNA variants. Variants were filtered based on blood heteroplasmy levels (≥1%) and reported association with disease. Overall, 10,157 exome and genome datasets from 9,923 affected individuals from 9,483 families within Solve-RD met the quality inclusion criteria. 136 mtDNA variants in 135 undiagnosed individuals were prioritized using the filtering approach. A focused MitoPhen-based phenotype similarity scoring method was tested in a separate genetically diagnosed "phenotype test cohort" consisting of nuclear gene and mtDNA diseases using a receiving operator characteristic evaluation. We applied the MitoPhen-based phenotype similarity score of >0.3, which was highly sensitive for detecting mtDNA diseases in the phenotype test cohort, to the filtered cohort of 135 undiagnosed individuals. This aided the prioritization of 34 out of 37 (92%) individuals who received confirmed and likely causative mtDNA disease diagnoses. The phenotypic evaluation was limited by the quality of input data in some individuals. The overall pipeline led to an additional diagnostic yield of 0.4% in a cohort where mitochondrial disease was not initially suspected. This highlights the value of our mtDNA analysis pipeline in diverse datasets.

Keywords:  Solve-RD; bioinformatics; mitochondrial DNA; phenotype similarity; reanalysis

DOI:  https://doi.org/10.1016/j.ajhg.2025.04.003
Nat Rev Drug Discov. 2025 May 02.

Ramping up mitochondrial DNA replication.

Katie Kingwell.

DOI: https://doi.org/10.1038/d41573-025-00079-x
EMBO Rep. 2025 Apr 29.

Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.

Marcos Zamora-Dorta, Sara Laine-Menéndez, David Abia, Pilar González-García, Luis C López, Paula Fernández-Montes, Enrique Calvo, Jesús Vázquez, José Antonio Enríquez, Eduardo Balsa.

  Defects in mitochondrial oxidative metabolism underlie many genetic disorders with limited treatment options. The incomplete annotation of mitochondrial proteins highlights the need for a comprehensive gene inventory, particularly for Oxidative Phosphorylation (OXPHOS). To address this, we developed a CRISPR/Cas9 loss-of-function library targeting nuclear-encoded mitochondrial genes and conducted galactose-based screenings to identify novel regulators of mitochondrial function. Our study generates a gene catalog essential for mitochondrial metabolism and maps a dynamic network of mitochondrial pathways, focusing on OXPHOS complexes. Computational analysis identifies RTN4IP1 and ECHS1 as key OXPHOS genes linked to mitochondrial diseases in humans. RTN4IP1 is found to be crucial for mitochondrial respiration, with complexome profiling revealing its role as an assembly factor required for the complete assembly of complex I. Furthermore, we discovered that ECHS1 controls oxidative metabolism independently of its canonical function in fatty acid oxidation. Its deletion impairs branched-chain amino acids (BCAA) catabolism, disrupting lipoic acid-dependent enzymes such as pyruvate dehydrogenase (PDH). This deleterious phenotype can be rescued by restricting valine intake or catabolism in ECHS1-deficient cells.

Keywords:  CRISPR Screening; ECHS1; Mitochondria; OXPHOS; RTN4IP1

DOI:  https://doi.org/10.1038/s44319-025-00459-9
Curr Stem Cell Res Ther. 2025 Apr 25.

Mitochondria Transfer in Mesenchymal Stem Cells: Unraveling the Mechanism and Therapeutic Potential.

Jingyi Chen, Zhilang Xie, Huayin Zhou, Yingxin Ou, Wenwen Tan, Aizhen Zhang, Yuying Li, Xingliang Fan.

