bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–02–02
29 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Correcting a pathogenic mitochondrial DNA mutation by base editing in mice.
  2. FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.
  3. Mitochondrial base editing: from principle, optimization to application.
  4. Characterization of Factors Associated With Death in Deceased Patients With Mitochondrial Disorders: A Multicenter Cross-Sectional Survey.
  5. Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.
  6. NADH Reductive Stress and Its Correlation with Disease Severity in Leigh Syndrome: A Pilot Study Using Patient Fibroblasts and a Mouse Model.
  7. Novel strategies targeting mitochondria-lysosome contact sites for the treatment of neurological diseases.
  8. Placental mitochondrial metabolic adaptation maintains cellular energy balance in pregnancy complicated by gestational hypoxia.
  9. The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.
  10. Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.
  11. Regulation of mitochondrial cristae organization by Myo19, Miro1/2 and Metaxin 3.
  12. De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy-Case Report and Literature Review.
  13. Remodeling of Mitochondria-Endoplasmic Reticulum Contact Sites Accompanies LUHMES Differentiation.
  14. Mechanism of chaperone recruitment and retention on mitochondrial precursors.
  15. Epigenetic Threads of Neurodegeneration: TFAM's Intricate Role in Mitochondrial Transcription.
  16. SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters.
  17. Comprehensive analysis of GDF15 as a biomarker in primary mitochondrial myopathies.
  18. Genome-wide CRISPR screens identify PTPN21 and WDR26 as modulators of the mitochondrial stress-induced ISR.
  19. Epigenetic modification increases skeletal muscle resilience to metabolic stress.
  20. SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation.
  21. Decrease of NAD+ Inhibits the Apoptosis of OLP T Cells via Inducing Mitochondrial Fission.
  22. Hierarchical inhibition of mTORC1 by glucose starvation-triggered AXIN lysosomal translocation and by AMPK.
  23. The landscape of rare mitochondrial DNA variants in sudden cardiac death: A potential role for ATP synthase.
  24. Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
  25. Characterization of the putative yeast mitochondrial triacylglycerol lipase Tgl2.
  26. Repurposing Mitochondria-Targeted Therapeutics for Kidney Diseases.
  27. Spiking Patterns in the Globus Pallidus Highlight Convergent Neural Dynamics across Diverse Genetic Dystonia Syndromes.
  28. Prenatal gene editing for neurodevelopmental diseases: Ethical considerations.
  29. Nicotinamide mononucleotide restores impaired metabolism, endothelial cell proliferation and angiogenesis in old sedentary male mice.
  1. Sci Transl Med. 2025 Jan 29. 17(783): eadr0792
    Correcting a pathogenic mitochondrial DNA mutation by base editing in mice.
    Jose D Barrera-Paez, Sandra R Bacman, Till Balla, Derek Van Booven, Durga P Gannamedi, James B Stewart, Beverly Mok, David R Liu, David B Lombard, Anthony J Griswold, Danny D Nedialkova, Carlos T Moraes.
      Primary mitochondrial disorders are most often caused by deleterious mutations in the mitochondrial DNA (mtDNA). Here, we used a mitochondrial DddA-derived cytosine base editor (DdCBE) to introduce a compensatory edit in a mouse model that carries the pathological mutation in the mitochondrial transfer RNA (tRNA) alanine (mt-tRNAAla) gene. Because the original m.5024C→T mutation (G→A in the mt-tRNAAla) destabilizes the mt-tRNAAla aminoacyl stem, we designed a compensatory m.5081G→A edit (C→T in the mt-tRNAAla) that could restore the secondary structure of the tRNAAla aminoacyl stem. For this, the DdCBE gene construct was initially tested in an m.5024C→T mutant cell line. The reduced mt-tRNAAla amounts in these cells were increased after editing up to 78% of the mtDNA. Then, DdCBE was packaged in recombinant adeno-associated virus 9 (AAV9) and intravenously administered by retro-orbital injections into mice. Expression of the transduced DdCBE was observed in the heart and skeletal muscle. Total mt-tRNAAla amounts were restored in heart and muscle by the m.5081G→A edit in a dose-dependent manner. Lactate amounts, which were increased in the heart, were also decreased in treated mice. However, the highest dose tested of AAV9-DdCBE also induced severe adverse effects in vivo because of the extensive mtDNA off-target editing that it generated. These results show that although DdCBE is a promising gene therapy tool for mitochondrial disorders, the doses of the therapeutic constructs must be carefully monitored to avoid deleterious off-target editing.
    DOI:  https://doi.org/10.1126/scitranslmed.adr0792
  2. J Cell Biol. 2025 Mar 03. pii: e202311082. [Epub ahead of print]224(3):
    FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.
    Alva G Sainz, Gladys R Rojas, Alexandra G Moyzis, Matthew P Donnelly, Kailash C Mangalhara, Melissa A Johnson, Pau B Esparza-Moltó, Kym J Grae, Reuben J Shaw, Gerald S Shadel.
      Mitochondrial retrograde signaling (MRS) pathways relay the functional status of mitochondria to elicit homeostatic or adaptive changes in nuclear gene expression. Budding yeast have "intergenomic signaling" pathways that sense the amount of mitochondrial DNA (mtDNA) independently of oxidative phosphorylation (OXPHOS), the primary function of genes encoded by mtDNA. However, MRS pathways that sense the amount of mtDNA in mammalian cells remain poorly understood. We found that mtDNA-depleted IMR90 cells can sustain OXPHOS for a significant amount of time, providing a robust model system to interrogate human intergenomic signaling. We identified FAM43A, a largely uncharacterized protein, as a CHK2-dependent early responder to mtDNA depletion. Depletion of FAM43A activates a mitochondrial biogenesis program, resulting in an increase in mitochondrial mass and mtDNA copy number via CHK2-mediated upregulation of the p53R2 form of ribonucleotide reductase. We propose that FAM43A performs a checkpoint-like function to limit mitochondrial biogenesis and turnover under conditions of mtDNA depletion or replication stress.
    DOI:  https://doi.org/10.1083/jcb.202311082
  3. Cell Biosci. 2025 Jan 24. 15(1): 9
    Mitochondrial base editing: from principle, optimization to application.
    Jinling Tang, Kunzhao Du.
