bims-mitmed 2025-02-16 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–02–16
24 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitofusin 2 displays fusion-independent roles in proteostasis surveillance.
Mitochondrial DNA or Genomic DNA Variant(s): Utility of Exhaustive Sequencing in Leigh Syndrome.
Diverse routes to mitophagy governed by ubiquitylation and mitochondrial import.
Overview of neuroimaging in primary mitochondrial disorders.
A microscopy-based screen identifies cellular kinases modulating mitochondrial translation.
FBXL4-Related Mitochondrial Depletion Syndrome Underscores the role of Mitophagy in Stem Cell Differentiation during Embryogenesis.
Mitochondria-loading erythrocytes transfer mitochondria to ameliorate inflammatory bone loss.
Pharmacologic activation of integrated stress response kinases inhibits pathologic mitochondrial fragmentation.
Mitochondrial DNA removal is essential for sperm development and activity.
Disruption of mitochondrial homeostasis and permeability transition pore opening in OPA1 iPSC-derived retinal ganglion cells.
Effects of periconceptional ethanol on mitochondrial content and oxidative stress in maternal liver and placentas from male and female fetuses in rats.
Editorial: Molecular and cellular pathways leading to mitochondrial dysfunction and neurodegeneration: lessons from in vivo models, volume II.
Adult Leigh Syndrome Associated with the m.15635T>C Mitochondrial DNA Variant Affecting the Cytochrome b (MT-CYB) Gene.
Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men.
The Placenta Regulates Intrauterine Fetal Growth via Exosomal PPARγ.
Thyroid Hormones and Brain Development: A Focus on the Role of Mitochondria as Regulators of Developmental Time.
Adenylate cyclase 10 promotes brown adipose tissue thermogenesis.
Genotype and phenotype spectrum of Charcot-Marie-Tooth disease due to mutations in SORD.
An mTOR paradox in sarcopenia via BCAA catabolism.
Cardiac manifestations in adult MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome)- a cross-sectional study.
An exploratory study to evaluate efficacy and safety of frequent Transcutaneous Electrical Stimulation for Leber Hereditary Optic Neuropathy.
Mitochondrial respiratory analysis of cryopreserved PBMCs isolated from human blood.
Unraveling microglial spatial organization in the developing human brain with DeepCellMap, a deep learning approach coupled with spatial statistics.
Porcine myogenesis in cloned wildtype and MYF5/MYOD/MYF6-null porcine embryo.

Nat Commun. 2025 Feb 10. 16(1): 1501

Mitofusin 2 displays fusion-independent roles in proteostasis surveillance.

Mariana Joaquim, Selver Altin, Maria-Bianca Bulimaga, Tânia Simões, Hendrik Nolte, Verian Bader, Camilla Aurora Franchino, Solenn Plouzennec, Karolina Szczepanowska, Elena Marchesan, Kay Hofmann, Marcus Krüger, Elena Ziviani, Aleksandra Trifunovic, Arnaud Chevrollier, Konstanze F Winklhofer, Elisa Motori, Margarete Odenthal, Mafalda Escobar-Henriques.

Mitochondria are essential organelles and their functional state dictates cellular proteostasis. However, little is known about the molecular gatekeepers involved, especially in absence of external stress. Here we identify a role of MFN2 in quality control independent of its function in organellar shape remodeling. MFN2 ablation alters the cellular proteome, marked for example by decreased levels of the import machinery and accumulation of the kinase PINK1. Moreover, MFN2 interacts with the proteasome and cytosolic chaperones, thereby preventing aggregation of newly translated proteins. Similarly to MFN2-KO cells, patient fibroblasts with MFN2-disease variants recapitulate excessive protein aggregation defects. Restoring MFN2 levels re-establishes proteostasis in MFN2-KO cells and rescues fusion defects of MFN1-KO cells. In contrast, MFN1 loss or mitochondrial shape alterations do not alter protein aggregation, consistent with a fusion-independent role of MFN2 in cellular homeostasis. In sum, our findings open new possibilities for therapeutic strategies by modulation of MFN2 levels.

DOI: https://doi.org/10.1038/s41467-025-56673-5
Am J Med Genet A. 2025 Feb 08. e64019

Mitochondrial DNA or Genomic DNA Variant(s): Utility of Exhaustive Sequencing in Leigh Syndrome.

Pauline Gaignard, Pierre-Hadrien Becker, Anne-Frederique Dessein, Elise Lebigot, Abdelhamid Slama, Karine Mention, Jamal Ghoumid.

  Pathogenic variants in the nuclear gene NDUFAF8 are a rare cause of mitochondrial complex I deficiency with only three cases described to date. We report here a new case of NDUFAF8 deficiency confirming the phenotype of NDUFAF8-induced complex I biochemical defect, Leigh syndrome and premature death. As a mitochondrial DNA variant in a gene encoding a complex I subunit was also identified in this patient, we discuss the molecular heterogeneity of Leigh syndrome and the need to explore the mitochondrial and nuclear genome to ensure a reliable diagnosis.

Keywords:  Leigh syndrome; NDUFAF8; complex I; mitochondrial DNA

DOI:  https://doi.org/10.1002/ajmg.a.64019
Trends Cell Biol. 2025 Feb 07. pii: S0962-8924(25)00003-0. [Epub ahead of print]

Diverse routes to mitophagy governed by ubiquitylation and mitochondrial import.

Michael J Clague, Sylvie Urbé.

