bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–07–06
67 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Selfish mutations promote age-associated erosion of mtDNA integrity in mammals.
  2. A constricted mitochondrial morphology formed during respiration.
  3. Genetic Underpinnings of Mitochondrial Cardiomyopathy: A Scoping 2010-2024 Update.
  4. Mitochondrial replacement techniques: The perspectives of mitochondrial disease specialists in Germany.
  5. Expanding the Genetic and Phenotypic Spectrum of POLRMT-Related Mitochondrial Disease.
  6. The role of NAD+ metabolism and its modulation of mitochondria in aging and disease.
  7. Tissue-specific responses to TFAM and mtDNA copy number manipulation in prematurely ageing mice.
  8. Molecular machineries and pathways of mitochondrial protein transport.
  9. Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
  10. The loss of OPA1 accelerates intervertebral disc degeneration and osteoarthritis in aged mice.
  11. Structural-functional characterization of the MIRO1-TRAK1 complex.
  12. Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans.
  13. Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms.
  14. An integrative modelling approach to the mitochondrial cristae.
  15. EXPRESSION OF CONCERN: Acetyl-L-Carnitine-Mediated Neuroprotection During Hypoxia Is Attributed to ERK1/2-Nrf2-Regulated Mitochondrial Biosynthesis.
  16. The mitochondrial disease biomarker GDF15 is dynamic, quantifiable in saliva, and correlates with disease severity.
  17. Modulating mitochondrial dynamics in CMT2A: a multifaceted platform for drug discovery and evaluation.
  18. Triglycerides are an important fuel reserve for synapse function in the brain.
  19. Neuronal glycolysis meets mitophagy to govern organismal wellbeing.
  20. Ubp2 modulates DJ-1-mediated redox-dependent mitochondrial dynamics in Saccharomyces cerevisiae.
  21. Genetically encoded and modular subcellular organelle probes reveal dysfunction in lysosomes and mitochondria driven by PRKN knockout.
  22. Autoregulation of the real-time kinetics of the human mitochondrial replicative helicase.
  23. Biotechnological approaches and therapeutic potential of mitochondria transfer and transplantation.
  24. Mitochondrial DNA genotypes modify m.3243A>G-associated mitochondrial disease via the 15-HETE/Akt/FoxO1 pathway.
  25. Letter to the Editor From Finsterer "Diverse Phenotypes of Mitochondrial Disease With Varying Levels of Heteroplasmy".
  26. Deficient AMPK-SENP1-Sirt3 signaling impairs mitochondrial complex I function in Parkinson's disease model.
  27. Mitochondrial thermal proteome profiling reveals aberrant activation of pyruvate dehydrogenase upon cuproptosis.
  28. Powering Up the Brain: Intercellular Mitochondrial Quality Control and Its Implication in Stroke.
  29. mtDNA transfer from senescent cancer cells to MDSCs promotes immunosuppression.
  30. Complexome profiling identifies changes in mitochondrial supercomplexes in murine heart failure.
  31. Neuromuscular pathology and mitochondrial dysfunction in sorbitol dehydrogenase gene-related distal hereditary motor neuropathies.
  32. The Somatic Mosaicism across Human Tissues Network.
  33. Mitochondrial transcription factor a as a guardian of mitochondrial integrity and emerging therapeutic target in human diseases: A review.
  34. Muscle needs NAD, but how much?
  35. The mechanisms and functions of mitochondria-encapsulating extracellular vesicles.
  36. Conformational dynamics and membrane insertion mechanism of B4GALNT1 in ganglioside synthesis.
  37. Genetic deletion or pharmacological inhibition of acetyl-CoA carboxylase 2 enhances fatty acid oxidation and improves cardiac function and survival in the murine ATGL knockout model of severe heart failure.
  38. Structure and biochemistry-guided engineering of an all-RNA system for DNA insertion with R2 retrotransposons.
  39. Dynamic binding of acetogenin-type inhibitors to mitochondrial complex I revealed by photoaffinity labeling.
  40. Effect of high-altitude exposure on skeletal muscle mitochondrial subcellular distribution, ultrastructure and respiration in sea-level residents.
  41. AAV9-mediated gene therapy restores liver function in the MEGDHEL mouse model.
  42. Cell-specific mitoproteomics reveals mitochondrial plasticity and applications.
  43. Mitochondrial Calcium Uniporter Regulates ITAM-Dependent Platelet Activation.
  44. Coupling of glucose metabolism with mitophagy via O-GlcNAcylation of PINK1.
  45. Mitochondrial transplantation: adaptive bio-enhancement.
  46. Skeletal muscle proteomics: considerations and opportunities.
  47. From one to many gene therapies.
  48. A subcellularly targeted photocaged inhibitor for mitochondrial carbonic anhydrase V.
  49. Parkinson's disease associated with LRRK2-R1441C mutation: Characterization and comparison with other LRRK2 mutations.
  50. Disruption of Lrpprc affects B cell development and proliferation in a mouse model of Leigh Syndrome French Canadian type.
  51. Mitochondrial tRNA processing: a neutral evolutionary ratchet innovation.
  52. MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction.
  53. Tafazzin-deficient zebrafish display mitochondrial dysfunction, neutropenia, and metabolic defects without myopathy.
  54. Phase Separation Regulates Metabolism, Mitochondria, and Diseases.
  55. Structural diversity and evolutionary constraints of oxidative phosphorylation.
  56. Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis.
  57. Comparison of Magnesium and Manganese Ions on the Structural and Catalytic Properties of Human DNA Polymerase Gamma.
  58. Human FASTK preferentially binds single-stranded and G-rich RNA.
  59. The ability of SAMHD1-deficient monocytes to trigger the type I IFN response depends on cGAS and mitochondrial DNA.
  60. Multidimensional third-generation sequencing of modified DNA bases allows interrogation of complex biological systems.
  61. Deficits in mitochondrial dynamics and iron balance result in templated insertions.
  62. Acute liver failure caused by amino acid or organic acid related inborn errors of metabolism.
  63. Leucine-Rich Repeat Kinase 2: Pathways to Parkinson's Disease.
  64. Diagnosis and Management of Non-HFE Hemochromatosis, Ferroportin Disease, and Rare Hereditary Iron-Loading Disorders.
  65. Proteostasis imbalance: Unraveling protein aggregation in neurodegenerative diseases and emerging therapeutic strategies.
  66. AI-enabled drug discovery reaches clinical milestone.
  67. Projection-TAGs enable multiplex projection tracing and multi-modal profiling of projection neurons.
  1. Nat Commun. 2025 Jul 01. 16(1): 5435
    Selfish mutations promote age-associated erosion of mtDNA integrity in mammals.
    Ekaterina Korotkevich, Daniel N Conrad, Zev J Gartner, Patrick H O'Farrell.