  Mesenchymal stem cells (MSCs) hold transformative potential in translational medicine due to their versatile differentiation abilities and regenerative properties. Notably, MSCs can transfer mitochondria to unrelated cells through intercellular mitochondrial transfer, offering a groundbreaking approach to halting the progression of mitochondrial diseases and restoring function to cells compromised by mitochondrial dysfunction. Although MSC mitochondrial transfer has demonstrated significant therapeutic promise across a range of diseases, its application in clinical settings remains largely unexplored. This review delves into the novel mechanisms by which MSCs execute mitochondrial transfer, highlighting its profound impact on cellular metabolism, immune modulation, and tissue regeneration. We provide an in-depth analysis of the therapeutic potential of MSC mitochondrial transfer, particularly in treating mitochondrial dysfunction-related diseases and advancing tissue repair strategies. Additionally, we propose innovative considerations for optimizing MSC mitochondrial transfer in clinical trials, emphasizing its potential to reshape the landscape of regenerative medicine and therapeutic interventions.

Keywords:  Mesenchymal stem cells; immunomodulation; mitochondrial transfer; oxidative stress; therapeutic potential.

DOI:  https://doi.org/10.2174/011574888X362739250416153254
Nat Metab. 2025 Apr 28.

Intracellular metabolic gradients dictate dependence on exogenous pyruvate.

Benjamin T Jackson, Angela M Montero, Sangita Chakraborty, Julia S Brunner, Paige K Arnold, Anna E Bridgeman, Pavlina K Todorova, Katrina I Paras, Lydia W S Finley.

During developmental transitions, cells frequently remodel metabolic networks, including changing reliance on metabolites such as glucose and glutamine to fuel intracellular metabolic pathways. Here we used embryonic stem (ES) cells as a model system to understand how changes in intracellular metabolic networks that characterize cell state transitions affect reliance on exogenous nutrients. We find that ES cells in the naive ground state of pluripotency increase uptake and reliance on exogenous pyruvate through the monocarboxylate transporter MCT1. Naive ES cells, but not their more committed counterparts, rely on exogenous pyruvate even when other sources of pyruvate (glucose, lactate) are abundant. Pyruvate dependence in naive ES cells is a consequence of their elevated mitochondrial pyruvate consumption at the expense of cytosolic NAD+ regeneration. Indeed, across a range of cell types, increased mitochondrial pyruvate consumption is sufficient to drive demand for extracellular pyruvate. Accordingly, restoring cytosolic NAD+ regeneration allows naive ES cells to tolerate pyruvate depletion in diverse nutrient microenvironments. Together, these data demonstrate that intracellular metabolic gradients dictate uptake and reliance on exogenous pyruvate and highlight mitochondrial pyruvate metabolism as a metabolic vulnerability of naive ES cells.

DOI: https://doi.org/10.1038/s42255-025-01289-8
Cell Metab. 2025 Apr 25. pii: S1550-4131(25)00217-7. [Epub ahead of print]

Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline.

Won-Suk Song, Xiyu Shen, Kang Du, Cuauhtemoc B Ramirez, Sang Hee Park, Yang Cao, Johnny Le, Hosung Bae, Joohwan Kim, Yujin Chun, Nikki Joyce Khong, Marie Kim, Sunhee Jung, Wonsuk Choi, Miranda L Lopez, Zaid Said, Zehan Song, Sang-Guk Lee, Dequina Nicholas, Yo Sasaki, Jeffrey Milbrandt, David K Imagawa, Dorota Skowronska-Krawczyk, Danica Chen, Gina Lee, Cholsoon Jang, Qin Yang.

  Liver-derived circulating nicotinamide from nicotinamide adenine dinucleotide (NAD+) catabolism primarily feeds systemic organs for NAD+ synthesis. We surprisingly found that, despite blunted hepatic NAD+ and nicotinamide production in liver-specific nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) deletion mice (liver-specific knockout [LKO]), circulating nicotinamide and extra-hepatic organs' NAD+ are unaffected. Metabolomics reveals a massive accumulation of a novel molecule in the LKO liver, which we identify as nicotinic acid riboside (NaR). We further demonstrate cytosolic 5'-nucleotidase II (NT5C2) as the NaR-producing enzyme. The liver releases NaR to the bloodstream, and kidneys take up NaR to synthesize NAD+ through nicotinamide riboside kinase 1 (NRK1) and replenish circulating nicotinamide. Serum NaR levels decline with aging, whereas oral NaR supplementation in aged mice boosts serum nicotinamide and multi-organ NAD+, including kidneys, and reduces kidney inflammation and albuminuria. Thus, the liver-kidney axis maintains systemic NAD+ homeostasis via circulating NaR, and NaR supplement ameliorates aging-associated NAD+ decline and kidney dysfunction.