  The selective removal of mitochondria by mitophagy proceeds via multiple mechanisms and is essential for human well-being. The PINK1/Parkin and NIX/BNIP3 pathways are strongly linked to mitochondrial dysfunction and hypoxia, respectively. Both are regulated by ubiquitylation and mitochondrial import. Recent studies have elucidated how the ubiquitin kinase PINK1 acts as a sensor of mitochondrial import stress through stable interaction with a mitochondrial import supercomplex. The stability of BNIP3 and NIX is regulated by the SCFFBXL4 ubiquitin ligase complex. Substrate recognition requires an adaptor molecule, PPTC7, whose availability is limited by mitochondrial import. Unravelling the functional implications of each mode of mitophagy remains a critical challenge. We propose that mitochondrial import stress prompts a switch between these two pathways.

Keywords:  BNIP3; FBXL4; PINK1; PPTC7; mitophagy; ubiquitin

DOI:  https://doi.org/10.1016/j.tcb.2025.01.003
Pediatr Radiol. 2025 Feb 12.

Overview of neuroimaging in primary mitochondrial disorders.

Sedat Giray Kandemirli, Khalid Al-Dasuqi, Bulent Aslan, Amy Goldstein, Cesar Augusto P F Alves.

  Advancements in understanding the clinical, biochemical, and genetic aspects of primary mitochondrial disorders, along with the identification of a broad range of phenotypes frequently involving the central nervous system, have opened a new and crucial area in neuroimaging. This expanding knowledge presents significant challenges for radiologists in clinical settings, as the neuroimaging features and their associated metabolic abnormalities become more complex. This review offers a comprehensive overview of the key neuroimaging features associated with the common primary mitochondrial disorders. It highlights both the classical imaging findings and the emerging diagnostic insights related to several previously identified causative genes for these diseases. The review also provides an in-depth description of the clinicoradiologic presentations and potential underlying mitochondrial defects, aiming to enhance diagnostic abilities of radiologists in identifying primary mitochondrial diseases in their clinical practice.

Keywords:  Kearns-Sayre syndrome; Leigh syndrome; Mitochondria; Mitochondrial diseases; Neuroimaging

DOI:  https://doi.org/10.1007/s00247-025-06172-y
Cell Rep. 2025 Jan 28. pii: S2211-1247(24)01494-3. [Epub ahead of print]44(1): 115143

A microscopy-based screen identifies cellular kinases modulating mitochondrial translation.

Roya Yousefi, Luis Daniel Cruz-Zaragoza, Anusha Valpadashi, Carina Hansohn, Drishan Dahal, Ricarda Richter-Dennerlein, Silvio Rizzoli, Henning Urlaub, Peter Rehling, David Pacheu-Grau.

  Mitochondrial DNA encodes 13 subunits of the oxidative phosphorylation (OXPHOS) system, which are synthesized inside the organelle and essential for cellular energy supply. How mitochondrial gene expression is regulated and integrated into cellular physiology is little understood. Here, we perform a high-throughput screen combining fluorescent labeling of mitochondrial translation products with small interfering RNA (siRNA)-mediated knockdown to identify cellular kinases regulating translation. As proof of principle, the screen identifies known kinases that affect mitochondrial translation, and it also reveals several kinases not yet linked to this process. Among the latter, we focus on the primarily cytosolic kinase, fructosamine 3 kinase (FN3K), which localizes partially to the mitochondria to support translation. FN3K interacts with the mitochondrial ribosome and modulates its assembly, thereby affecting translation. Overall, our work provides a reliable approach to identify protein functions for mitochondrial gene expression in a high-throughput manner.

Keywords:  CP: Metabolism; CP: Molecular biology; cellular kinases; click chemistry; mito-FUNCAT; mitochondrial translation; siRNA library

DOI:  https://doi.org/10.1016/j.celrep.2024.115143
Stem Cell Rev Rep. 2025 Feb 12.

FBXL4-Related Mitochondrial Depletion Syndrome Underscores the role of Mitophagy in Stem Cell Differentiation during Embryogenesis.

Pankaj Prasun.

  FBXL4- related mitochondrial depletion syndrome is a very rare inherited disorder characterized by global developmental delays, hypotonia, seizures, growth failure, and early onset lactic acidosis. Often, it is associated with structural brain and heart defects, and facial dysmorphism suggesting an embryogenesis defect. FBXL4 encodes F-box and leucine-rich repeat protein 4 (FBXL4) which is involved in mitochondrial quality control and maintenance by regulating mitophagy. A recent study suggests that FBXL4 deficiency leads to increased mitophagy. Fine tuning of mitophagy is essential for stem cell differentiation during embryogenesis. The disruption of this process is the likely explanation of developmental defects in FBXL4- related mitochondrial depletion syndrome.

Keywords:  Embryogenesis; FBXL4; Mitochondria; Mitophagy; Stem cell Differentiation

DOI:  https://doi.org/10.1007/s12015-025-10854-3
Acta Biomater. 2025 Feb 10. pii: S1742-7061(25)00106-0. [Epub ahead of print]

Mitochondria-loading erythrocytes transfer mitochondria to ameliorate inflammatory bone loss.

Shi Cheng, Lu Zhou, Wu-Yin Wang, Meng-Jie Zhang, Qi-Chao Yang, Wen- Da Wang, Kong-Huai Wang, Zhi-Jun Sun, Lu Zhang.