      Mutations in mitochondrial DNA (mtDNA) accumulate during aging and contribute to age-related conditions. High mtDNA copy number masks newly emerged recessive mutations; however, phenotypes develop when cellular levels of a mutant mtDNA rise above a critical threshold. The process driving this increase is unknown. Single-cell DNA sequencing of mouse and human hepatocytes detected increases in abundance of mutant alleles in sequences governing mtDNA replication. These alleles provided a replication advantage (drive) leading to accumulation of the affected genome along with a wide variety of associated passenger mutations, some of which are detrimental. The most prevalent human mtDNA disease variant, the 3243A>G allele, behaved as a driver, suggesting that drive underlies prevalence. We conclude that replicative drive amplifies linked mtDNA mutations to a threshold at which phenotypes are seen thereby promoting age-associated erosion of the mtDNA and influencing the transmission and progression of mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60477-y
  2. Nat Commun. 2025 Jul 01. 16(1): 5314
    A constricted mitochondrial morphology formed during respiration.
    Manish K Singh, Laetitia Cavellini, Maria Angeles Morcillo-Parra, Christina Kunz, Mickaël Lelek, Perrine Bomme, Aurélia Barascu, Cynthia Alsayyah, Maria Teresa Teixeira, Naïma Belgareh-Touzé, Adeline Mallet, Lea Dietrich, Christophe Zimmer, Mickael M Cohen.
      Mitochondria assemble in a dynamic tubular network. Their morphology is governed by mitochondrial fusion and fission, which regulate most mitochondrial functions including oxidative phosphorylation. Yet, the link between mitochondrial morphology and respiratgion remains unclear. Here, we uncover a mitochondrial morphology dedicated to respiratory growth of Saccharomyces cerevisiae, which we refer to as "Ringo". The Ringo morphology is characterized by stable constrictions of mitochondrial tubules. Ringo constrictions are mediated by the yeast dynamin Dnm1 and, unlike mitochondrial fission, occur in the absence of contacts with the endoplasmic reticulum. Our data show that blocking formation of the Ringo morphology correlates with decreased respiration, decreased expression of OXPHOS subunits and perturbed mitochondrial DNA distribution. These results open important perspectives about the link between mitochondrial form and function.
    DOI:  https://doi.org/10.1038/s41467-025-60658-9
  3. DNA Cell Biol. 2025 Jul 02.
    Genetic Underpinnings of Mitochondrial Cardiomyopathy: A Scoping 2010-2024 Update.
    Insaf Moudian, Joaira Bakkach, Zeineb Zian, Naima Ghailani Nourouti, Amina Barakat, Mohcine Bennani Mechita.
      Mitochondrial cardiomyopathy is a rare specific myocardial condition characterized by abnormal myocardium structure and/or function due to mitochondrial respiratory chain deficiency. This cardiac disorder results from mutations in mitochondrial DNA or nuclear genes affecting mitochondrial function. These mutations disrupt oxidative phosphorylation and consequently lead to energy deficit in the myocardial tissue and systemic symptoms due to impaired mitochondrial metabolism. In the current review, we aimed to highlight genetic and molecular underpinnings of mitochondrial cardiomyopathy. The impact of mitochondrial DNA characteristics on mitochondrial cardiomyopathy, mutations in both mitochondrial and nuclear genomes, as well as diagnostic limitations and future therapies, will be presented in this work.
    Keywords:  ETC genes; mitochondria; mitochondrial cardiomyopathy; mtDNA; mutations; tRNA
    DOI:  https://doi.org/10.1089/dna.2025.0089
  4. Soc Sci Med. 2025 May 15. pii: S0277-9536(25)00507-6. [Epub ahead of print]382 118177
    Mitochondrial replacement techniques: The perspectives of mitochondrial disease specialists in Germany.
    Jacquelyne Luce.
      'Mitochondrial disease' is an umbrella category for neurogenetic and metabolic diseases which are associated with mitochondrial dysfunction caused by genetic variations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). This article draws on interviews with four mitochondrial disease specialists in Germany in order to explore their perspectives on mitochondrial replacement techniques (MRTs), emerging 'IVF-based technologies' which could potentially prevent the transmission of mitochondrial DNA disease. MRTs aim to exchange (or replace) the cytoplasm of an intended parent's egg cell, which contains disease-causing mtDNA, with the cytoplasm from an egg cell of another individual (aka the mitochondrial donor). MRTs are legal and regulated by assisted reproduction legislation in the UK (since 2015) and Australia (since 2022) for the explicit purpose of reducing the risk of transmitting an mtDNA variant associated with a high risk of severe mitochondrial disease. MRTs are not available in Germany. In other countries, MRTs are offered by fertility clinics for a variety of indications, ranging from the prevention of mitochondrial disease to broader experiences of fertility difficulties. Mitochondrial disease specialists in Germany emphasized the predictability of mitochondrial unpredictability and a mitochondrial disease severity spectrum. Closely engaging with the use of two concepts by the specialists I interviewed-'predictability/unpredictability' and 'severity'-which also appeared in formal and public representations and discussions in the UK, I show how the invocation of these notions may paradoxically both enable and curtail support for the clinical implementation of MRTs.
    Keywords:  Assisted reproduction; Mitochondrial disease; Mitochondrial replacement techniques; Predictability; Rare disease; Severity spectrum; Unpredictability
    DOI:  https://doi.org/10.1016/j.socscimed.2025.118177
  5. Clin Genet. 2025 Jun 29.
    Expanding the Genetic and Phenotypic Spectrum of POLRMT-Related Mitochondrial Disease.
    Mahmoud R Fassad, Sebastian Valenzuela, Monika Oláhová, Jack J Collier, Charlotte V Y Knowles, Eleni Mavraki, Miriam Elbracht, Nergis Güzel, Thomas Herberhold, Ingo Kurth, Andrea Maier, Larissa Mattern, Carol Saunders, Helen McCullagh, Katrin Õunap, Saskia B Wortmann, Andre Reis, Lei Zhang, Claes M Gustafsson, Robert McFarland, Robert W Taylor.
      Mitochondrial diseases are a complex group of conditions exhibiting significant phenotypic and genetic heterogeneity. Genomic testing is increasingly used as the first step in the diagnostic pathway for mitochondrial diseases. We used next-generation sequencing followed by bioinformatic data analysis to identify potentially damaging variants in the POLRMT gene (NM_005035.4) in six new affected individuals. Structural protein analysis predicted the detrimental impact of variants on POLRMT protein structure. Patients show extended phenotypic abnormalities often presenting early in life with features including global developmental delay, cognitive impairment, short stature and muscular hypotonia. This study expands the genetic and phenotypic landscape of mitochondrial disease associated with POLRMT variants.