      In recent years, mitochondrial DNA (mtDNA) base editing systems have emerged as bioengineering tools. DddA-derived cytosine base editors (DdCBEs) have been developed to specifically induce C-to-T conversion in mtDNA by the fusion of sequence-programmable transcription activator-like effector nucleases (TALENs) or zinc-finger nucleases (ZFNs), and split deaminase derived from interbacterial toxins. Similar to DdCBEs, mtDNA adenine base editors have been developed with the ability to introduce targeted A-to-G conversions into human mtDNA. In this review, we summarize the principles of mtDNA base-editing systems and elaborate on the evolution of different platforms of mtDNA base editors, including their deaminase replacement, engineering of DddAtox variants, structure optimization and editing outcomes. Finally, we highlight their applications in animal models and human embroys and discuss the future developmental direction and challenges of mtDNA base editors.
    Keywords:  DdCBEs; Genetic engineering; Mitochondrial DNA; TALENs; mtDNA base editing
    DOI:  https://doi.org/10.1186/s13578-025-01351-8
  4. Neurology. 2025 Feb 25. 104(4): e209779
    Characterization of Factors Associated With Death in Deceased Patients With Mitochondrial Disorders: A Multicenter Cross-Sectional Survey.
    as the Hong Kong Mitochondrial Diseases Interest Group
       BACKGROUND AND OBJECTIVES: Mitochondrial disorders are multiorgan disorders resulting in significant morbidity and mortality. We aimed to characterize death-associated factors in an international cohort of deceased individuals with mitochondrial disorders.
    METHODS: This cross-sectional multicenter observational study used data provided by 26 mitochondrial disease centers from 8 countries from January 2022 to March 2023. Individuals with genetically confirmed mitochondrial disorders were included, along with patients with clinically or genetically diagnosed Leigh syndrome. Collected data included demographic and genetic diagnosis variables, clinical phenotype, involvement of organs and systems, conditions leading to death, and supportive care. We defined pediatric and adult groups based on age at death before or after 18 years, respectively. We used Kruskal-Wallis with post hoc Dunn test with Bonferroni correction and Fisher exact test for comparisons, Spearman rank test for correlations, and multiple linear regression for multivariable analysis.
    RESULTS: Data from 330 deceased individuals with mitochondrial disorders (191 [57.9%] pediatric) were analyzed. The shortest survival times were observed in hepatocerebral syndrome (median 0.3, interquartile range [IQR] 0.2-0.6 years) and mitochondrial cardiomyopathy (median 0.3, IQR 0.2-5.2 years) and the longest in chronic progressive external ophthalmoplegia plus (median 26.5, IQR 22.8-40.2 years) and sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (median 21.0, IQR 13.8-28.5 years). Respiratory failure and pulmonary infections were the most common conditions associated with death (52/330, 15.7% and 46/330, 13.9%, respectively). Noninvasive ventilation was required more often in children (57/191, 29.8%) than adults (12/139, 8.6%, p < 0.001), as was nasogastric or gastric tube (131/191, 68.6% in children and 39/139, 28.1% in adults, p < 0.001). On multivariate analysis, individuals with movement disorders and nuclear gene involvement had increased odds of any respiratory support use (OR 2.42 (95% CI 1.17-5.22) and OR 2.39 (95% CI 1.16-5.07), respectively).
    DISCUSSION: This international collaboration highlights the importance of respiratory care and infection management and provides a reference for prognostication across different mitochondrial disorders.
    DOI:  https://doi.org/10.1212/WNL.0000000000209779
  5. Nat Cell Biol. 2025 Jan 24.
    Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.
      
    DOI:  https://doi.org/10.1038/s41556-024-01603-8
  6. Biomolecules. 2024 Dec 31. pii: 38. [Epub ahead of print]15(1):
    NADH Reductive Stress and Its Correlation with Disease Severity in Leigh Syndrome: A Pilot Study Using Patient Fibroblasts and a Mouse Model.
    Tamaki Ishima, Natsuka Kimura, Mizuki Kobayashi, Chika Watanabe, Eriko F Jimbo, Ryosuke Kobayashi, Takuro Horii, Izuho Hatada, Kei Murayama, Akira Ohtake, Ryozo Nagai, Hitoshi Osaka, Kenichi Aizawa.
      Nicotinamide adenine dinucleotide (NAD) is a critical cofactor in mitochondrial energy production. The NADH/NAD+ ratio, reflecting the balance between NADH (reduced) and NAD+ (oxidized), is a key marker for the severity of mitochondrial diseases. We recently developed a streamlined LC-MS/MS method for the precise measurement of NADH and NAD+. Utilizing this technique, we quantified NADH and NAD+ levels in fibroblasts derived from pediatric patients and in a Leigh syndrome mouse model in which mitochondrial respiratory chain complex I subunit Ndufs4 is knocked out (KO). In patient-derived fibroblasts, NAD+ levels did not differ significantly from those of healthy controls (p = 0.79); however, NADH levels were significantly elevated (p = 0.04), indicating increased NADH reductive stress. This increase, observed despite comparable total NAD(H) levels between the groups, was attributed to elevated NADH levels. Similarly, in the mouse model, NADH levels were significantly increased in the KO group (p = 0.002), further suggesting that NADH elevation drives reductive stress. This precise method for NADH measurement is expected to outperform conventional assays, such as those for lactate, providing a simpler and more reliable means of assessing disease progression.
    Keywords:  LC-MS/MS; Leigh syndrome; NADH; Ndufs4-KO mice; mitochondrial diseases; reductive stress
    DOI:  https://doi.org/10.3390/biom15010038
  7. Front Mol Neurosci. 2024 ;17 1527013
    Novel strategies targeting mitochondria-lysosome contact sites for the treatment of neurological diseases.
    Yinyin Xie, Wenlin Sun, Aoya Han, Xinru Zhou, Shijie Zhang, Changchang Shen, Yi Xie, Cui Wang, Nanchang Xie.
      Mitochondria and lysosomes are critical for neuronal homeostasis, as highlighted by their dysfunction in various neurological diseases. Recent studies have identified dynamic membrane contact sites between mitochondria and lysosomes, independent of mitophagy and the lysosomal degradation of mitochondrial-derived vesicles (MDVs), allowing bidirectional crosstalk between these cell compartments, the dynamic regulation of organelle networks, and substance exchanges. Emerging evidence suggests that abnormalities in mitochondria-lysosome contact sites (MLCSs) contribute to neurological diseases, including Parkinson's disease, Charcot-Marie-Tooth (CMT) disease, lysosomal storage diseases, and epilepsy. This article reviews recent research advances regarding the tethering processes, regulation, and function of MLCSs and their role in neurological diseases.