  Inflammatory diseases frequently result in bone loss, a condition for which effective therapeutic interventions are lacking. Mitochondrial transfer and transplantation hold promise in tissue repair and disease treatments. However, the application of mitochondrial transfer in alleviating disorders has been limited due to its uncontrollable nature. Moreover, a key challenge in this field is maintaining the quality of isolated mitochondria (Mito), as dysfunctional Mito can exacerbate disease progression. Therefore, we employ Mito loading erythrocytes (named MiLE) to achieve maintenance of mitochondrial quality. In addition, MiLE can be cryopreserved, allowing for long-term preservation of mitochondrial quality and facilitating the future application of mitochondrial transfer. In the inflammatory microenvironment, MiLE supplying Mito as well as O2 to macrophages. By undergoing metabolic reprogramming, MiLE suppresses lipopolysaccharide-induced osteoclast differentiation and promotes macrophage polarization from M1 to M2 phenotype, ultimately ameliorating inflammatory bone destruction. In summary, this work tackles the challenges of uncontrollable mitochondrial transfer and mitochondrial quality maintenance, and offers an opportunity for future exploration of organelle transplantation. STATEMENT OF SIGNIFICANCE: The application of mitochondrial transfer for the alleviation of pathologies has been hindered by the intrinsic limitations in terms of control and selectivity. Furthermore, maintaining mitochondrial integrity and functionality following isolation poses a significant challenge. In a pioneering approach, our research team developed a method for encapsulating mitochondria within erythrocytes, termed Mitochondria-Loading Erythrocytes (MiLE), which ensures extended mitochondrial functionality and controlled transfer. Within an inflammatory microenvironment, MiLE supplies both mitochondria and O2 to macrophages. By undergoing metabolic reprogramming, MiLE alleviates lipopolysaccharide-induced osteoclast differentiation and promotes macrophage polarization from M1 to M2 phenotype, ultimately ameliorating inflammatory bone destruction.

Keywords:  Inflammatory bone loss; Mitochondria-loading erythrocytes; Mitochondrial transfer

DOI:  https://doi.org/10.1016/j.actbio.2025.02.024
Elife. 2025 Feb 12. pii: RP100541. [Epub ahead of print]13

Pharmacologic activation of integrated stress response kinases inhibits pathologic mitochondrial fragmentation.

Kelsey R Baron, Samantha Oviedo, Sophia Krasny, Mashiat Zaman, Rama Aldakhlallah, Prerona Bora, Prakhyat Mathur, Gerald Pfeffer, Michael J Bollong, Timothy E Shutt, Danielle A Grotjahn, R Luke Wiseman.

  Excessive mitochondrial fragmentation is associated with the pathologic mitochondrial dysfunction implicated in the pathogenesis of etiologically diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) - comprising the four eIF2α kinases PERK, GCN2, PKR, and HRI - is a prominent stress-responsive signaling pathway that regulates mitochondrial morphology and function in response to diverse types of pathologic insult. This suggests that pharmacologic activation of the ISR represents a potential strategy to mitigate pathologic mitochondrial fragmentation associated with human disease. Here, we show that pharmacologic activation of the ISR kinases HRI or GCN2 promotes adaptive mitochondrial elongation and prevents mitochondrial fragmentation induced by the calcium ionophore ionomycin. Further, we show that pharmacologic activation of the ISR reduces mitochondrial fragmentation and restores basal mitochondrial morphology in patient fibroblasts expressing the pathogenic D414V variant of the pro-fusion mitochondrial GTPase MFN2 associated with neurological dysfunctions, including ataxia, optic atrophy, and sensorineural hearing loss. These results identify pharmacologic activation of ISR kinases as a potential strategy to prevent pathologic mitochondrial fragmentation induced by disease-relevant chemical and genetic insults, further motivating the pursuit of highly selective ISR kinase-activating compounds as a therapeutic strategy to mitigate mitochondrial dysfunction implicated in diverse human diseases.

Keywords:  cell biology; human; integrated stress response; mitochondrial fragmentation; mitochondrial morphology; mouse; stress signaling

DOI:  https://doi.org/10.7554/eLife.100541
EMBO J. 2025 Feb 11.

Mitochondrial DNA removal is essential for sperm development and activity.

Zhe Chen, Fan Zhang, Annie Lee, Michaela Yamine, Zong-Heng Wang, Guofeng Zhang, Christian Combs, Hong Xu.

  Active mitochondrial DNA (mtDNA) elimination during spermatogenesis has emerged as a conserved mechanism ensuring the uniparental mitochondrial inheritance in animals. However, given the existence of post-fertilization processes degrading sperm mitochondria, the physiological significance of mtDNA removal during spermatogenesis is not clear. Here we show that mtDNA clearance is indispensable for sperm development and activity. We uncover a previously unappreciated role of Poldip2 as a mitochondrial exonuclease that is specifically expressed in late spermatogenesis and required for sperm mtDNA elimination in Drosophila. Loss of Poldip2 impairs mtDNA clearance in elongated spermatids and impedes the progression of individualization complexes that strip away cytoplasmic materials and organelles. Over time, poldip2 mutant sperm exhibit marked nuclear genome fragmentation, and the flies become completely sterile. Notably, these phenotypes were rescued by expressing a mitochondrially targeted bacterial exonuclease, which ectopically removes mtDNA. Our work illustrates the developmental necessity of mtDNA clearance for effective cytoplasm removal at the end of spermatid morphogenesis, and for preventing potential nuclear-mitochondrial genome imbalance in mature sperm, in which nuclear genome activity is shut down.

Keywords:   Drosophila spermatogenesis; EndoG; Exonuclease; Male Sterile; Maternal Inheritance

DOI:  https://doi.org/10.1038/s44318-025-00377-5
Acta Neuropathol Commun. 2025 Feb 13. 13(1): 28

Disruption of mitochondrial homeostasis and permeability transition pore opening in OPA1 iPSC-derived retinal ganglion cells.