    Keywords:  POLRMT; mitochondrial disease; neurodevelopmental disorders; variant classification
    DOI:  https://doi.org/10.1111/cge.70011
  6. npj metabolic health and disease... 2025 Jun 18. 3(1): 26
    The role of NAD+ metabolism and its modulation of mitochondria in aging and disease.
    Khalishah Yusri, Sandra Jose, Karen S Vermeulen, Trina Chia Min Tan, Vincenzo Sorrentino.
      Nicotinamide adenine dinucleotide (NAD+) is a coenzyme involved in a plethora of physiological reactions, with a key relevance in supporting mitochondrial function. Due to its critical role in these cellular processes, declining levels of NAD+ are associated with general aging and chronic disorders, including cognitive decline, sarcopenia, and metabolic diseases. These conditions are also typified by loss of mitochondrial health through dysfunction of homeostatic components such as mitophagy, unfolded protein response, and the antioxidant system. Therefore, raising cellular NAD+ through vitamin B3 family precursors or via drug-based interventions has become a broadly used strategy to restore mitochondrial and organismal homeostasis, with NAD+ precursors becoming a popular supplementation approach. As increasing components of the NAD+ biology are unraveled, this comprehensive review summarizes the advances in mechanisms of NAD+ metabolism and its modulation via compound-based strategies. Furthermore, it highlights the role of NAD+ in mitochondrial homeostasis in aging and disease conditions, the latest results of NAD+-boosting therapeutics in clinical trials, and areas of further translational development.
    DOI:  https://doi.org/10.1038/s44324-025-00067-0
  7. Elife. 2025 Jun 30. pii: RP104461. [Epub ahead of print]14
    Tissue-specific responses to TFAM and mtDNA copy number manipulation in prematurely ageing mice.
    Laura Sophie Kremer, Guanbin Gao, Giovanni Rigoni, Roberta Filograna, Mara Mennuni, Rolf Wibom, Ákos Végvári, Camilla Koolmeister, Nils-Göran Larsson.
      Somatic mitochondrial DNA (mtDNA) mutations are implicated as important drivers of ageing and age-related diseases. Their pathological effect can be counteracted by increasing the absolute amount of wild-type mtDNA via moderately upregulating TFAM, a protein important for mtDNA packaging and expression. However, strong TFAM overexpression can also have detrimental effects as it results in mtDNA hypercompaction and subsequent impairment of mtDNA gene expression. Here, we have experimentally addressed the propensity of moderate TFAM modulation to improve the premature ageing phenotypes of mtDNA mutator mice, carrying random mtDNA mutations. Surprisingly, we detect tissue-specific endogenous compensatory mechanisms acting in mtDNA mutator mice, which largely affect the outcome of TFAM modulation. Accordingly, moderate overexpression of TFAM can have negative and beneficial effects in different tissues of mtDNA mutator mice. We see a similar behavior for TFAM reduction, which improves brown adipocyte tissue homeostasis, while other tissues are unaffected. Our findings highlight that the regulation of mtDNA copy number and gene expression is complex and causes tissue-specific effects that should be considered when modulating TFAM levels. Additionally, we suggest that TFAM is not the sole determinant of mtDNA copy number in situations where oxidative phosphorylation (OXPHOS) is compromised, but other important players must be involved.
    Keywords:  biochemistry; chemical biology; genetics; genomics; mitochondrial DNA; mouse; mtDNA copy number; mtDNA mutations; tissue specificity
    DOI:  https://doi.org/10.7554/eLife.104461
  8. Nat Rev Mol Cell Biol. 2025 Jul 03.
    Molecular machineries and pathways of mitochondrial protein transport.
    Toshiya Endo, Nils Wiedemann.
      Mitochondria contain about 1,000-1,500 different proteins, most of which are encoded by the nuclear genome and synthesized in the cytosol, although a handful are specified by the mitochondrial DNA and translated within mitochondria. The coordinated transport of nucleus-encoded proteins into mitochondria, followed by their proper folding, assembly and/or integration into mitochondrial membranes, is central to mitochondrial biogenesis. In this Review, we describe the pathways and machineries for protein transport across and insertion into the inner and outer mitochondrial membranes, as well as the targeting and sorting signals, and energy requirements for these processes. These machineries include the TOM and SAM complexes in the outer membrane and the TIM complexes in the inner membrane, and some components in the intermembrane space. We emphasize recent developments in our understanding of the protein structures of the transport machineries and discuss mechanisms for the shift of protein localization and correction of mislocalization.
    DOI:  https://doi.org/10.1038/s41580-025-00865-w
  9. Nat Commun. 2025 Jul 01. 16(1): 5465
    Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
    Nuo Sun, Hayley Barta, Samhita Chaudhuri, Kangxuan Chen, Jiacheng Jin, Hongke Luo, Mingchong Yang, Judith Krigman, Ruohan Zhang, Shridhar Sanghvi, Shiori Sekine, Hannah Sanders, Dominic Kolonay, Mudra Patel, Kedryn Baskin, Harpreet Singh, Pengyi Zhang, Gang Xin, Toren Finkel.
      The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) to sustain its high energy demands. FAO deficiencies can cause muscle weakness, cardiomyopathy, and, in severe cases, neonatal/infantile mortality. Although FAO deficits are thought to induce mitochondrial stress and activate mitophagy, a quality control mechanism that eliminates damaged mitochondria, the mechanistic link in the heart remains unclear. Here we show that mitophagy is unexpectedly suppressed in FAO-deficient hearts despite pronounced mitochondrial stress, using a cardiomyocyte-specific carnitine palmitoyltransferase 2 (CPT2) knockout model. Multi-omics profiling reveals impaired PINK1/Parkin signaling and dysregulation of PARL, a mitochondrial protease essential for PINK1 processing. Strikingly, deletion of USP30, a mitochondrial deubiquitinase that antagonizes PINK1/Parkin function, restores mitophagy, improves cardiac function, and significantly extends survival in FAO-deficient animals. These findings redefine the mitophagy response in FAO-deficient hearts and establish USP30 as a promising therapeutic target for metabolic cardiomyopathies and broader heart failure characterized by impaired FAO.
    DOI:  https://doi.org/10.1038/s41467-025-60670-z
  10. Nat Commun. 2025 Jul 01. 16(1): 5996
    The loss of OPA1 accelerates intervertebral disc degeneration and osteoarthritis in aged mice.
    Vedavathi Madhu, Miriam Hernandaz-Meadows, Ashley Coleman, Kimheak Sao, Kameron Inguito, Owen Haslam, Paige K Boneski, Hiromi Sesaki, Ruteja A Barve, John A Collins, Makarand V Risbud.