Keywords:  NAD(+); aging; kidney; liver; nicotinic acid riboside

DOI:  https://doi.org/10.1016/j.cmet.2025.04.007
Antioxidants (Basel). 2025 Mar 28. pii: 401. [Epub ahead of print]14(4):

Dysfunctional Mitochondria Characterize Amyotrophic Lateral Sclerosis Patients' Cells Carrying the p.G376D TARDBP Pathogenetic Substitution.

Giuseppe Petito, Victoria Stefania Del Fiore, Arianna Cuomo, Federica Cioffi, Gilda Cobellis, Antonia Lanni, Flora Guerra, Cecilia Bucci, Rosalba Senese, Roberta Romano.

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the degeneration of upper and lower motor neurons in the brain, brainstem and spinal cord. About 10% of familial ALS cases are linked to pathogenetic substitution in TARDBP, the gene encoding the TDP-43 protein. A novel rare causative variant in TARDBP (p.G376D) was recently reported in ALS patients. It leads to TDP-43 cytoplasmic mislocalization, increased oxidative stress and reduced cell viability. However, functional studies on the effects of this molecular defect have not yet been carried out. Mitochondria are highly dynamic organelles, and their deregulation has emerged as a key factor in many diseases, among which is ALS. Therefore, this study aimed at determining the impact of this causative variant on mitochondria. In cellular models expressing TDP-43G376D and in fibroblasts derived from patients carrying this molecular defect, we observed alterations of mitochondrial functionality. We demonstrated increased localization of the mutated protein to mitochondria and a reduced abundance of subunits of complex I and complex II of the mitochondrial respiratory chain, associated with a decrease in mitochondrial membrane potential, in cellular respiration and in cytochrome C oxidase (COX) activity. Moreover, ALS cells showed increased mitochondrial fragmentation and reduced abundance of antioxidant enzymes causing increased oxidative stress. These results expand our knowledge about the molecular mechanisms underlying ALS pathogenesis associated with TDP-43 p.G376D and could help to identify new therapeutic strategies to counteract this disease.

Keywords:  TARDBP; TDP-43; amyotrophic lateral sclerosis; mitochondria; oxidative stress

DOI:  https://doi.org/10.3390/antiox14040401
Trends Endocrinol Metab. 2025 Apr 25. pii: S1043-2760(25)00070-0. [Epub ahead of print]

NAD augmentation as a disease-modifying strategy for neurodegeneration.

Christian Dölle, Charalampos Tzoulis.

  Neurodegenerative diseases (NDDs) pose a significant and rapidly growing global health challenge, but there are no effective therapies to delay or halt progression. In recent years augmentation of nicotinamide adenine dinucleotide (NAD) has emerged as a promising disease-modifying strategy that targets multiple key disease pathways across multiple NDDs, such as mitochondrial dysfunction, energy deficits, proteostasis, and neuroinflammation. Several early clinical trials of NAD augmentation have been completed, and many more are currently underway, reflecting the growing optimism and urgency within the field. We discuss the rationale and evolving therapeutic landscape of NAD augmentation. We argue that, to fully realize its therapeutic potential, it is essential to determine the specific contexts in which NAD supplementation is most effective and to address crucial knowledge gaps.

Keywords:  Parkinson's disease; neurodegenerative disease; therapeutic

DOI:  https://doi.org/10.1016/j.tem.2025.03.013
Med Sci Sports Exerc. 2025 May 01.

Combining In Vivo 2-Photon Imaging with Photoactivatable Fluorescent Labeling Shows Low Rates of Mitochondrial Dynamics in Skeletal Muscle.

Colleen L O'Reilly, Arik Davidyan, Katarzyna Cizio, Stephen M Doidge, Matthew P Bubak, Agnieszka K Borowik, Tommy L Lewis, Benjamin F Miller.