    Keywords:  lysosomal dynamics; mitochondria-lysosome contact sites; mitochondrial network; mitophagy; neurological diseases; substance exchanges
    DOI:  https://doi.org/10.3389/fnmol.2024.1527013
  8. J Physiol. 2025 Jan 27.
    Placental mitochondrial metabolic adaptation maintains cellular energy balance in pregnancy complicated by gestational hypoxia.
    Wen Tong, Beth J Allison, Kirsty L Brain, Olga V Patey, Youguo Niu, Kimberley J Botting, Sage G Ford, Tess A Garrud, Peter F B Wooding, Qiang Lyu, Lin Zhang, Jin Ma, Alice P Sowton, Katie A O'Brien, Tereza Cindrova-Davies, Hong Wa Yung, Graham J Burton, Andrew J Murray, Dino A Giussani.
      The mechanisms that drive placental dysfunction in pregnancies complicated by hypoxia and fetal growth restriction remain poorly understood. Changes to mitochondrial respiration contribute to cellular dysfunction in conditions of hypoxia and have been implicated in the pathoaetiology of pregnancy complications, such as pre-eclampsia. We used bespoke isobaric hypoxic chambers and a combination of functional, molecular and imaging techniques to study cellular metabolism and mitochondrial dynamics in sheep undergoing hypoxic pregnancy. We show that hypoxic pregnancy in sheep triggers a shift in capacity away from β-oxidation and complex I-mediated respiration, while maintaining total oxidative phosphorylation capacity. There are also complex-specific changes to electron transport chain composition and a switch in mitochondrial dynamics towards fission. Hypoxic placentas show increased activation of the non-canonical mitochondrial unfolded protein response pathway and enhanced insulin like growth factor 2 signalling. Combined, therefore, the data show that the hypoxic placenta undergoes significant metabolic and morphological adaptations to maintain cellular energy balance. Chronic hypoxia during pregnancy in sheep activated placental mitochondrial stress pathways, leading to alterations in mitochondrial respiration, mitochondrial energy metabolism and mitochondrial dynamics, as seen in the placenta of women with pre-eclampsia. KEY POINTS: Hypoxia shifts mitochondrial respiration away from β-oxidation and complex I. Complex-specific changes occur in the electron transport chain composition. Activation of the non-canonical mitochondrial unfolded protein response pathway is heightened in hypoxic placentas. Enhanced insulin like growth factor 2 signalling is observed in hypoxic placentas. Hypoxic placentas undergo significant functional adaptations for energy balance.
    Keywords:  chronic hypoxia; metabolic homeostasis; mitochondrial reactive oxygen species; mitochondrial respiration; non‐canonical mitochondrial unfolded protein response; placental metabolism
    DOI:  https://doi.org/10.1113/JP287897
  9. Nat Commun. 2025 Jan 25. 16(1): 1021
    The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.
    Foozhan Tahmasebinia, Yinglu Tang, Rushi Tang, Yi Zhang, Will Bonderer, Maisa de Oliveira, Bretton Laboret, Songjie Chen, Ruiqi Jian, Lihua Jiang, Michael Snyder, Chun-Hong Chen, Yawei Shen, Qing Liu, Boxiang Liu, Zhihao Wu.
      The 40S ribosomal subunit recycling pathway is an integral link in the cellular quality control network, occurring after translational errors have been corrected by the ribosome-associated quality control (RQC) machinery. Despite our understanding of its role, the impact of translation quality control on cellular metabolism remains poorly understood. Here, we reveal a conserved role of the 40S ribosomal subunit recycling (USP10-G3BP1) complex in regulating mitochondrial dynamics and function. The complex binds to fission-fusion proteins located at mitochondrial hotspots, regulating the functional assembly of endoplasmic reticulum-mitochondria contact sites (ERMCSs). Furthermore, it alters the activity of mTORC1/2 pathways, suggesting a link between quality control and energy fluctuations. Effective communication is essential for resolving proteostasis-related stresses. Our study illustrates that the USP10-G3BP1 complex acts as a hub that interacts with various pathways to adapt to environmental stimuli promptly. It advances our molecular understanding of RQC regulation and helps explain the pathogenesis of human proteostasis and mitochondrial dysfunction diseases.
    DOI:  https://doi.org/10.1038/s41467-025-56346-3
  10. Cell Death Dis. 2025 Jan 25. 16(1): 40
    Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.
    Lohans Pedrera, Laura Prieto Clemente, Alina Dahlhaus, Sara Lotfipour Nasudivar, Sofya Tishina, Daniel Olmo González, Jenny Stroh, Fatma Isil Yapici, Randhwaj Pratap Singh, Nils Grotehans, Thomas Langer, Ana J García-Sáez, Silvia von Karstedt.
      Constitutive mitochondrial dynamics ensure quality control and metabolic fitness of cells, and their dysregulation has been implicated in various human diseases. The large GTPase Dynamin-related protein 1 (Drp1) is intimately involved in mediating constitutive mitochondrial fission and has been implicated in mitochondrial cell death pathways. During ferroptosis, a recently identified type of regulated necrosis driven by excessive lipid peroxidation, mitochondrial fragmentation has been observed. Yet, how this is regulated and whether it is involved in ferroptotic cell death has remained unexplored. Here, we provide evidence that Drp1 is activated upon experimental induction of ferroptosis and promotes cell death execution and mitochondrial fragmentation. Using time-lapse microscopy, we found that ferroptosis induced mitochondrial fragmentation and loss of mitochondrial membrane potential, but not mitochondrial outer membrane permeabilization. Importantly, Drp1 accelerated ferroptotic cell death kinetics. Notably, this function was mediated by the regulation of mitochondrial dynamics, as overexpression of Mitofusin 2 phenocopied the effect of Drp1 deficiency in delaying ferroptosis cell death kinetics. Mechanistically, we found that Drp1 is phosphorylated and activated after induction of ferroptosis and that it translocates to mitochondria. Further activation at mitochondria through the phosphatase PGAM5 promoted ferroptotic cell death. Remarkably, Drp1 depletion delayed mitochondrial and plasma membrane lipid peroxidation. These data provide evidence for a functional role of Drp1 activation and mitochondrial fragmentation in the acceleration of ferroptotic cell death, with important implications for targeting mitochondrial dynamics in diseases associated with ferroptosis.