      Recent studies have highlighted the importance of mitochondria in NP cells and articular chondrocyte health. Since the understanding of mechanisms governing mitochondrial dynamics in these tissues is lacking, we investigated the role of OPA1, a mitochondrial fusion protein, in their homeostasis. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate. OPA1 governed the morphology of multiple organelles, including peroxisomes, early endosomes and cis-Golgi and loss resulted in the dysregulation of autophagy. Metabolic profiling and 13C-flux analyses revealed TCA cycle anaplerosis and altered metabolism in OPA1-deficient NP cells. Noteworthy, Opa1AcanCreERT2 mice showed age-dependent disc degeneration, osteoarthritis, and vertebral osteopenia. RNA-Sequencing of Opa1cKO NP tissue revealed dysregulation of metabolism, autophagy, cytoskeletal reorganization, and extracellular matrix and shared strong thematic similarities with a subset of human degenerative NP samples. Our findings underscore that maintenance of mitochondrial dynamics and multi-organelle cross-talk is critical in preserving metabolic homeostasis of disc and cartilage.
    DOI:  https://doi.org/10.1038/s41467-025-60933-9
  11. Nat Commun. 2025 Jul 04. 16(1): 6173
    Structural-functional characterization of the MIRO1-TRAK1 complex.
    Erika E Ravitch, Elana E Baltrusaitis, Tania A Perez, Kyle R Barrie, Adam R Fenton, Erika L F Holzbaur, Roberto Dominguez.
      Mitochondrial Rho GTPase (MIRO) features N- and C-terminal GTPase domains (nGTPase and cGTPase) flanking two pairs of EF-hands, and functions as a master scaffold on the outer mitochondrial membrane. It regulates mitochondrial motility by recruiting trafficking kinesin-binding protein (TRAK), which in turn recruits kinesin-1 and dynein-dynactin. The MIRO-TRAK interaction remains incompletely understood. Here, we describe the cryo-electron microscopy structure of TRAK1569-623 bound to MIRO1. The complex forms a dimer, mediated by interactions through the second EF-hand pair, cGTPase, and TRAK1. TRAK1569-623 binds in a cleft between the nGTPase and first EF-hand pair, inserting side chains into hydrophobic pockets of both domains. Another MIRO1-binding site involves TRAK1425-428, which binds in a pocket between the second EF-hand pair and cGTPase. Both binding sites are validated by mutagenesis and binding assays, showing no clear dependence on cofactor conditions (calcium or nucleotide). In cells, both sites contribute to TRAK1's mitochondrial localization.
    DOI:  https://doi.org/10.1038/s41467-025-61174-6
  12. Nat Commun. 2025 Jul 02. 16(1): 6083
    Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans.
    Iman Man Hu, Marte Molenaars, Yorrick R J Jaspers, Bauke V Schomakers, Michel van Weeghel, Amber Bakker, Melanie Modder, Joseph P Dewulf, Guido T Bommer, Arwen W Gao, Georges E Janssens, Riekelt H Houtkooper.
      Perturbing mitochondrial translation represents a conserved longevity intervention, with proteostasis processes proposed to mediate the resulting lifespan extension. Here, we explore whether other mechanisms may contribute to lifespan extension upon mitochondrial translation inhibition. Using multi-omics and functional in vivo screening, we identify the ethylmalonyl-CoA decarboxylase orthologue C32E8.9 in C. elegans as an essential factor for longevity induced by mitochondrial translation inhibition. Reducing C32E8.9 completely abolishes lifespan extension from mitochondrial translation inhibition, while mitochondrial unfolded protein response activation remains unaffected. We show that C32E8.9 mediates immune responses and lipid remodeling, which play crucial roles in the observed lifespan extension. Mechanistically, sma-4 (a TGF-β co-transcription factor) serves as an effector of C32E8.9, responsible for the immune response triggered by mitochondrial translation inhibition. Collectively, these findings underline the importance of the "immuno-metabolic stress responses" in longevity upon mitochondrial translation inhibition and identify C32E8.9 as a central factor orchestrating these responses.
    DOI:  https://doi.org/10.1038/s41467-025-61433-6
  13. J Clin Invest. 2025 Jul 01. pii: e185000. [Epub ahead of print]135(13):
    Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms.
    Milan Stoiljkovic, Jae Eun Song, Hee-Kyung Hong, Heiko Endle, Luis Varela, Jonatas Catarino, Xiao-Bing Gao, Zong-Wu Liu, Peter Sotonyi, Sabrina Diano, Jonathan Cedernaes, Joseph T Bass, Tamas L Horvath.
      Sustaining the strong rhythmic interactions between cellular adaptations and environmental cues has been posited as essential for preserving the physiological and behavioral alignment of an organism to the proper phase of the daily light/dark (LD) cycle. Here, we demonstrate that mitochondria and synaptic input organization of suprachiasmatic (SCN) vasoactive intestinal peptide-expressing (VIP-expressing) neurons showed circadian rhythmicity. Perturbed mitochondrial dynamics achieved by conditional ablation of the fusogenic protein mitofusin 2 (Mfn2) in VIP neurons caused disrupted circadian oscillation in mitochondria and synapses in SCN VIP neurons, leading to desynchronization of entrainment to the LD cycle in Mfn2-deficient mice that resulted in an advanced phase angle of their locomotor activity onset, alterations in core body temperature, and sleep-wake amount and architecture. Our data provide direct evidence of circadian SCN clock machinery dependence on high-performance, Mfn2-regulated mitochondrial dynamics in VIP neurons for maintaining the coherence in daily biological rhythms of the mammalian organism.
    Keywords:  Behavior; Cell biology; Metabolism; Mitochondria; Neuroscience; Synapses
    DOI:  https://doi.org/10.1172/JCI185000
  14. Commun Biol. 2025 Jul 01. 8(1): 972
    An integrative modelling approach to the mitochondrial cristae.
    Chelsea M Brown, Marieke S S Westendorp, Rubi Zarmiento-Garcia, Jan A Stevens, Bart M H Bruininks, Sarah L Rouse, Siewert J Marrink, Tsjerk A Wassenaar.
      Mitochondria are implicated in many cellular functions such as energy production and apoptosis but also disease pathogenesis. To effectively perform these roles, the mitochondrial inner membrane has invaginations known as cristae that dramatically increase the surface area. This works to provide more space for membrane proteins that are essential to the roles of mitochondria. While separate components of this have been studied computationally, it remains a challenge to combine elements into an overall model. Here, we present a comprehensive model of a crista junction from a human mitochondrion and the accompanying workflow to construct it. Our coarse-grained representation of a crista shows how various experimentally determined features of organelles can be combined with molecular modelling to give insights into the interactions and dynamics of complicated biological systems. This work is presented as an initial 'living' model for this system, intended to be built upon and improved as our understanding, methodology and resources develop.
    DOI:  https://doi.org/10.1038/s42003-025-08381-5
  15. Hippocampus. 2025 Jul;35(4): e70022
    EXPRESSION OF CONCERN: Acetyl-L-Carnitine-Mediated Neuroprotection During Hypoxia Is Attributed to ERK1/2-Nrf2-Regulated Mitochondrial Biosynthesis.