   INTRODUCTION: Mitochondrial dynamics involve two distinct and opposing processes, fusion and fission. Traditionally we assess fusion and fission by snapshots of protein markers at distinct time points or in vitro models to infer outcomes in vivo. Recent technological advancements enable visualization of mitochondrial dynamics in vivo using fluorescent microscopy.
METHODS: Our study modified this technique to evaluate mitochondrial dynamics in skeletal muscle, comparing young (6mo) and old (24mo) mice in vivo and contrasting this to ex vivo and in vitro models. We hypothesized that in vitro and ex vivo models would have higher rates of dynamics than in vivo models and that young animals would have higher rates than old animals. We electroporated mitochondrial matrix-targeted photo-activatable GFP into the tibialis anterior (TA) of young and old C57Bl6 mice and imaged using multiphoton microscopy. We also measured rates of mitochondrial dynamics using single fibers isolated from the TA of the electroporated mice, as well as C2C12 myotubes transfected with the same plasmids.
RESULTS: We found that the rates of dynamic events in vivo are slower than previously indicated, with the C2C12 myoblasts having the fastest rates of dynamic events across all models. We also observed that dynamic rates are slower in old animals compared to young animals. Finally, we found that rates of dynamic events were higher in old animals after an acute bout of exercise.
CONCLUSIONS: Our data demonstrate it is possible to directly measure rates of mitochondrial dynamics in vivo. This technique provides a powerful tool to answer experimental questions about mitochondrial dynamics of skeletal muscle.

Keywords:  FISSION; FUSION; MITOCHONDRIAL DYNAMICS; SKELETAL MUSCLE

DOI:  https://doi.org/10.1249/MSS.0000000000003748
Nat Commun. 2025 Apr 29. 16(1): 4029

Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.

Mateus Prates Mori, Oswaldo A Lozoya, Ashley M Brooks, Carl D Bortner, Cristina A Nadalutti, Birgitta Ryback, Brittany P Rickard, Marta Overchuk, Imran Rizvi, Tatiana Rogasevskaia, Kai Ting Huang, Prottoy Hasan, György Hajnóczky, Janine H Santos.

Maintenance of the mitochondrial inner membrane potential (ΔΨm) is critical for many aspects of mitochondrial function. While ΔΨm loss and its consequences are well studied, little is known about the effects of mitochondrial hyperpolarization. In this study, we used cells deleted of ATP5IF1 (IF1), a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of increased resting ΔΨm. We found that the nuclear DNA hypermethylates when the ΔΨm is chronically high, regulating the transcription of mitochondrial, carbohydrate and lipid genes. These effects can be reversed by decreasing the ΔΨm and recapitulated in wild-type (WT) cells exposed to environmental chemicals that cause hyperpolarization. Surprisingly, phospholipid changes, but not redox or metabolic alterations, linked the ΔΨm to the epigenome. Sorted hyperpolarized WT and ovarian cancer cells naturally depleted of IF1 also showed phospholipid remodeling, indicating this as an adaptation to mitochondrial hyperpolarization. These data provide a new framework for how mitochondria can impact epigenetics and cellular biology to influence health outcomes, including through chemical exposures and in disease states.

DOI: https://doi.org/10.1038/s41467-025-59427-5
Biomolecules. 2025 Apr 09. pii: 553. [Epub ahead of print]15(4):

Modulation of Lonp1 Activity by Small Compounds.

Giada Zanini, Giulia Micheloni, Giorgia Sinigaglia, Valentina Selleri, Anna Vittoria Mattioli, Milena Nasi, Ciro Leonardo Pierri, Marcello Pinti.