    DOI:  https://doi.org/10.1038/s41419-024-07312-2
  11. J Cell Sci. 2025 Jan 30. pii: jcs.263637. [Epub ahead of print]
    Regulation of mitochondrial cristae organization by Myo19, Miro1/2 and Metaxin 3.
    Samruddhi S Shembekar, Petra Nikolaus, Ulrike Honnert, Marcus Höring, Aya Attia, Karin Topp, Birgit Lohmann, Gerhard Liebisch, Martin Bähler.
      The actin-based motor myosin-19 (Myo19) exerts force on mitochondrial membrane receptors Miro1/2, influencing endoplasmic reticulum (ER)-mitochondria contact sites and mitochondrial cristae structure. The Mitochondrial Intermembrane Bridging (MIB) complex connects the outer and inner mitochondrial membranes at the cristae junction through the MICOS system. However, the interaction between Myo19, Miro1/2, and the MIB/MICOS complex in cristae regulation remains unclear. This study investigates the roles of Miro1/2 and metaxin 3 (Mtx3), a MIB complex component, in linking Myo19 to MIB/MICOS. We show that Miro1/2 interact with Myo19 and the MIB complex, but not with Mtx3. Their mitochondrial membrane anchors are not essential for MIB interaction or cristae structure. However, Mtx3 is crucial for Myo19 and Miro1/2's connection to MIB/MICOS. Deleting Miro1/2 mimics Myo19 deficiency effects on ER-mitochondria contacts and cristae structure, while Mtx3 deletion does not. Notably, the loss of Myo19 and Miro1/2 alters mitochondrial lipid composition, reducing cardiolipin and its precursors, suggesting Myo19 and Miro1/2 influence cristae indirectly via lipid transfer at ER-mitochondria contact sites.
    Keywords:  Cristae organization; Lipid transfer; Mitochondria; Myosin; Rho GTPases
    DOI:  https://doi.org/10.1242/jcs.263637
  12. Int J Mol Sci. 2025 Jan 20. pii: 846. [Epub ahead of print]26(2):
    De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy-Case Report and Literature Review.
    Martina Magistrati, Luisa Zupin, Eleonora Lamantea, Enrico Baruffini, Daniele Ghezzi, Andrea Legati, Fulvio Celsi, Flora Maria Murru, Valeria Capaci, Maurizio Pinamonti, Rossana Bussani, Marco Carrozzi, Cristina Dallabona, Massimo Zeviani, Maria Teresa Bonati.
      Pathogenic variants in DNM1L, encoding dynamin-like protein-1 (DRP1), cause a lethal encephalopathy. DRP1 defective function results in altered mitochondrial networks, characterized by elongated/spaghetti-like, highly interconnected mitochondria. We validated in yeast the pathogenicity of a de novo DNM1L variant identified by whole exome sequencing performed more than 10 years after the patient's death. Meanwhile, we reviewed the broadness and specificities of DNM1L-related phenotype. The patient, who exhibited developmental delay in her third year, developed a therapy-refractory myoclonic status epilepticus, followed by neurological deterioration with brain atrophy and refractory epilepsy. She died of heart failure due to hypertrophic cardiomyopathy. She was found to be heterozygous for the DNM1L variant (NM_ 012062.5):c.1201G>A, p.(Gly401Ser). We demonstrated its deleterious impact and dominant negative effect by assessing haploid and diploid mutant yeast strains, oxidative growth, oxygen consumption, frequency of petite, and architecture of the mitochondrial network. Structural modeling of p.(Gly401Ser) predicted the interference of the mutant protein in the self-oligomerization of the DRP1 active complex. DNM1L-related phenotypes include static or (early) lethal encephalopathy and neurodevelopmental disorders. In addition, there may be ophthalmological impairment, peripheral neuropathy, ataxia, dystonia, spasticity, myoclonus, and myopathy. The clinical presentations vary depending on mutations in different DRP1 domains. Few pathogenic variants, the p.(Gly401Ser) included, cause an encephalocardiomyopathy with refractory status epilepticus.
    Keywords:  DNM1L; burst suppression; global developmental regression; hypertrophic cardiomyopathy (HC); lethal encephalocardiomyopathy; refractory status epilepticus (RSE); retrospective post-mortem diagnosis
    DOI:  https://doi.org/10.3390/ijms26020846
  13. Biomolecules. 2025 Jan 14. pii: 126. [Epub ahead of print]15(1):
    Remodeling of Mitochondria-Endoplasmic Reticulum Contact Sites Accompanies LUHMES Differentiation.
    Emad Norouzi Esfahani, Tomas Knedlik, Sang Hun Shin, Ana Paula Magalhães Rebelo, Agnese De Mario, Caterina Vianello, Luca Persano, Elena Rampazzo, Paolo Edomi, Camilla Bean, Dario Brunetti, Luca Scorrano, Samuele Greco, Marco Gerdol, Marta Giacomello.
      Neural progenitor cells (NPCs) are often used to study the subcellular mechanisms underlying differentiation into neurons in vitro. Works published to date have focused on the pathways that distinguish undifferentiated NPCs from mature neurons, neglecting the earlier and intermediate stages of this process. Current evidence suggests that mitochondria interaction with the ER is fundamental to a wide range of intracellular processes. However, it is not clear whether and how the mitochondria-ER interactions differ between NPCs and their differentiated counterparts. Here we take advantage of the widely used NPC line LUHMES to provide hints on the mitochondrial dynamic trait changes that occur during the first stage of their maturation into dopaminergic-like neurons. We observed that the morphology of mitochondria, their interaction with the ER, and the expression of several mitochondria-ER contact site resident proteins change, which suggests the potential contribution of mitochondria dynamics to NPC differentiation. Further studies will be needed to explore in depth these changes, and their functional outcomes, which may be relevant to the scientific community focusing on embryonic neurogenesis and developmental neurotoxicity.
    Keywords:  LUHMES; MERCs; Neural precursor cells; differentially expressed genes; mitochondria; mitochondria–ER contact sites
    DOI:  https://doi.org/10.3390/biom15010126
  14. Mol Biol Cell. 2025 Jan 29. mbcE25010035
    Mechanism of chaperone recruitment and retention on mitochondrial precursors.
    Szymon Juszkiewicz, Sew-Yeu Peak-Chew, Ramanujan S Hegde.