      
    DOI:  https://doi.org/10.1002/hipo.70022
  16. Mol Genet Metab. 2025 Jun 16. pii: S1096-7192(25)00170-2. [Epub ahead of print]145(4): 109179
    The mitochondrial disease biomarker GDF15 is dynamic, quantifiable in saliva, and correlates with disease severity.
    Qiuhan Huang, Caroline Trumpff, Anna S Monzel, Shannon Rausser, Jack Devine, Cynthia C Liu, Catherine Kelly, Mangesh Kurade, Shufang Li, Kris Engelstad, Kurenai Tanji, Vincenzo Lauriola, Tian Wang, Shuang Wang, Richard Sloan, Robert-Paul Juster, Michio Hirano, Martin Picard.
      Circulating growth differentiation factor 15 (GDF15) is a biomarker of mitochondrial diseases and aging, but its natural dynamics and response to acute stress in blood and other biofluids have not been well defined. Using extensive samples from MiSBIE participants with rare mitochondrial diseases (MitoD), we examined GDF15 biology in 290 plasma and 860 saliva aliquots from 40 subjects with the m.3243 A > G mutation (n = 25) or with single, large-scale mtDNA deletions (n = 15). Compared to healthy controls, both MitoD groups exhibited significantly elevated blood and saliva GDF15 (p < 0.0001). To examine the origin of GDF15 protein in saliva, we profiled GDF15 expression in 48 tissues from the GTEx dataset and identified high GDF15 expression in salivary gland secretory cells. Despite being chronically elevated in MitoD, saliva GDF15 further increased in response to experimental laboratory mental stress alone (without physical exertion), whereas the stress-induced plasma GDF15 reactivity was blunted in MitoD compared to controls. Using a home-based saliva collection protocol, we show that similar to other stress-related metabolic hormones, saliva GDF15 is highest upon awakening and declines rapidly by 61.2 % within 45 min. Elevated saliva GDF15 levels persisted throughout the day in MitoD. Clinically, saliva GDF15 correlated with neurological symptoms, fatigue, and functional capacity. Importantly, stress-evoked changes in GDF15 did not amplify noisy disease severity associations, but rather consistently increased the effects sizes for GDF15-symptoms connections, pointing to converging psychobiology underlying the responses to mitochondrial OxPhos defects and acute mental stress. These results open the door to exploring saliva GDF15 as a non-invasive monitoring approach for mitochondrial diseases and call for further studies examining the psychobiological processes linking mitochondria, mental stress, and GDF15 dynamics.
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109179
  17. Biophys Rep. 2025 Jun 30. 11(3): 143-155
    Modulating mitochondrial dynamics in CMT2A: a multifaceted platform for drug discovery and evaluation.
    Yang Liu, Chen Yan, Borui Cao, Dejun Kong, Jiaqi Li, Wenlei Li, Yingjie Guo, Zhongyang Yuan, Yumiao Gao, Yubo Zhang, Ran Sui, Guo Chen, Xiaojiang Hao, Quan Chen.
      Mitochondrial dynamics, encompassing fusion and fission processes, plays a crucial role in regulating mitochondrial distribution, motility, and material exchange within cells, particularly in the nervous system. Mitofusin-2 (MFN2), a GTPase localized to the outer mitochondrial membrane, mediates mitochondrial fusion through dimerization and conformational changes. Mutations in MFN2 are causal for Charcot-Marie-Tooth disease type 2A (CMT2A), an inherited peripheral neuropathy for which no curative treatment currently exists. Herein, we have developed a comprehensive mitochondrial drug-screening and evaluation platform to facilitate the identification of potential therapeutic candidates. This work builds upon our previous research with S89, a small molecule agonist derived from spiramine alkaloids that promotes mitochondrial fusion by interacting with endogenous MFN1 and effectively mitigates axonal degeneration in CMT2A patient-derived motor neurons. This platform integrates three sequential stages of assessment: (1) initial screening in Mfn knockout mouse embryonic fibroblasts (MEFs) to identify compounds capable of reversibly rescuing mitochondrial fragmentation; (2) evaluation in primary neuronal cultures derived from CMT2A mouse dorsal root ganglia and cortex to assess the compounds' efficacy in restoring mitochondrial morphology, axonal transport, and neurite outgrowth; and (3) final assessment in CMT2A patient-derived induced pluripotent stem cell (iPSC)-differentiated motor neurons to determine the candidates' therapeutic potential in human peripheral nervous system cells. This multi-tiered approach facilitates rapid compound screening with increasing physiological relevance, enhancing the efficiency and translational potential of identifying therapeutic candidates for CMT2A.
    Keywords:  CMT2A neuronal system; Charcot-Marie-Tooth disease type 2A (CMT2A); Mitochondrial fusion; Mitofusin-2 (MFN2); Screening and evaluation platform; Small molecule compounds
    DOI:  https://doi.org/10.52601/bpr.2024.240037
  18. Nat Metab. 2025 Jul 01.
    Triglycerides are an important fuel reserve for synapse function in the brain.
    Mukesh Kumar, Yumei Wu, Justin Knapp, Catherine L Pontius, Daehun Park, Rose E Witte, Rachel McAllister, Kallol Gupta, Kartik N Rajagopalan, Pietro De Camilli, Timothy A Ryan.
      Proper fuelling of the brain is critical to sustain cognitive function, but the role of fatty acid (FA) combustion in this process has been elusive. Here we show that acute block of a neuron-specific triglyceride lipase, DDHD2 (a genetic driver of complex hereditary spastic paraplegia), or of the mitochondrial lipid transporter CPT1 leads to rapid onset of torpor in adult male mice. These data indicate that in vivo neurons are probably constantly fluxing FAs derived from lipid droplets (LDs) through β-oxidation to support neuronal bioenergetics. We show that in dissociated neurons, electrical silencing or blocking of DDHD2 leads to accumulation of neuronal LDs, including at nerve terminals, and that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion to drive local mitochondrial ATP production. These data demonstrate that nerve terminals can make use of LDs during electrical activity to provide metabolic support and probably have a critical role in supporting neuron function in vivo.
    DOI:  https://doi.org/10.1038/s42255-025-01321-x
  19. Trends Endocrinol Metab. 2025 Jul 02. pii: S1043-2760(25)00120-1. [Epub ahead of print]
    Neuronal glycolysis meets mitophagy to govern organismal wellbeing.
    Daniel Jimenez-Blasco, Rebeca Lapresa, Jesus Agulla, Angeles Almeida, Juan P Bolaños.