Michael Whitehead, Joshua P Harvey, Paul E Sladen, Giada Becchi, Kritarth Singh, Yujiao Jennifer Sun, Thomas Burgoyne, Michael R Duchen, Patrick Yu-Wai-Man, Michael E Cheetham.

  Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, characterised by the selective loss of retinal ganglion cells (RGCs). Over 60% of DOA cases are caused by pathogenic variants in the OPA1 gene, which encodes a dynamin-related GTPase protein. OPA1 plays a key role in the maintenance of the mitochondrial network, mitochondrial DNA integrity and bioenergetic function. However, our current understanding of how OPA1 dysfunction contributes to vision loss in DOA patients has been limited by access to patient-derived RGCs. Here, we used induced pluripotent stem cell (iPSC)-RGCs to study how OPA1 dysfunction affects cellular homeostasis in human RGCs. iPSCs derived from a DOA+ patient with the OPA1 R445H variant and isogenic CRISPR-Cas9-corrected iPSCs were differentiated to iPSC-RGCs. Defects in mitochondrial networks and increased levels of reactive oxygen species were observed in iPSC-RGCs carrying OPA1 R445H. Ultrastructural analyses also revealed changes in mitochondrial shape and cristae structure, with decreased endoplasmic reticulum (ER): mitochondrial contact length in DOA iPSC-RGCs. Mitochondrial membrane potential was reduced and its maintenance was also impaired following inhibition of the F1Fo-ATP synthase with oligomycin, suggesting that mitochondrial membrane potential is maintained in DOA iPSC-RGCs through reversal of the ATP synthase and ATP hydrolysis. These impairments in mitochondrial structure and function were associated with defects in cytosolic calcium buffering following ER calcium release and store-operated calcium entry, and following stimulation with the excitatory neurotransmitter glutamate. In response to mitochondrial calcium overload, DOA iPSC-RGCs exhibited increased sensitivity to opening of the mitochondrial permeability transition pore. These data reveal novel aspects of DOA pathogenesis in R445H patient-derived RGCs. The findings suggest a mechanism in which primary defects in mitochondrial network dynamics disrupt core mitochondrial functions, including bioenergetics, calcium homeostasis, and opening of the permeability transition pore, which may contribute to vision loss in DOA patients.

Keywords:  Calcium homeostasis; Dominant optic atrophy; Mitochondrial networks; Neurodegeneration; OPA1; Retinal ganglion cells; iPSCs

DOI:  https://doi.org/10.1186/s40478-025-01942-z
J Physiol. 2025 Feb 09.

Effects of periconceptional ethanol on mitochondrial content and oxidative stress in maternal liver and placentas from male and female fetuses in rats.

Sarah S Steane, Tulika Das, Jacinta I Kalisch-Smith, Dinithi T Mahaliyanage, Lisa K Akison, Karen M Moritz, James S M Cuffe.

  Alcohol exposure during pregnancy disrupts fetal development and programs lifelong disease. We have shown, in rats, that alcohol exposure during the periconceptional period (PC:EtOH), causes placental dysfunction and cardiometabolic disease in offspring. The process of metabolising alcohol can cause oxidative stress and damage mitochondrial DNA (mtDNA). It is unknown whether alcohol metabolism in a rat model of PC:EtOH impacts oxidative stress markers and mitochondrial content in maternal and placental tissues. We aimed to determine whether PC:EtOH induced oxidative stress and reduced mtDNA in maternal liver and the placental labyrinth and junctional zone. Sprague-Dawley rats were given an ethanol liquid (12.5% v/v) or control (0%) diet for one oestrous cycle before mating to embryonic day (E) 4. Maternal livers were collected at E5 and E20. Placentas were collected at E20 and separated into the junctional zone and labyrinth zone. PC:EtOH reduced Cyp2e1 mRNA levels and mtDNA in the E5 liver with lower mtDNA persisting to E20, at which time mitochondrial proteins were also decreased. PC:EtOH also reduced mitochondrial content in the E20 junctional zone, although mitochondrial protein levels were unaffected. Superoxide dismutase activity was increased in the placental junctional zone and there was no evidence of oxidative stress. The present study demonstrates that alcohol exposure around conception, reduces mitochondrial content within the maternal liver and the junctional zone of the placenta towards the end of pregnancy. These prolonged deficits may have disrupted metabolic processes required for a healthy pregnancy. The study further supports avoiding alcohol when planning a pregnancy. KEY POINTS: Even when alcohol is consumed only around conception (PC:EtOH), it can have profound impacts on the developing baby. Here, we use our established rat model to investigate if PC:EtOH causes oxidative stress and reduces mitochondrial content in the maternal liver immediately after exposure on embryonic day (E) 5. We also investigate these parameters at the end of pregnancy (E20) in maternal liver and the placenta. PC:EtOH reduced mitochondrial DNA content in the maternal liver by 77% at E5 and by 40% at E20. At E20, expression of proteins that form the electron transport chain were also reduced. The placenta had a more subtle reduction in mitochondrial DNA content, but protein levels of mitochondrial complexes were unchanged. There was no evidence of oxidative stress in the maternal liver or placenta in response to PC:EtOH. The lack of oxidative stress in the placenta may be a result of compensatory increases in antioxidants.

Keywords:  DOHAD; alcohol metabolism; mtDNA; superoxide dismutase

DOI:  https://doi.org/10.1113/JP287566
Front Neurosci. 2025 ;19 1557013

Editorial: Molecular and cellular pathways leading to mitochondrial dysfunction and neurodegeneration: lessons from in vivo models, volume II.