      Nearly all mitochondrial proteins are imported into mitochondria from the cytosol. How nascent mitochondrial precursors acquire and sustain import-competence in the cytosol under normal and stress conditions is incompletely understood. Here, we show that under normal conditions, the Hsc70 and Hsp90 systems interact with and redundantly minimize precursor degradation. During acute import stress, Hsp90 buffers precursor degradation, preserving proteins in an import-competent state until stress resolution. Unexpectedly, buffering by Hsp90 relies critically on a mitochondrial targeting signal (MTS), the absence of which greatly decreases precursor-Hsp90 interaction. Site-specific photo-crosslinking and biochemical reconstitution showed how the MTS directly engages co-chaperones of Hsc70 (St13 and Stip1) and Hsp90 (p23 and Cdc37) to facilitate chaperone retention on the mature domain. Thus, the MTS has a previously unappreciated role in regulating chaperone dynamics on mitochondrial precursors to buffer their degradation and maintain import competence, functions that may facilitate restoration of mitochondrial homeostasis after acute import stress.
    DOI:  https://doi.org/10.1091/mbc.E25-01-0035
  15. CNS Neurol Disord Drug Targets. 2025 Jan 24.
    Epigenetic Threads of Neurodegeneration: TFAM's Intricate Role in Mitochondrial Transcription.
    Aishwarya Bharathi H M, Prabitha Prabhakaran, Logesh Rajan, Narasimha M Beeraka, Bijo Mathew, Prashantha Kumar Br.
      There is a myriad of activities that involve mitochondria that are crucial for maintaining cellular equilibrium and genetic stability. In the pathophysiology of neurodegenerative illnesses, mitochondrial transcription influences mitochondrial equilibrium, which in turn affects their biogenesis and integrity. Among the crucial proteins for keeping the genome in optimal repair is mitochondrial transcription factor A, more commonly termed TFAM. TFAM's non-specific DNA binding activity demonstrates its involvement in the control of mitochondrial DNA (mtDNA) transcription. The role of TFAM in controlling packing, stability, and replication when assessing the quantity of the mitochondrial genome is well recognised. Despite mounting evidence linking lower mtDNA copy numbers to various age-related diseases, the correlation between TFAM abundance and neurodegenerative disease remains insufficient. This review delves into the link between neurodegeneration and mitochondrial dysfunction caused by oxidative stress. Additionally, the article will go into detail about how TFAM controls mitochondrial transcription, which is responsible for encoding key components of the oxidative phosphorylation (OXPHOS) system.
    Keywords:  Neurodegeneration; TFAM.; mitochondrial dysfunction; mitochondrial transcription; oxidative stress; transcription factors
    DOI:  https://doi.org/10.2174/0118715273334342250108043032
  16. Nat Commun. 2025 Jan 30. 16(1): 1181
    SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters.
    Mingyang Chen, Luexiang Yuan, Binxin Chen, Hui Chang, Jun Luo, Hengbin Zhang, Zhongjian Chen, Jiao Kong, Yaodong Yi, Mengru Bai, Minlei Dong, Hui Zhou, Huidi Jiang.
      Nicotinamide (NAM), a main precursor of NAD+, is essential for cellular fuel respiration, energy production, and other cellular processes. Transporters for other precursors of NAD+ such as nicotinic acid and nicotinamide mononucleotide (NMN) have been identified, but the cellular transporter of nicotinamide has not been elucidated. Here, we demonstrate that equilibrative nucleoside transporter 1 and 2 (ENT1 and 2, encoded by SLC29A1 and 2) drive cellular nicotinamide uptake and establish nicotinamide metabolism homeostasis. In addition, ENT1/2 exhibits a strong capacity to change the cellular metabolite composition and the transcript, especially those related to nicotinamide. We further observe that ENT1/2 regulates cellular respiration and senescence, contributing by altering the NAD+ pool level and mitochondrial status. Changes to cellular respiration, mitochondrial status and senescence by ENT1/2 knockdown are reversed by NMN supplementation. Together, ENT1 and ENT2 act as both cellular nicotinamide-level keepers and nicotinamide biological regulators through their NAM transport functions.
    DOI:  https://doi.org/10.1038/s41467-025-56402-y
  17. Mol Genet Metab. 2025 Jan 20. pii: S1096-7192(25)00014-9. [Epub ahead of print]144(3): 109023
    Comprehensive analysis of GDF15 as a biomarker in primary mitochondrial myopathies.
    Paloma Martín-Jimenez, Laura Bermejo-Guerrero, María Navarro-Riquelme, Pablo Serrano-Lorenzo, Rocío Garrido-Moraga, Aurelio Hernández-Laín, Ana Hernández-Voth, David Lora, Montserrat Morales, Joaquín Arenas, Alberto Blázquez, Miguel Ángel Martín, Cristina Domínguez-González.
       BACKGROUND AND OBJECTIVES: Mitochondrial diseases are caused by defects in oxidative phosphorylation, with primary mitochondrial myopathies (PMM) being a subset where muscle involvement is predominant. PMM presents symptoms ranging from exercise intolerance to progressive muscle weakness, often involving ocular muscles, leading to ptosis and progressive external ophthalmoplegia (PEO). PMM can be due to variants in mitochondrial or nuclear DNA. Growth differentiation factor 15 (GDF15) has been identified as an accurate biomarker for mitochondrial dysfunction. This study evaluates the utility of GDF15 as a biomarker for monitoring PMM.
    METHODS: This observational study involved 50 adult PMM patients. Clinical data were collected alongside functional motor outcomes measured by the Motor Research Council scale, 6-min walk test, North Star Ambulatory Assessment, and 100-m run test (100MRT). Biomarkers including serum lactate, creatine kinase (CK), creatinine, and plasma GDF15 were assessed.
    RESULTS: Patients exhibited diverse phenotypes, including exercise intolerance (8 %), progressive myopathy (22 %), isolated PEO (24 %), and PEO plus (42 %). Significant correlations were found among motor function tests, with 100MRT being particularly sensitive. Biomarker analysis showed elevated lactate in 32 %, elevated CK in 54 %, reduced creatinine in 76 %, and elevated GDF15 in 86 % of cases. GDF15 levels correlated with motor performance, lactate levels, and mtDNA mutation load in muscle. Creatinine levels were strongly linked to disease severity.
    DISCUSSION: This study underscores the heterogeneity of PMM and the importance of reliable biomarkers. GDF15 was consistently elevated across all PMM phenotypes and genotypes, correlating well with disease severity. Reduced creatinine also emerged as a potential prognostic marker.