      Neurons are exceptionally energy-demanding cells but have limited energy storage, relying on a constant supply of fuel and oxygen. Although glucose is the brain's main energy source, neurons reduce glycolysis under normal conditions. This surprising strategy helps to protect mitochondria by preserving nicotinamide-adenine dinucleotide (NAD+), a vital cofactor consumed by glycolysis. NAD+ is needed for sirtuin-driven mitophagy, a process that removes damaged mitochondria. By saving NAD+, neurons can maintain healthy, energy-efficient mitochondria. These mitochondria then use alternative fuels such as lactate and ketone bodies from astrocytes. Here, we discuss the way in which this balance between reduced glycolysis and active mitophagy supports brain function and overall metabolic health, highlighting a sophisticated system that prioritizes mitochondrial quality for long-term cognitive performance and systemic homeostasis.
    Keywords:  NAD; glycolysis; mitophay; neuron; organismal wellbeing
    DOI:  https://doi.org/10.1016/j.tem.2025.05.005
  20. PLoS Genet. 2025 Jul 03. 21(7): e1011353
    Ubp2 modulates DJ-1-mediated redox-dependent mitochondrial dynamics in Saccharomyces cerevisiae.
    Sananda Biswas, Patrick D'Silva.
      Mitochondrial integrity is a crucial determinant of overall cellular health. Mitochondrial dysfunction and impediments in regulating organellar homeostasis contribute majorly to the pathophysiological manifestation of several neurological disorders. Mutations in human DJ-1 (PARK7) have been implicated in the deregulation of mitochondrial homeostasis, a critical cellular etiology observed in Parkinson's disease progression. DJ-1 is a multifunctional protein belonging to the DJ-1/ThiJ/PfpI superfamily, conserved across the phylogeny. Although the pathophysiological significance of DJ-1 has been well-established, the underlying molecular mechanism(s) by which DJ-1 paralogs modulate mitochondrial maintenance and other cellular processes remains elusive. Using Saccharomyces cerevisiae as the model organism, we unravel the intricate mechanism by which yeast DJ-1 paralogs (collectively called Hsp31 paralogs) modulate mitochondrial homeostasis. Our study establishes a genetic synthetic interaction between Ubp2, a cysteine-dependent deubiquitinase, and DJ-1 paralogs. In the absence of DJ-1 paralogs, mitochondria adapt to a highly tubular network due to enhanced expression of Fzo1. Intriguingly, the loss of Ubp2 restores the mitochondrial integrity in the DJ-1 deletion background by modulating the ubiquitination status of Fzo1. Besides, the loss of Ubp2 in the absence of DJ-1 restores mitochondrial respiration and functionality by regulating the mitophagic flux. Further, Ubp2 deletion makes cells resistant to oxidative stress without DJ-1 paralogs. For the first time, our study deciphers functional crosstalk between Ubp2 and DJ-1 in regulating mitochondrial homeostasis and cellular health.
    DOI:  https://doi.org/10.1371/journal.pgen.1011353
  21. iScience. 2025 Jul 18. 28(7): 112816
    Genetically encoded and modular subcellular organelle probes reveal dysfunction in lysosomes and mitochondria driven by PRKN knockout.
    Camille Goldman, Tatyana Kareva, Lily Sarrafha, Braxton R Schuldt, Abhishek Sahasrabudhe, Tim Ahfeldt, Joel W Blanchard.
      Cellular processes including lysosomal and mitochondrial dysfunction are implicated in the development of many diseases. Quantitative visualization of mitochondria and lysosomes is crucial to understand how these organelles are dysregulated during disease. To address a gap in live-imaging tools, we developed GEM-SCOPe (genetically encoded and modular subcellular organelle probes), a modular toolbox of fluorescent markers designed to inform on localization, distribution, turnover, and oxidative stress of specific organelles. We expressed GEM-SCOPe in differentiated astrocytes and neurons from a human pluripotent stem cell PRKN-knockout model of Parkinson's disease and identified disease-associated changes in proliferation, lysosomal distribution, mitochondrial transport and turnover, and reactive oxygen species. We demonstrate GEM-SCOPe is a powerful panel that provides critical insight into the subcellular mechanisms underlying Parkinson's disease in human cells. GEM-SCOPe can be expanded upon and applied to a diversity of cellular models to glean an understanding of the mechanisms that promote disease onset and progression.
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112816
  22. Nat Commun. 2025 Jul 01. 16(1): 5460
    Autoregulation of the real-time kinetics of the human mitochondrial replicative helicase.
    Ismael Plaza-G A, María Ortiz-Rodríguez, Seth P Buchanan, Samuel Miguez-Amil, Kateryna M Lemishko, Fernando Moreno-Herrero, Rafael Fernandez-Leiro, Grzegorz L Ciesielski, Borja Ibarra.
      The human mitochondrial helicase Twinkle is essential for mitochondrial DNA (mtDNA) replication and integrity. Using biochemical and single-molecule techniques, we investigated Twinkle's real-time kinetics, including DNA loading, unwinding, and rewinding, and their regulation by its N-terminal Zinc-binding domain (ZBD), C-terminal tail, and mitochondrial SSB protein (mtSSB). Our results indicate that Twinkle rapidly scans dsDNA to locate the fork, where specific interactions halt diffusion. During unwinding, ZBD-DNA interactions and C-terminal tail control of ATPase activity downregulate kinetics, slowing down the helicase. Binding of mtSSB to DNA likely outcompetes ZBD-DNA interactions, alleviating the downregulatory effects of this domain. Furthermore, we show that ZBD-DNA interactions and ATP binding also regulate rewinding kinetics following helicase stalling. Our findings reveal that ZBD and C-terminal tail play a major role in regulation of Twinkle´s real-time kinetics. Their interplay constitutes an auto-regulatory mechanism that may be relevant for coordinating the mtDNA maintenance activities of the helicase.
    DOI:  https://doi.org/10.1038/s41467-025-60289-0
  23. Nat Commun. 2025 Jul 01. 16(1): 5709
    Biotechnological approaches and therapeutic potential of mitochondria transfer and transplantation.
    Gokhan Burcin Kubat, Pasquale Picone, Erkan Tuncay, Leila Aryan, Antonella Girgenti, Laura Palumbo, Ibrahim Turkel, Firat Akat, Keshav K Singh, Domenico Nuzzo.
      Mitochondrial dysfunction contributes to aging and diseases like neurodegeneration and cardiovascular disorders. Mitochondria transfer and transplantation (MTT) represent promising therapeutic strategies aimed at restoring cellular function by introducing functional mitochondria into damaged cells. However, challenges like transfer efficiency, stability, and cellular integration limit clinical application. Recent biotechnological advances-such as liposomes, extracellular vesicles, and surface modifications-enhance mitochondrial protection, targeting, and biocompatibility. This Perspective highlights recent progress in MTT, its therapeutic potential, and current limitations. We also discuss the need for scalable, clinically translatable approaches and appropriate regulatory frameworks to realize the full potential of mitochondria-based nanotherapies in modern medicine.