Shabab B Hannan, Federica De Lazzari, Aurora Gomez-Duran, Juan A Navarro, Gloria Brea-Calvo, Alvaro Sanchez-Martinez.



Keywords:  ATAD3; Drosophila; Parkinson's disease; Pink1; SARS-CoV-2; Usp14; metformin; mitochondria

DOI:  https://doi.org/10.3389/fnins.2025.1557013
Int J Mol Sci. 2025 Jan 27. pii: 1116. [Epub ahead of print]26(3):

Adult Leigh Syndrome Associated with the m.15635T>C Mitochondrial DNA Variant Affecting the Cytochrome b (MT-CYB) Gene.

Concetta Valentina Tropeano, Chiara La Morgia, Alessandro Achilli, Luisa Iommarini, Gaia Tioli, Leonardo Caporali, Anna Olivieri, Maria Lucia Valentino, Rocco Liguori, Piero Barboni, Andrea Martinuzzi, Caterina Tonon, Raffaele Lodi, Antonio Torroni, Valerio Carelli, Anna Maria Ghelli.

  We report on a sporadic patient suffering Leigh syndrome characterized by bilateral lesions in the lenticular nuclei and spastic dystonia, intellectual disability, sensorineural deafness, hypertrophic cardiomyopathy, exercise intolerance, and retinitis pigmentosa. Complete sequencing of mitochondrial DNA revealed the heteroplasmic nucleotide change m.15635T>C affecting a highly conserved amino acid position (p.Ser297Pro) in the cytochrome b (MT-CYB) gene on a haplogroup K1c1a background, which includes a set of four non-synonymous polymorphisms also present in the same gene. Biochemical studies documented respiratory chain impairment due to complex III defect. This variant fulfils the criteria for being pathogenic and was previously reported in a sporadic case of fatal neonatal polyvisceral failure.

Keywords:  Leigh syndrome; MT-CYB; Respiratory complex III; mtDNA

DOI:  https://doi.org/10.3390/ijms26031116
Cell Rep Med. 2025 Feb 06. pii: S2666-3791(25)00041-2. [Epub ahead of print] 101968

Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men.

Marina Cefis, Vincent Marcangeli, Rami Hammad, Jordan Granet, Jean-Philippe Leduc-Gaudet, Pierrette Gaudreau, Caroline Trumpff, Qiuhan Huang, Martin Picard, Mylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, José A Morais, Gilles Gouspillou.

  Aging-related muscle atrophy and weakness contribute to loss of mobility, falls, and disability. Mitochondrial dysfunction is widely considered a key contributing mechanism to muscle aging. However, mounting evidence positions physical activity as a confounding factor, making unclear whether muscle mitochondria accumulate bona fide defects with aging. To disentangle aging from physical activity-related mitochondrial adaptations, we functionally profiled skeletal muscle mitochondria in 51 inactive and 88 active men aged 20-93. Physical activity status confers partial protection against age-related decline in physical performance. Mitochondrial respiration remains unaltered in active participants, indicating that aging per se does not alter mitochondrial respiratory capacity. Mitochondrial reactive oxygen species (ROS) production is unaffected by aging and higher in active participants. In contrast, mitochondrial calcium retention capacity decreases with aging regardless of physical activity and correlates with muscle mass, performance, and the stress-responsive metabokine/mitokine growth differentiation factor 15 (GDF15). Targeting mitochondrial calcium handling may hold promise for treating aging-related muscle impairments.

Keywords:  calcium retention capacity; functional capacities; intermuscular fat accumulation; mitochondria; mitochondrial permeability transition pore; muscle atrophy and weakness; physical performance; reactive oxygen species; sarcopenia; skeletal muscle aging

DOI:  https://doi.org/10.1016/j.xcrm.2025.101968
Adv Sci (Weinh). 2025 Feb 14. e2404983

The Placenta Regulates Intrauterine Fetal Growth via Exosomal PPARγ.

Xiaofang Luo, Biao Huang, Ping Xu, Hao Wang, Baozhen Zhang, Li Lin, Jiujiang Liao, Mingyu Hu, Xiyao Liu, Jiayu Huang, Yong Fu, Mark D Kilby, Rodney E Kellems, Xiujun Fan, Yang Xia, Philip N Baker, Hongbo Qi, Chao Tong.

  Abnormal adipogenesis is a major contributor to fetal growth restriction (FGR) and its associated complications. However, the underlying etiology remains unclear. Here, it is reported that the placentas of women with pregnancies complicated with FGR exhibit peroxisome proliferator-activated receptor γ (PPARγ) inactivation. In mice, trophoblast-specific ablation of murine PPARγ reproduces the phenotype of human fetuses with FGR and defective adipogenesis. Coculture of trophoblasts with preadipocytes significantly improves preadipocyte commitment and differentiation and increases the transcription of a series of adipogenic genes via intercellular transfer of exosomal PPARγ proteins. Moreover, nanoparticle-mediated placenta-specific delivery of rosiglitazone (RGZ) significantly rescues adipogenesis defects in an FGR-induced mouse model. In summary, the placenta is a major reservoir of PPARγ. An insufficient supply of placental PPARγ to fetal preadipocytes via exosomes during late gestation is a major mechanism underlying FGR. Preclinically, placenta-targeted RGZ administration can be a promising interventional therapy for FGR and/or defective intrauterine fat development.

Keywords:  PPARγ; adipogenesis; exosomes; fetal growth restriction; placentas; trophoblasts

DOI:  https://doi.org/10.1002/advs.202404983
Cells. 2025 Jan 21. pii: 150. [Epub ahead of print]14(3):

Thyroid Hormones and Brain Development: A Focus on the Role of Mitochondria as Regulators of Developmental Time.