  The Lon protease homolog 1 (LONP1) is an ATP-dependent mitochondrial protease essential for maintaining proteostasis, bioenergetics, and cellular homeostasis. LONP1 plays a pivotal role in protein quality control, mitochondrial DNA maintenance, and oxidative phosphorylation system (OXPHOS) regulation, particularly under stress conditions. Dysregulation of LONP1 has been implicated in various pathologies, including cancer, metabolic disorders, and reproductive diseases, positioning it as a promising pharmacological target. This review examines compounds that modulate LONP1 activity, categorizing them into inhibitors and activators. Inhibitors such as CDDO and its derivatives selectively target LONP1, impairing mitochondrial proteolysis, inducing protein aggregation, and promoting apoptosis, particularly in cancer cells. Compounds like Obtusilactone A and proteasome inhibitors (e.g., MG262) demonstrate potent cytotoxicity, further expanding the therapeutic landscape. Conversely, LONP1 activators, including Artemisinin derivatives and 84-B10, restore mitochondrial function and protect against conditions such as polycystic ovary syndrome (PCOS) and acute kidney injury (AKI). Future research should focus on improving the specificity, bioavailability, and pharmacokinetics of these modulators. Advances in structural biology and drug discovery will enable the development of novel LONP1-targeted therapies, addressing diseases driven by mitochondrial dysfunction and proteostasis imbalance.

Keywords:  CDDO; Lon protease; artemisinin; bardoxolone; bortezomib; cancer therapy; proteasome inhibitors; protein quality control; proteostasis

DOI:  https://doi.org/10.3390/biom15040553
Biomolecules. 2025 Apr 12. pii: 573. [Epub ahead of print]15(4):

TSC-mTORC1 Pathway in Postnatal V-SVZ Neurodevelopment.

David M Feliciano, Angelique Bordey.

  In restricted regions of the rodent brain, neurogenesis persists throughout life, hinting that perhaps similar phenomena may exist in humans. Neural stem cells (NSCs) that reside within the ventricular-subventricular zone (V-SVZ) continually produce functional cells, including neurons that integrate into the olfactory bulb circuitry. The ability to achieve this feat is based on genetically encoded transcriptional programs that are controlled by environmentally regulated post-transcriptional signaling pathways. One such pathway that molds V-SVZ neurogenesis is the mTOR pathway. This pathway integrates nutrient sufficiency with growth factor signaling to control distinct steps of neurogenesis. Alterations in mTOR pathway signaling occur in numerous neurodevelopmental disorders. Here, we provide a narrative review for the role of the mTOR pathway in this process and discuss the use of this region to study the mTOR pathway in both health and disease.

Keywords:  TSC; TSC1; TSC2; mTOR; mTORC1; neurogenesis

DOI:  https://doi.org/10.3390/biom15040573
EMBO J. 2025 Apr 25.

Altering metabolism programs cell identity via NAD+-dependent deacetylation.

Robert A Bone, Molly P Lowndes, Silvia Raineri, Alba R Riveiro, Sarah L Lundregan, Morten Dall, Karolina Sulek, Jose A H Romero, Luna Malzard, Sandra Koigi, Indra J Heckenbach, Victor Solis-Mezarino, Moritz Völker-Albert, Catherine G Vasilopoulou, Florian Meier, Ala Trusina, Matthias Mann, Michael L Nielsen, Jonas T Treebak, Joshua M Brickman.

  Cells change their metabolic profiles in response to underlying gene regulatory networks, but how can alterations in metabolism encode specific transcriptional instructions? Here, we show that forcing a metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the early mammalian blastocyst in cultures. This shift in cellular identity depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS) triggered by the replacement of D-glucose by D-galactose in ESC media. Enhanced OXPHOS in turn activates NAD + -dependent deacetylases of the Sirtuin family, resulting in the deacetylation of histones and key transcription factors to focus enhancer activity while reducing transcriptional noise, which results in a robustly enhanced ESC phenotype. This exploitation of a NAD + /NADH coenzyme coupled to OXPHOS as a means of programming lineage-specific transcription suggests new paradigms for how cells respond to alterations in their environment, and implies cellular rejuvenation exploits enzymatic activities for simultaneous activation of a discrete enhancer set alongside silencing genome-wide transcriptional noise.

Keywords:  Aging; Enhancers; Metabolism; Pluripotency; Sirtuins

DOI:  https://doi.org/10.1038/s44318-025-00417-0
Cell. 2025 Apr 25. pii: S0092-8674(25)00405-2. [Epub ahead of print]

Regional differences in progenitor metabolism shape brain growth during development.