    DOI:  https://doi.org/10.1038/s41467-025-61239-6
  24. Biochim Biophys Acta Mol Cell Res. 2025 Jun 30. pii: S0167-4889(25)00117-X. [Epub ahead of print]1872(7): 120012
    Mitochondrial DNA genotypes modify m.3243A>G-associated mitochondrial disease via the 15-HETE/Akt/FoxO1 pathway.
    Qian Wang, Chang You, Xiaoning Qu, YiQing Zhang, Yuxiao Bai, Xianlong Lin, Zhaoxia Wang, Hezhi Fang, Jianxin Lyu, Minghua Jiang, Ya Wang.
      Mitochondrial disease caused by mitochondrial DNA (mtDNA) 3243A>G mutation is characterized by high levels of clinical heterogeneity. Varied m.3243A>G mutation loads among patients are used to, but cannot fully explain, disease heterogeneity. Here, we found that mtDNA genotypes (haplogroups) modify m.3243A>G-associated natural selection and cell fate determination. mtDNA haplogroup M7 was less prevalent in a multi-center m.3243A>G disease cohort. Further functional studies using cybrids showed that M7 accelerated cell proliferation and shortened G0/G1 cell cycle when compared with cybrid carrying a non-M7 haplogroup (D5). However, mitochondrial function and cell viability were even worse in M7 cybrid than D5 cybrid when treated with mitochondrial oxidative phosphorylation (OXPHOS) inhibitors, indicating that M7 drives negative selection in patients with m.3243A>G during evolution. By adopting multi-omics strategies, we showed a lesser increase of 15-hydroxyeicosatetraenoic acid (15-HETE) levels in M7 cybrid owing to OXPHOS inhibition, leading to insufficient Akt/FoxO1 activation and increased apoptosis. Notably, 15-HETE administration activated Akt/FoxO1 phosphorylation and abolished apoptosis difference between M7 and D5 cybrids, suggesting that augmented 15-HETE was vital to protect cells from death. Collectively, our work identified a genetic modifier of m.3243A>G-associated mitochondrial disease and demonstrated that the mitochondrial retrograde 15-HETE/Akt/FOXO1 signaling cascade plays an important role in protecting cells from OXPHOS dysfunction-induced cell death.
    Keywords:  15-HETE; Akt-FoxO1 signaling; Mitochondrial disease; m.3243A>G; mtDNA haplogroup
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.120012
  25. JCEM Case Rep. 2025 Aug;3(8): luaf127
    Letter to the Editor From Finsterer "Diverse Phenotypes of Mitochondrial Disease With Varying Levels of Heteroplasmy".
    Josef Finsterer.
      
    DOI:  https://doi.org/10.1210/jcemcr/luaf127
  26. Transl Neurodegener. 2025 Jul 01. 14(1): 34
    Deficient AMPK-SENP1-Sirt3 signaling impairs mitochondrial complex I function in Parkinson's disease model.
    Xiaoyu Sun, Jianyi Shen, Yimei Shu, Tianshi Wang, Lu He, Ruinan Shen, Yifan Zhou, Jinke Cheng, Suzhen Lin, Jianqing Ding.
       BACKGROUND: Epidemiological studies have revealed increased Parkinson's disease (PD) risk among individuals exposed to pesticides like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP is frequently used to induce PD-like symptoms in research models by disrupting mitochondrial complex I (CI) function and causing dopaminergic neuronal loss in the nigrostriatal region. However, the pathway(s) through which MPTP impairs mitochondrial CI function remain to be elucidated. In this study, we aim to identify the molecular mechanisms through which MPTP modulates CI function and define the specific subunits of mitochondrial CI affected by MPTP.
    METHODS: Male mice encompassing either wild-type Sirt3 or Sirt3 K223R de-SUMOylation mutation, were intraperitoneally injected with either MPTP or saline. In vitro experiments were conducted using the SH-SY5Y cell line with or without the Sirt3 de-SUMOylation mutation. Movement performance, mitochondrial function, and protein acetylation were evaluated.
    RESULTS: MPTP exposure, both in vitro and in vivo, disrupted the AMPK-SENP1-Sirt3 axis, leading to impairment of mitochondrial function. Specifically, MPTP suppressed activation of AMPK, impeding the entry of SENP1 into the mitochondria. The lack of mitochondrial SENP1 resulted in increased levels of SUMOylated Sirt3, which inhibited its deacetylase activity. This led to a significant increase in the acetylation of CI subunits NDUFS3 and NDUFA5, which resulted in reduced CI activity and inhibition of mitochondrial function, and eventually dopaminergic neuronal death. In this pathway, sustained deSUMOylation mutation of Sirt3 (K223R in mice, K288R in humans) mitigated the impact of MPTP on mitochondrial dysregulation, as well as dopaminergic neuronal death and behavioral deficits.
    CONCLUSION: The disordered AMPK-SENP1-Sirt3 pathway plays a crucial role in the MPTP-induced CI dysfunction and PD-like phenotype, which provide valuable insights into the mechanisms of PD pathogenesis.
    Keywords:  MPTP; Mitochondrial complex I; Parkinson's disease; SENP1; Sirt3
    DOI:  https://doi.org/10.1186/s40035-025-00489-2
  27. Cell Rep. 2025 Jul 02. pii: S2211-1247(25)00708-9. [Epub ahead of print]44(7): 115937
    Mitochondrial thermal proteome profiling reveals aberrant activation of pyruvate dehydrogenase upon cuproptosis.
    Zongyu Huang, Yanjun Liu, Ya Zeng, Jun Wang, Siyuan Sun, Chris Soon Heng Tan, Peng R Chen.
      Cuproptosis, a copper-induced form of regulated cell death, holds therapeutic promise in cancer but remains mechanistically unclear. We developed Mito-TPCA, a mitochondrial thermal proximity coaggregation strategy combining enzyme-catalyzed proteome labeling with thermal profiling, to map mitochondrial protein-protein interaction dynamics during cuproptosis. This approach revealed that copper disrupts the association of pyruvate dehydrogenase kinases (PDKs) with the pyruvate dehydrogenase (PDH) complex by targeting lipoyl domains, triggering PDH dephosphorylation and aberrant activation. We demonstrate that this PDH activation is a key driver of cuproptosis and contributes to the heightened susceptibility of cancer cells. These findings establish PDH dephosphorylation/activation as a central mechanism of cuproptosis and a potential anti-cancer therapeutic target. Mito-TPCA offers a versatile platform to study mitochondrial protein complex dynamics in live cells.
    Keywords:  CP: Metabolism; CP: Molecular biology; cancer cell susceptibility; cuproptosis; mitochondrial thermal proteome; proximity labeling; pyruvate dehydrogenase aberrant activation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115937
  28. Curr Neuropharmacol. 2025 Jun 30.
    Powering Up the Brain: Intercellular Mitochondrial Quality Control and Its Implication in Stroke.