    Keywords:  Biomarker; GDF15; Mitochondrial disease; Natural history; Primary mitochondrial myopathy
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109023
  18. Life Metab. 2024 Aug;3(4): loae020
    Genome-wide CRISPR screens identify PTPN21 and WDR26 as modulators of the mitochondrial stress-induced ISR.
    Wen Li, Mingyue Dong, Kaiyu Gao, Jialiang Guan, Ying Liu.
      
    DOI:  https://doi.org/10.1093/lifemeta/loae020
  19. Nat Metab. 2025 Jan 27.
    Epigenetic modification increases skeletal muscle resilience to metabolic stress.
      
    DOI:  https://doi.org/10.1038/s42255-024-01211-8
  20. Nat Commun. 2025 Jan 24. 16(1): 978
    SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation.
    Izabella A Pena, Jeffrey S Shi, Sarah M Chang, Jason Yang, Samuel Block, Charles H Adelmann, Heather R Keys, Preston Ge, Shveta Bathla, Isabella H Witham, Grzegorz Sienski, Angus C Nairn, David M Sabatini, Caroline A Lewis, Nora Kory, Matthew G Vander Heiden, Myriam Heiman.
      Many essential proteins require pyridoxal 5'-phosphate, the active form of vitamin B6, as a cofactor for their activity. These include enzymes important for amino acid metabolism, one-carbon metabolism, polyamine synthesis, erythropoiesis, and neurotransmitter metabolism. A third of all mammalian pyridoxal 5'-phosphate-dependent enzymes are localized in the mitochondria; however, the molecular machinery involved in the regulation of mitochondrial pyridoxal 5'-phosphate levels in mammals remains unknown. In this study, we used a genome-wide CRISPR interference screen in erythroleukemia cells and organellar metabolomics to identify the mitochondrial inner membrane protein SLC25A38 as a regulator of mitochondrial pyridoxal 5'-phosphate. Loss of SLC25A38 causes depletion of mitochondrial, but not cellular, pyridoxal 5'-phosphate, and impairs cellular proliferation under both physiological and low vitamin B6 conditions. Metabolic changes associated with SLC25A38 loss suggest impaired mitochondrial pyridoxal 5'-phosphate-dependent enzymatic reactions, including serine to glycine conversion catalyzed by serine hydroxymethyltransferase-2 as well as ornithine aminotransferase. The proliferation defect of SLC25A38-null K562 cells in physiological and low vitamin B6 media can be explained by the loss of serine hydroxymethyltransferase-2-dependent production of one-carbon units and downstream de novo nucleotide synthesis. Our work points to a role for SLC25A38 in mitochondrial pyridoxal 5'-phosphate accumulation and provides insights into the pathology of congenital sideroblastic anemia.
    DOI:  https://doi.org/10.1038/s41467-025-56130-3
  21. J Inflamm Res. 2025 ;18 1091-1106
    Decrease of NAD+ Inhibits the Apoptosis of OLP T Cells via Inducing Mitochondrial Fission.
    Zhuo-Yu Zhang, Fang Wang, Gang Zhou.
       Purpose: Oral lichen planus (OLP) is a chronic, immune-mediated inflammatory disease involving T cells. Mitochondrial fission plays a crucial role in T cell fate through structural remodeling. Nicotinamide adenine dinucleotide (NAD+) regulates mitochondrial remodeling and function. This study explored the role of NAD+ in modulating mitochondrial fission and apoptosis in T cells under the OLP immune-inflammatory environment.
    Patients and Methods: T cells and plasma were isolated from peripheral blood. Mitochondrial morphology was characterized by transmission electron microscopy and Mito-Tracker staining. OLP plasma-exposed Jurkat T cells were infected with the Drp1 shRNA virus to investigate the role of mitochondrial fission in OLP T cell apoptosis. OLP T cells and OLP plasma-exposed Jurkat T cells were treated with either β-nicotinamide mononucleotide (an NAD+ synthesis precursor) or FK866 (an NAD+ synthesis inhibitor) to assess the effect of NAD+ regulation on mitochondrial remodeling and T cell apoptosis.
    Results: OLP T cells exhibited fragmented mitochondria with elevated dynamin-related protein 1 (Drp1) and reduced mitofusin 2 (Mfn2) expression, accompanied by decreased apoptosis. Drp1 knockdown in OLP plasma-exposed Jurkat T cells increased apoptosis and reduced proliferation. NAD+ levels were reduced in both OLP T cells and OLP plasma-treated Jurkat T cells, leading to enhanced mitochondrial fission, decreased mitochondrial membrane potential (MMP) and respiration function, and reduced apoptosis rate. β-nicotinamide mononucleotide supplementation restored NAD+ levels, suppressed mitochondrial fission, improved MMP, and promoted apoptosis in these cells.
    Conclusion: Reduced NAD+ levels in OLP T cells enhanced mitochondrial fission and contributed to decreased apoptosis. NAD+ supplementation mitigated these effects, suggesting a potential therapeutic strategy for restoring T cell homeostasis in OLP.
    Keywords:  T cells; mitochondria; nicotinamide adenine dinucleotide; oral lichen planus
    DOI:  https://doi.org/10.2147/JIR.S502273
  22. Life Metab. 2023 Jun;2(3): load005
    Hierarchical inhibition of mTORC1 by glucose starvation-triggered AXIN lysosomal translocation and by AMPK.
    Mengqi Li, Xiaoyan Wei, Jinye Xiong, Jin-Wei Feng, Chen-Song Zhang, Sheng-Cai Lin.
      When glucose is replete, mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is active and anchored to the lysosomal surface via the two GTPases, Ras-related GTPase (RAG) and Ras homolog enriched in brain (Rheb), which are regulated by Ragulator and tuberous sclerosis complex 2 (TSC2), respectively. When glucose is low, aldolase senses low fructose-1,6-bisphosphate level and promotes the translocation of AXIN-liver kinase B1 (LKB1) to the lysosomal surface, which leads to the activation of AMP-activated protein kinase (AMPK) and the inhibition of RAGs, sundering mTORC1 from the lysosome and causing its inactivation. AMPK can also inactivate mTORC1 by phosphorylating Raptor and TSC2. However, the hierarchy of AXIN- and AMPK-mediated inhibition of mTORC1 remains poorly defined. Here, we show that AXIN translocation does not require AMPK expression or activity. In glucose starvation conditions, knockout of AXIN extended the half-life of mTORC1 inhibition from 15 to 60 min, whereas knockout of AMPK only extended it to 30 min. RAGBGTP (constitutively active RAGB) almost entirely blocked the lysosomal dissociation and inhibition of mTORC1 under glucose starvation, but it did not inhibit AMPK, indicating that under these conditions, it is AXIN lysosomal translocation that inhibits mTORC1, and it does so via inhibition of RAGs. 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a mimetic of AMP, which activates both cytosolic AMPK and lysosomal AMPK, fully inhibited mTORC1 even when it is stably anchored to the lysosome by RAGBGTP, whereas glucose starvation mildly inhibited such anchored mTORC1. Together, we demonstrate that the lysosomal translocation of AXIN plays a primary role in glucose starvation-triggered inhibition of mTORC1 by inhibiting RAGs, and that AMPK activity inhibits mTORC1 through phosphorylating Raptor and TSC2, especially under severe stress.