Natalia Baumann, Robin J Wagener, Awais Javed, Eleonora Conti, Philipp Abe, Andrea Lopes, Roberto Sansevrino, Adrien Lavalley, Elia Magrinelli, Timea Szalai, Daniel Fuciec, Clothilde Ferreira, Sabine Fièvre, Andreane Fouassier, Davide D'Amico, Oliver Harschnitz, Denis Jabaudon.

  Mammals have particularly large forebrains compared with other brain parts, yet the developmental mechanisms underlying this regional expansion remain poorly understood. Here, we provide a single-cell-resolution birthdate atlas of the mouse brain (www.neurobirth.org), which reveals that while hindbrain neurogenesis is transient and restricted to early development, forebrain neurogenesis is temporally sustained through reduced consumptive divisions of ventricular zone progenitors. This atlas additionally reveals region-specific patterns of direct and indirect neurogenesis. Using single-cell RNA sequencing, we identify evolutionarily conserved cell-cycle programs and metabolism-related molecular pathways that control regional temporal windows of proliferation. We identify the late neocortex-enriched mitochondrial protein FAM210B as a key regulator using in vivo gain- and loss-of-function experiments. FAM210B elongates mitochondria and increases lactate production, which promotes progenitor self-replicative divisions and, ultimately, the larger clonal size of their progeny. Together, these findings indicate that spatiotemporal heterogeneity in mitochondrial function regulates regional progenitor cycling behavior and associated clonal neuronal production during brain development.

Keywords:  brain development; metabolism; mitochondria dynamics; progenitor diversity

DOI:  https://doi.org/10.1016/j.cell.2025.04.003
Stem Cell Res. 2025 Apr 25. pii: S1873-5061(25)00075-3. [Epub ahead of print]86 103725

Generation of two human induced pluripotent stem cell lines from Allan-Herndon-Dudley syndrome (AHDS) patients with SLC16A2:G401R or SLC16A2: H192R mutation.

Katarzyna A Ludwik, Judit Küchler, David Sebinger, Robert Opitz, Peter Kühnen, Harald Stachelscheid.

Allan-Herndon-Dudley syndrome (AHDS) is an X-linked disorder characterized by profound psychomotor impairment. It is caused by mutations in the SLC16A2 gene, which encodes monocarboxylate transporter 8 (MCT8), a crucial thyroid hormone transporter. Here we report generation of two male patient-derived iPSC lines harboring either SLC16A2:G401R or SLC16A2:H192R.

DOI: https://doi.org/10.1016/j.scr.2025.103725
EMBO Rep. 2025 Apr 30.

mTOR controls ependymal cell differentiation by targeting the alternative cell cycle and centrosomal proteins.

Alexia Bankolé, Ayush Srivastava, Asm Shihavuddin, Khaled Tighanimine, Marion Faucourt, Vonda Koka, Solene Weill, Ivan Nemazanyy, Alissa J Nelson, Matthew P Stokes, Nathalie Delgehyr, Auguste Genovesio, Alice Meunier, Stefano Fumagalli, Mario Pende, Nathalie Spassky.

  Ependymal cells are multiciliated glial cells lining the ventricles of the mammalian brain. Their differentiation from progenitor cells involves cell enlargement and progresses through centriole amplification phases and ciliogenesis. These phases are accompanied by the sharp up-regulation of mTOR Complex 1 activity (mTORC1), a master regulator of macromolecule biosynthesis and cell growth, whose function in ependymal cell differentiation is unknown. We demonstrate that mTORC1 inhibition by rapamycin preserves the progenitor pool by reinforcing quiescence and preventing alternative cell cycle progression for centriole amplification. Overexpressing E2F4 and MCIDAS circumvents mTORC1-regulated processes, enabling centriole amplification despite rapamycin, and enhancing mTORC1 activity through positive feedback. Acute rapamycin treatment in multicentriolar cells during the late phases of differentiation causes centriole regrouping, indicating a direct role of mTORC1 in centriole dynamics. By phosphoproteomic and phosphomutant analysis, we reveal that the mTORC1-mediated phosphorylation of GAS2L1, a centrosomal protein that links actin and microtubule cytoskeletons, participates in centriole disengagement. This multilayered and sequential control of ependymal development by mTORC1, from the progenitor pool to centriolar function, has implications for pathophysiological conditions like aging and hydrocephalus-prone genetic diseases.