Filip Vujovic, Ramin M Farahani.

  Thyroid hormones (THs) regulate metabolism in a homeostatic state in an adult organism. During the prenatal period, prior to the establishment of homeostatic mechanisms, THs assume additional functions as key regulators of brain development. Here, we focus on reviewing the role of THs in orchestrating cellular dynamics in a developing brain. The evidence from the reviewed scientific literature suggests that the developmental roles of the hormones are predominantly mediated by non-genomic mitochondrial effects of THs due to attenuation of genomic effects of THs that antagonise non-genomic impacts. We argue that the key function of TH signalling during brain development is to orchestrate the tempo of self-organisation of neural progenitor cells. Further, evidence is provided that major neurodevelopmental consequences of hypothyroidism stem from an altered tempo of cellular self-organisation.

Keywords:  brain development; mitochondria; reactive oxygen species; self-organisation; thyroid hormones

DOI:  https://doi.org/10.3390/cells14030150
iScience. 2025 Feb 21. 28(2): 111833

Adenylate cyclase 10 promotes brown adipose tissue thermogenesis.

Anupam Das, Christine Mund, Eman Hagag, Ruben Garcia-Martin, Eleftheria Karadima, Anke Witt, Mirko Peitzsch, Andreas Deussen, Triantafyllos Chavakis, Thomas Noll, Vasileia Ismini Alexaki.

  Brown adipose tissue (BAT) thermogenesis dissipates energy through heat production and thereby it opposes metabolic disease. It is mediated by mitochondrial membrane uncoupling, yet the mechanisms sustaining the mitochondrial membrane potential (ΔΨm) in brown adipocytes are poorly understood. Here we show that isocitrate dehydrogenase (IDH) activity and the expression of the soluble adenylate cyclase 10 (ADCY10), a CO2/bicarbonate sensor residing in mitochondria, are upregulated in BAT of cold-exposed mice. IDH inhibition or ADCY10 deficiency reduces cold resistance of mice. Mechanistically, IDH increases the ΔΨm in brown adipocytes via ADCY10. ADCY10 sustains complex I activity and the ΔΨm via exchange protein activated by cAMP1 (EPAC1). However, neither IDH nor ADCY10 inhibition affect uncoupling protein 1 (UCP1) expression. Hence, we suggest that ADCY10, acting as a CO2/bicarbonate sensor, mediates the effect of IDH on complex I activity through cAMP-EPAC1 signaling, thereby maintaining the ΔΨm and enabling thermogenesis in brown adipocytes.

Keywords:  Cell biology; Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2025.111833
Brain. 2025 Feb 13. pii: awaf021. [Epub ahead of print]

Genotype and phenotype spectrum of Charcot-Marie-Tooth disease due to mutations in SORD.

Andrea Cortese, Maike F Dohrn, Riccardo Curro, Sara Negri, Petra Lassuthova, Chiara Pisciotta, Stefano Tozza, Abdullah Al-Ajmi, Changyoung Feng, Pedro J Tomaselli, Gorka Fernandez-Eulate, Saif Haddad, Matilde Laurà, Alexander M Rossor, Elisa Vegezzi, Stefano Facchini, James N Sleigh, Adriana Rebelo, Danique Beijer, Jacquelyn Raposo, Mario Saporta, Barbora Lauerova, Helena F Pernice, Pascal Achenbach, Ulrike Schöne, Tayir Alon, Marcus Deschauer, Isabell Cordts, Carolin D Obermaier, Natalie Winter, Peter D Creigh, Janet E Sowden, Tyler Rehbein, Stefania Magri, Alessandro Bertini, Paola Saveri, Paolo Ripellino, Jingyu Huang, Aleksandra Nadaj-Pakleza, Alison Ross, James K L Holt, Kathryn M Brennan, Rivka Sukenik-Halevy, Varoona Bizaoui, Yesim Parman, Esra Battaloglu, Arman Cakar, Hadil Alrohaif, Simon Hammans, Kishore R Kumar, Marina L Kennerson, Hülya Kayserili, Defne A Amado, Katrin Hahn, Paola Valentino, Francesca Cavalcanti, Carlo Gaetano, Franco Taroni, Geir J Braathen, Henry Houlden, Tanya Stojkovic, Stojan Peric, Alessandra Bolino, Stefano C Previtali, Yi-Chung Lee, Ayşe N Başak, Sherifa A Hamed, Ricardo Rojas-Garcia, Kristl G Claeys, Wilson Marques, Teresa Sevilla, Beate Schlotter-Weigel, Fiore Manganelli, Ruxu Zhang, David N Herrmann, Steven S Scherer, Pavel Seeman, Davide Pareyson, Mary M Reilly, Michael E Shy, Stephan Züchner.