    Keywords:  AMPK; glucose sensing; mTORC1
    DOI:  https://doi.org/10.1093/lifemeta/load005
  23. Heliyon. 2025 Jan 15. 11(1): e41592
    The landscape of rare mitochondrial DNA variants in sudden cardiac death: A potential role for ATP synthase.
    Elena Luppi, Monica De Luise, Carla Bini, Guido Pelletti, Gaia Tioli, Ivana Kurelac, Luisa Iommarini, Susi Pelotti, Giuseppe Gasparre.
      Sudden cardiac death (SCD) is a major health concern, which can be the sign of a latent mitochondrial disease. However, mitochondrial DNA (mtDNA) contribution is largely unexplored in SCD at population level. Recently, mtDNA variants have been associated with congenital cardiopathy and higher risk of ischemic heart disease, suggesting them as potential risk factors also in SCD. Therefore, we aimed to define the mtDNA mutational landscape in such phenotype, by sequencing the whole blood mtDNA genome in a pilot cohort of 28 unrelated subjects. Coding variants were prioritized according to their population and haplogroup frequency. Out of 28 patients, 36% were diagnosed with coronary artery disease, 39% with structural defects and 25% with unspecified cardiac disease. The overall frequency of macro-haplogroups followed the distribution in the European population. No known or novel mtDNA pathogenic variants were found. Two rRNA and 8 missense variants were rarer than polymorphisms as they had a frequency lower than 1% in population databases. 5/8 missense variants clustered in ATP synthase genes and 4/8 missense variants were previously detected in patients with suspected mitochondriopathy. We concluded that primary mitochondrial disease is not a major cause of SCD, but rare mtDNA variants may occur (35.7% in our cohort vs 0.65% in the population; p < 0.01), potentially modifying the risk.
    Keywords:  Heart disease; M chromosome; Mitochondrial genome; Mitochondrial haplogroups; SNVs; Sudden cardiac death
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e41592
  24. Trends Endocrinol Metab. 2025 Jan 28. pii: S1043-2760(25)00003-7. [Epub ahead of print]
    Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
    Brandon Chen, Yatrik M Shah, Costas A Lyssiotis.
      Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox demands within the same cell. They demonstrate that subcellular mitochondrial heterogeneity enables metabolic compartmentalization to permit concurrent oxidative ATP production and reductive proline biosynthesis.
    Keywords:  metabolic compartmentalization; mitochondria dynamics; mitochondrial ultrastructure; organelle communication; proline metabolism
    DOI:  https://doi.org/10.1016/j.tem.2025.01.003
  25. J Biol Chem. 2025 Jan 23. pii: S0021-9258(25)00064-X. [Epub ahead of print] 108217
    Characterization of the putative yeast mitochondrial triacylglycerol lipase Tgl2.
    Vitasta Tiku, Zacharias Fakih, Takashi Tatsuta, Martin Jung, Doron Rapaport, Kai Stefan Dimmer.
      Mitochondria derive the majority of their lipids from other organelles through contact sites. These lipids, primarily phosphoglycerolipids, are the main components of mitochondrial membranes. In the cell, neutral lipids like triacylglycerides (TAGs) are stored in lipid droplets, playing an important role in maintaining cellular health. Enzymes like lipases mobilize these TAGs according to cellular needs. Neutral lipids have not yet been reported to play an important role in mitochondria so the presence of a putative TAG lipase - Tgl2, in yeast mitochondria is surprising. Moreover, TGL2 and MCP2, a high-copy suppressor for ERMES deficient cells, display genetic interactions suggesting a potential link of both proteins to lipid metabolism. In this study, we characterize in detail Tgl2. We show that Tgl2 forms dimers through intermolecular disulfide bridges and a cysteine-dependent high molecular weight complex. Furthermore, we could identify the lipase motif and catalytic triad of Tgl2 through in silico comparison with other lipases. Mutating each of the three catalytically active residues resulted in variants that failed to rescue the growth phenotype of mcp2Δ tgl2Δ double deletion strain supporting the assumption that these residues are indeed essential for the protein's function. Additionally, we discovered that the catalytically active aspartate residue (D259) is important for protein stability. Steady state level analyses with unstable variants of Tgl2 led to the identification of Yme1 as the protease responsible for its quality control. Finally, we provide evidence that the overall increase in TAGs in cells lacking Mcp2 and Tgl2 originates from the mitochondria. Collectively, our study provides new insights into a key player in mitochondrial lipid homeostasis.
    Keywords:  intermembrane space; lipases; lipids; mitochondria
    DOI:  https://doi.org/10.1016/j.jbc.2025.108217
  26. Kidney Int. 2025 Jan 22. pii: S0085-2538(25)00071-7. [Epub ahead of print]
    Repurposing Mitochondria-Targeted Therapeutics for Kidney Diseases.
    Austin D Thompson, S Paul Victor, Natalie E Scholpa, Rick G Schnellmann.
      The kidney is one of the most metabolically demanding organs in the human body and requires a large amount of energy, in the form of adenosine triphosphate (ATP), to perform and maintain normal renal functions. To meet this energy demand, proximal tubule cells within the nephron segments of the renal cortex are mitochondrially dense with high oxygen consumption rates. Mitochondria are complex organelles involved in diverse cellular and molecular functions, including the production of ATP, calcium homeostasis, and phospholipid regulation. Mitochondrial dysfunction is critical in the onset and progression of kidney disease. Dysfunctional renal mitochondria have been linked with alterations in redox homeostasis, impaired bioenergetics, oxidative stress, and inflammation, all of which result in renal cell injury and death, as well as fibrotic accumulation in kidney injury and disease. As such, interest in the development and/or repurposing of mitochondria-targeted therapeutics for the potential treatment of kidney diseases has recently surged. While novel therapeutics and promising new drug targets have been identified, drug repurposing for kidney diseases offers numerous advantages over traditional drug discovery initiatives, including reduced cost, time of therapeutic development, and preclinical testing, in addition to known pharmacokinetics/pharmacodynamics and safety profiles. Here, we provide an overview of mitochondrial dysfunction in the context of kidney injury and disease and shed light on promising mitochondria-targeted therapeutic agents that display repurposing potential for the restoration of renal function and/or acceleration of renal recovery.