Keywords:  Cell Cycle; Ciliogenesis; Cytoskeleton; Differentiation; mTOR

DOI:  https://doi.org/10.1038/s44319-025-00460-2
Dev Cell. 2025 Apr 18. pii: S1534-5807(25)00206-0. [Epub ahead of print]

Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.

Wanxin Guo, Congcong Zhang, Qianjun Zhou, Tianxiang Chen, Xin Xu, Jianfeng Zhang, Xuewen Yu, Han Wu, Xiao Zhang, Lifang Ma, Kun Qian, Daniel J Klionsky, Rui Kang, Guido Kroemer, Yongchun Yu, Daolin Tang, Jiayi Wang.

  Ferroptosis is a type of oxidative cell death, although its key metabolic processes remain incompletely understood. Here, we employ a comprehensive multiomics screening approach that identified cellular communication network factor 1 (CCN1) as a metabolic catalyst of ferroptosis. Upon ferroptosis induction, CCN1 relocates to mitochondrial complexes, facilitating electron transfer flavoprotein subunit alpha (ETFA)-dependent fatty acid β-oxidation. Compared with a traditional carnitine O-palmitoyltransferase 2 (CPT2)-ETFA pathway, the CCN1-ETFA pathway provides additional substrates for mitochondrial reactive oxygen species production, thereby stimulating ferroptosis through lipid peroxidation. A high-fat diet can enhance the anticancer efficacy of ferroptosis in lung cancer mouse models, depending on CCN1. Furthermore, primary lung cancer cells derived from patients with hypertriglyceridemia or high CCN1 expression demonstrate increased susceptibility to ferroptosis in vitro and in vivo. These findings do not only identify the metabolic role of mitochondrial CCN1 but also establish a strategy for enhancing ferroptosis-based anticancer therapies.

Keywords:  CCN1; cell death; mitochondria

DOI:  https://doi.org/10.1016/j.devcel.2025.04.004
Environ Sci Technol. 2025 Apr 28.

Uncovering Mitochondrial Defects Induced by Chemicals: A Case Study of Low-Dose Medium-Chain Chlorinated Paraffin Exposure.

Ningbo Geng, Shuangshuang Chen, Yangyang Bian, Chengcheng Shi, Chenhao Huang, Lin Cheng, Yun Luo, Ying Yu, Yuan Gao, Li Wang, Haijun Zhang, Yufeng Gong, Jiping Chen.

  Given the susceptibility of mitochondria to environmental pollutants, mitochondrial defects are critical end points for chemical safety evaluation. In this study, we present a comprehensive strategy for assessing mitochondrial toxicity, exemplified through a case study on medium-chain chlorinated paraffins (MCCPs, CxH2x+2-yCly with 14-17 carbon atoms), one of the most abundant organic pollutants in the human body. Our results demonstrate that MCCP exposure at levels commonly found in humans significantly reduces cellular ATP content by impairing mitochondrial respiration rather than glycolysis. Using an optimized mitochondrial metabolomics approach combined with dose-resolved proteomics, we elucidated the molecular mechanisms underlying MCCP-induced mitochondrial defects, including inhibition of the electron transport chain, mitochondrial membrane damage, accumulation of reactive oxygen species, and disruptions in nucleotide metabolism. Notably, over 80% of the MCCP-regulated mitochondrial proteins exhibited EC50 values below the human internal levels of MCCPs, highlighting a significant threat to human health. This proposed strategy for mitochondrial toxicity assessment is expected to facilitate future research in mitochondrial toxicology.

Keywords:  MCCPs; Seahorse respirometry; TCA; mitochondrial metabolomics; oxidative phosphorylation; proteomics-based dose−response curve

DOI:  https://doi.org/10.1021/acs.est.4c09460