  Biallelic loss-of-function mutations in the sorbitol dehydrogenase (SORD) gene cause the most common recessive type of Charcot-Marie-Tooth disease (CMT), CMT-SORD. However, the full genotype-phenotype spectrum and progression of the disease remain to be defined. Notably, a multicenter phase 2/3 study to test the efficacy of govorestat (NCT05397665), a new aldose reductase inhibitor, is currently ongoing. Diagnosing CMT-SORD will become imperative when disease-modifying therapies become available. In this cross-sectional multicentre study, we identified 144 patients from 126 families, including 99 males (69%) and 45 females (31%). Patients represented multiple ancestries, including European, Hispanic, Chinese, Near Eastern, and Northern African. We confirmed c.757delG (p.Ala253GlnfsTer27) as the most common pathogenic allele, followed by c.458C>A (p.Ala153Asp), while other variants were identified mostly in single cases. The average sorbitol level in CMT-SORD patients was significantly higher compared to controls and heterozygous carriers, independently from serum storage duration, sex, or variant type. Two-thirds of cases were diagnosed with CMT2 while one-third had distal hereditary motor neuropathy (dHMN). Disease onset was usually in the second decade of life. Although foot dorsiflexion was the most affected muscle group, dorsal and plantar flexion had a similar degree of weakness in most cases (difference of Medical Research Council score ≤ 1). One fourth of patients used ankle foot orthoses, usually in their 30s, but most patients maintained independent ambulation later in life. Nerve conduction studies (NCS) were suggestive of a motor predominant axonal neuropathy, with reduced conduction velocities in the intermediate range in one fourth of the cases. Sensory conductions in the upper limbs appeared more frequently affected than in the lower limbs. Foot dorsiflexion and plantar flexion decreased significantly with age. Male sex was significantly associated with the severity of distal lower limb weakness (plantar flexion) and a larger change over time (dorsiflexion). In conclusion, CMT-SORD is a frequent recessive form of axonal, motor predominant CMT, with prominent foot dorsiflexion and plantar flexion involvement. Fasting serum sorbitol is a reliable biomarker of the condition that can be utilized for pathogenicity assessment of identified rare SORD variants.

Keywords:  SORD; aldose reductase; hereditary neuropathy; natural history; polyol pathway

DOI:  https://doi.org/10.1093/brain/awaf021
Nat Aging. 2025 Feb 13.

An mTOR paradox in sarcopenia via BCAA catabolism.

Jerome N Feige.

DOI: https://doi.org/10.1038/s43587-025-00815-3
Orphanet J Rare Dis. 2025 Feb 10. 20(1): 62

Cardiac manifestations in adult MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome)- a cross-sectional study.

Dietrich Stoevesandt, Axel Schlitt, Philipp Röntgen, Torsten Kraya.

   BACKROUND: Cardiac involvement has been reported in different mitochondrial geno- and phenotypes, including mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like (MELAS) syndrome. However, cardiac manifestations are diverse and not well described.
METHODS: We prospectively examined cardiac manifestations in 11 adult patients with MELAS syndrome harboring the MTTL1 m.3243A < G-mutation using patient records, cardiac MRI (1.5 Tesla), echocardiography, electrocardiogram (ECG), laboratory tests of cardiac markers (CK, CK-MB, Trop I, BNP), and clinical severity (NMDAS = Newcastle Mitochondrial Disease Scale).
RESULTS: Among 11 consecutive patients with MELAS syndrome (73% male, mean age 37.5 ± 10.6 years) cardiac manifestations were found in nine (82%). Pathology was mainly detected using MRI (9 of 11, 82%). Six patients showed diffuse late enhancement in the left ventricle, one a left ventricular ejection fraction (LVEF) below 30%, two with a LVEF in the range of 40-50% in the cardiac MRI, and another five patients presenting diastolic dysfunction as defined by echocardiography. Only one patient with late enhancement on MRI also showed a conduction block in the ECG. There was no correlation between the cardiac manifestations and the NMDAS score or heteroplasmy grade.
CONCLUSIONS: Cardiac involvement in MELAS syndrome harboring the MTTL1 m.3243A > G mutation mostly entails cardiomyopathy, which was particularly evident in the cardiac MRI. Only one patient (1/11, 9.1%) had conduction defects. Thus, cardiac testing including cardiac MRI, echocardiography and ECG seems to be important for prognosis of MELAS patients.

Keywords:  Cardiac MRI; Cardiac disease; Cardiomyopathy; M.3243A > G mutation; MELAS

DOI:  https://doi.org/10.1186/s13023-025-03534-5
Sci Rep. 2025 Feb 09. 15(1): 4829

An exploratory study to evaluate efficacy and safety of frequent Transcutaneous Electrical Stimulation for Leber Hereditary Optic Neuropathy.

Fumio Takano, Kaori Ueda, Takuji Kurimoto, Mina Arai, Takayuki Nagai, Yuko Yamada-Nakanishi, Makoto Nakamura.

  Electrical stimulation (ES) may be effective for intractable retinal or optic nerve diseases. We studied frequent transcutaneous ES in a single-center, single-arm prospective study in patients with Leber hereditary optic neuropathy (LHON) who carry the mitochondrial (mt) 11778 G > A mutation. A 30-min ES was applied to either eye every other day for 12 weeks. The primary outcome was the difference in the logarithm of the minimum angle of resolution (LogMAR) at baseline and 1 week after completion of ES treatment. The secondary outcomes included changes in visual field; LogMAR; critical flicker frequency; and inner retinal thickness. Safety endpoints included the corneal endothelial cell density and complications during ES. Fourteen patients participated in the study; four dropped out. The median (interquartile range) LogMAR values before stimulation and 1, 4, and 8 weeks after ES were 1.60 (1.45-1.80), 1.70 (1.35-1.80), 1.60 (1.43-1.73), and 1.50 (1.43-1.73), respectively, indicating no significant improvement (primary outcome: Wilcoxon's signed rank test, p = 1.000, secondary outcome: Friedman test, p = 0.229). There were no improvements in any secondary efficacy endpoints and no complications. In conclusion, frequent transcutaneous ES did not improve visual acuity in patients with LHON carrying the mt11778 G > A mutation.