    Keywords:  Drug Repurposing; Kidney Disease; Mitochondrial Dysfunction; Mitochondrial Therapeutics
    DOI:  https://doi.org/10.1016/j.kint.2024.12.020
  27. Ann Neurol. 2025 Jan 30.
    Spiking Patterns in the Globus Pallidus Highlight Convergent Neural Dynamics across Diverse Genetic Dystonia Syndromes.
    Ahmet Kaymak, Fabiana Colucci, Mahboubeh Ahmadipour, Nico Golfrè Andreasi, Sara Rinaldo, Zvi Israel, David Arkadir, Roberta Telese, Vincenzo Levi, Giovanna Zorzi, Jacopo Carpaneto, Miryam Carecchio, Holger Prokisch, Michael Zech, Barbara Garavaglia, Hagai Bergman, Roberto Eleopra, Alberto Mazzoni, Luigi M Romito.
       OBJECTIVE: Genetic dystonia is a complex movement disorder with diverse clinical manifestations resulting from pathogenic mutations in associated genes. A recent paradigm shift emphasizes the functional convergence among dystonia genes, hinting at a shared pathomechanism. However, the neural dynamics supporting this convergence remain largely unexplored.
    METHODS: Herein, we analyzed microelectrode recordings acquired during pallidal deep brain stimulation surgery from 31 dystonia patients with pathogenic mutations in the AOPEP, GNAL, KMT2B, PANK2, PLA2G6, SGCE, THAP1, TOR1A, and VPS16 genes. We identified 1,694 single units whose activity was characterized by a broad set of neural features.
    RESULTS: AOPEP, PANK2, and THAP1 displayed higher firing regularity, whereas GNAL, PLA2G6, KMT2B, and SGCE shared a large fraction of bursting neurons (> 26.6%), significantly exceeding the rate in other genes. TOR1A and VPS16 genes constituted an intermediate group, bridging these 2 groups, due to having the highest degree of spiking irregularity. Hierarchical clustering algorithms based on these dynamics confirmed the results obtained with first-order comparisons.
    INTERPRETATION: Despite lacking common molecular pathways, dystonia genes share largely overlapping structures of neural patterns, in particular the degree of pallidal spiking regularity and bursting activity. We propose that the degree of desynchronization facilitated by pallidal neural bursts may explain the variability in deep brain stimulation (DBS) of the globus pallidus internus (GPi) surgery outcomes across genetic dystonia syndromes. Lastly, investigating the effects of genetic mutations on low-frequency pallidal activity could optimize personalized adaptive DBS treatments in patients with genetic dystonia. ANN NEUROL 2025.
    DOI:  https://doi.org/10.1002/ana.27185
  28. Am J Hum Genet. 2025 Jan 22. pii: S0002-9297(25)00003-5. [Epub ahead of print]
    Prenatal gene editing for neurodevelopmental diseases: Ethical considerations.
    Rami M Major, Eric T Juengst.
      Neurodevelopmental diseases (NDDs) are notoriously difficult to treat because clinical symptoms stem from developmental processes that begin before birth. Prenatal gene editing could fill the treatment gap for NDDs by targeting and permanently correcting the genetic variants that underlie these pathogenic developmental processes. At the same time, there is a risk of unintended edits to the fetus or the pregnant person that could result in serious adverse consequences that are difficult, if not impossible, to undo. This raises ethical concerns that make the development of prenatal gene editing especially challenging. To date, there are no frameworks for considering the steps necessary for an ethical path forward for prenatal gene editing specifically. The 60-year history of in utero therapy has included the development of frameworks for other therapies that can provide starting points for addressing the unique issues of prenatal gene editing. We identified 12 themes from 17 ethical frameworks, literature, consensus statements, and government reports on prenatal interventions that could set precedents for prenatal gene editing interventions. In considering these alongside current criteria for postnatal gene therapies for NDDs, we discuss a path forward for prenatal gene editing interventions of NDDs.
    Keywords:  ethics; fetal therapy; prenatal gene editing
    DOI:  https://doi.org/10.1016/j.ajhg.2025.01.003
  29. iScience. 2025 Jan 17. 28(1): 111656
    Nicotinamide mononucleotide restores impaired metabolism, endothelial cell proliferation and angiogenesis in old sedentary male mice.
    Kevin Kiesworo, Thomas Agius, Michael R Macarthur, Martine Lambelet, Arnaud Lyon, Jing Zhang, Guillermo Turiel, Zheng Fan, Sènan d'Almeida, Korkut Uygun, Heidi Yeh, Sébastien Déglise, Katrien de Bock, Sarah J Mitchell, Alejandro Ocampo, Florent Allagnat, Alban Longchamp.
      Aging is accompanied by a decline in neovascularization potential and increased susceptibility to ischemic injury. Here, we confirm the age-related impaired neovascularization following ischemic leg injury and impaired angiogenesis. The age-related deficits in angiogenesis arose primarily from diminished EC proliferation capacity, but not migration or VEGF sensitivity. Aged EC harvested from the mouse skeletal muscle displayed a pro-angiogenic gene expression phenotype, along with considerable changes in metabolic genes. Metabolomics analysis and 13C glucose tracing revealed impaired ATP production and blockade in glycolysis and TCA cycle in late passage HUVECs, which occurred at nicotinamide adenine dinucleotide (NAD⁺)-dependent steps, along with NAD+ depletion. Supplementation with nicotinamide mononucleotide (NMN), a precursor of NAD⁺, enhances late-passage EC proliferation and sprouting angiogenesis from aged mice aortas. Taken together, our study illustrates the importance of NAD+-dependent metabolism in the maintenance of EC proliferation capacity with age, and the therapeutic potential of NAD precursors.
    Keywords:  Cellular physiology; Metabolomics
    DOI:  https://doi.org/10.1016/j.isci.2024.111656
This page is being maintained by Thomas Krichel. It was last updated on 2025‒02‒02 at 8:09.