Keywords:  Electrical stimulation; Leber Hereditary Optic Neuropathy; Mitochondrial disease; Prospective study; Visual field

DOI:  https://doi.org/10.1038/s41598-025-89076-z
Cryobiology. 2025 Feb 13. pii: S0011-2240(25)00018-5. [Epub ahead of print]118 105212

Mitochondrial respiratory analysis of cryopreserved PBMCs isolated from human blood.

C Payne, E Louw, N Baines, B Botha, C Lombard, B Allwood, G Maarman.

  Mitochondrial bioenergetics of PBMCs have been linked with several factors that contribute to a better understanding of several human diseases. Due to the complex logistics of clinical studies, samples are often cryopreserved for later analysis. Current data on whether cryopreservation negatively affects the mitochondrial function of PBMCs is discrepant. We isolated and cryopreserved peripheral blood mononuclear cells (PBMCs) from human whole blood and tested mitochondrial function using a substrate-uncoupler-inhibitor-titration protocol on the Oroboros instrument. After three months of storage in a cryopreservation medium (at -80 °C), several aspects of mitochondrial bioenergetics were measured. We demonstrate that cryopreservation did not adversely affect mitochondrial parameters (routine, leak, complex-I linked OXPHOS, cytochrome-c response, ETS capacity, the contributions of the N and S-pathways to ETS, ROX, complex-IV activity and mitochondrial coupling). Therefore, after three months of cryopreservation at -80 °C, human PBMC-mitochondria were fully coupled and functional. Therefore, clinical studies may cryopreserve PBMCs for later mitochondrial analyses.

Keywords:  Cryopreserved PBMCs; Mitochondrial respiration; Oroboros

DOI:  https://doi.org/10.1016/j.cryobiol.2025.105212
Nat Commun. 2025 Feb 13. 16(1): 1577

Unraveling microglial spatial organization in the developing human brain with DeepCellMap, a deep learning approach coupled with spatial statistics.

Theo Perochon, Zeljka Krsnik, Marco Massimo, Yana Ruchiy, Alejandro Lastra Romero, Elyas Mohammadi, Xiaofei Li, Katherine R Long, Laura Parkkinen, Klas Blomgren, Thibault Lagache, David A Menassa, David Holcman.

Mapping cellular organization in the developing brain presents significant challenges due to the multidimensional nature of the data, characterized by complex spatial patterns that are difficult to interpret without high-throughput tools. Here, we present DeepCellMap, a deep-learning-assisted tool that integrates multi-scale image processing with advanced spatial and clustering statistics. This pipeline is designed to map microglial organization during normal and pathological brain development and has the potential to be adapted to any cell type. Using DeepCellMap, we capture the morphological diversity of microglia, identify strong coupling between proliferative and phagocytic phenotypes, and show that distinct spatial clusters rarely overlap as human brain development progresses. Additionally, we uncover an association between microglia and blood vessels in fetal brains exposed to maternal SARS-CoV-2. These findings offer insights into whether various microglial phenotypes form networks in the developing brain to occupy space, and in conditions involving haemorrhages, whether microglia respond to, or influence changes in blood vessel integrity. DeepCellMap is available as an open-source software and is a powerful tool for extracting spatial statistics and analyzing cellular organization in large tissue sections, accommodating various imaging modalities. This platform opens new avenues for studying brain development and related pathologies.

DOI: https://doi.org/10.1038/s41467-025-56560-z
Commun Biol. 2025 Feb 11. 8(1): 217

Porcine myogenesis in cloned wildtype and MYF5/MYOD/MYF6-null porcine embryo.

Yong-Ho Choe, Satyabrata Das, Xiao Ma, Hyeonjeong Lee, Jacob R Sorensen, Daniel B Hoffman, Chan-Hee Jo, Casey P Johnson, Nicolette Cassel, Daniel J Garry, Sarah M Greising, Mary G Garry.

The pig is an important animal model increasingly used for biomedical research, particularly in transplantation strategies involving xenotransplantation or the development of human organs in pig for exotransplantation. Pigs, however, are less characterized than other animal models. In this study, we produced wildtype (WT) pig embryos via somatic cell nuclear transfer (SCNT) technology and compared them to skeletal muscle null embryos (lacking MYF5/MYOD/MYF6) at embryonic day 41, 62, and 90, critical stages of porcine myogenesis. Magnetic resonance imaging (MRI) and histological analyses revealed progressive development of skeletal muscle in WT embryos but not in null embryos whereas development of viscera progressed equally in both groups. Molecular analyses highlighted dynamic changes in myogenic gene expression and myofiber formation, demonstrating an organized progression of myogenesis in WT embryos. Morphologically, the null embryos exhibited abnormalities, including marked edema and underdeveloped limbs. MRI revealed severe skeletal abnormalities, including the absence of ribs, sternum, and associated vertebral malformations. In addition, histological analysis confirmed the complete lack of myofiber formation. Immunohistochemical analysis revealed the absence of myogenic stem cells and muscle differentiation, and RNA sequencing demonstrated that the skeletal muscle development process was entirely disrupted in null embryos. Additionally, analysis of neuromuscular junctions (NMJs) in the null embryos revealed that functional NMJ formation was absent, consistent with the lack of skeletal muscle formation. Importantly, these defects culminated in embryonic lethality after day 62 in the null embryos. We determined that the myogenic regulatory gene cascade is crucial for porcine embryo development and viability. The deletion of skeletal muscle is essential for the creating a vacant niche to allow for complementation of null porcine embryos with human induced pluripotent stem cells. Characterization of this skeletal muscle null pig model provide an important platform for engineering humanized muscle in gene-edited pigs.

DOI: https://doi.org/10.1038/s42003-025-07648-1