    Xinyu Zhou, Shenzhe Wu, Tianxi Huang, Yue Li, Jianhong Yang, Zhen Gu, Xiangnan Zhang.
      Mitochondria are critical for neuronal survival and function, and their dysregulation is closely related to the incidence and prevalence of various neurological disorders, including stroke. Mitochondrial quality control (MQC) is vital for maintaining mitochondrial integrity, particularly in neurons. Under ischemic conditions, neurons evolve a range of adaptive strategies to preserve mitochondria function dynamically, either by generating functional mitochondria or by eliminating dysfunctional ones via autophagy, both of which play key roles in keeping neuronal survival under the conditions of stroke. Besides these intracellular strategies, the intercellular mechanisms underlying MQC have been observed in the nervous system. Functional mitochondria from healthy cells can be supplemented to ischemic neurons in distinct manners and thus restore the mitochondrial network of recipient cells. Conversely, injured neurons release dysfunctional mitochondria, which can be further degraded by adjacent glial cells. Alternatively, the discarded mitochondria act as a threat to surrounding cells and can disrupt the homeostasis of the nervous system. In this review, the key discoveries in intercellular MQC in the nervous system were summarized, and further discussed the implications of intercellular MQC strategies for stroke therapy.
    Keywords:  Intercellular mitochondrial quality control; intercellular mitochondrial transport; stroke.; trans mitophagy
    DOI:  https://doi.org/10.2174/011570159X388351250620065716
  29. Trends Cancer. 2025 Jul 02. pii: S2405-8033(25)00153-0. [Epub ahead of print]
    mtDNA transfer from senescent cancer cells to MDSCs promotes immunosuppression.
    Israel Cañadas, Takahiko Murayama, Lorenzo Galluzzi.
      Sublethal apoptotic stress causing the permeabilization of some mitochondria coupled with cytosolic mitochondrial DNA (mtDNA) accumulation is known to promote cellular senescence. Lai et al. have recently demonstrated that this may be accompanied by mtDNA release within extracellular vesicles that promote local immunosuppression via myeloid-derived suppressor cells.
    Keywords:  NF-κB; PD-L1; SASP; STING; VDAC; prostate cancer
    DOI:  https://doi.org/10.1016/j.trecan.2025.06.010
  30. Am J Physiol Heart Circ Physiol. 2025 Jun 30.
    Complexome profiling identifies changes in mitochondrial supercomplexes in murine heart failure.
    Claire Fong-McMaster, Ella McIlroy, Michelle M Levesque, Stephanie Myers, Serena M Pulente, Gurrose Gahla, Ilka Lorenzen-Schmidt, Miroslava Cuperlovic-Culf, Arsalan S Haqqani, Erin E Mulvihill, Mary-Ellen Harper.
      Heart failure is characterized by metabolic derangements such as altered substrate metabolism and mitochondrial dysfunction. Mitochondrial supercomplexes, which are higher-order molecular structures comprised of multi-subunit complexes of the electron transport chain, are decreased in heart failure. To investigate the supercomplex proteome composition in heart failure, we used an in vivo myocardial infarction (MI) model in which mice exhibited reduced cardiac function, confirmed by two-dimensional echocardiography at 4 weeks post-infarction. To assess proteins within supercomplexes, we used an emerging technique known as complexome profiling. This technique involved separating out mitochondrial protein complexes using Blue-Native PAGE combined with mass spectrometry to identify proteins within supercomplex gel bands. We identified band-dependent decreases or increases in the relative abundance of subunits of the electron transport chain between MI and sham mice. Decreased abundance of proteins involved in α-ketoglutarate dehydrogenase metabolism including DLST was also identified in the supercomplex bands of MI mice compared to sham mice. In addition, decreased abundance of redox-related proteins such as SOD2 and changes in ribosome protein subunits were identified in the MI mitochondria. In conclusion, we identified changes in the mitochondrial supercomplex proteome in a murine model of heart failure, providing insight and novel mechanisms that may be contributing to the metabolic dysfunction in heart failure.
    Keywords:  Blue-Native PAGE; Respirasome; cardiomyopathy; mass spectrometry; oxidative phosphorylation
    DOI:  https://doi.org/10.1152/ajpheart.00278.2025
  31. J Neuropathol Exp Neurol. 2025 Jun 21. pii: nlaf070. [Epub ahead of print]
    Neuromuscular pathology and mitochondrial dysfunction in sorbitol dehydrogenase gene-related distal hereditary motor neuropathies.
    Zhenyu Li, Xujun Chu, Yize Li, Zhiying Xie, Meng Yu, Jianwen Deng, He Lv, Wei Zhang, Qiang Gang, Zhaoxia Wang, Lingchao Meng, Yun Yuan.
      Biallelic variants in sorbitol dehydrogenase (SORD) have been reported to be a major cause of autosomal recessive distal hereditary motor neuropathy (dHMN). In this study, the clinical and pathological features of 10 patients with SORD gene-related dHMN are reported. Homozygous c.757delG variant was detected in 6 patients while c.757delG, c.786 + 1G>A, c.218C>T, and a novel c.104T>A compound heterozygous variants were observed in the others. Serum sorbitol, xylitol, and D-arabinitol were measured by gas chromatography-mass spectrometry; increased sorbitol and xylitol, and decreased D-arabinitol were identified. Sural nerve biopsies showed mild loss of large, myelinated fibers, and a few thin myelinated fibers. Skeletal muscle biopsies exhibited a neurogenic pattern with vacuoles, tubular aggregates, and abnormal mitochondria. Proteomic analyses of muscle tissue were performed to explore potential mechanisms. Complex I deficiency was dominant in the proteomic analysis and the malic acid/oxaloacetic acid ratio was significantly higher in the patients than in controls. In summary, SORD gene-related dHMN is a systemic disorder of carbohydrate metabolism with subclinical myopathologic changes, including tubular aggregates and vacuoles. Mitochondrial complex I deficiency, may be a key mechanism in SORD gene-related dHMN.
    Keywords:  SORD; carbohydrate metabolism; distal hereditary motor neuropathy; mitochondria; tubular aggregate
    DOI:  https://doi.org/10.1093/jnen/nlaf070
  32. Nature. 2025 Jul;643(8070): 47-59
    The Somatic Mosaicism across Human Tissues Network.
    Somatic Mosaicism across Human Tissues Network
      From fertilization onwards, the cells of the human body acquire variations in their DNA sequence, known as somatic mutations. These postzygotic mutations arise from intrinsic errors in DNA replication and repair, as well as from exposure to mutagens. Somatic mutations have been implicated in some diseases, but a fundamental understanding of the frequency, type and patterns of mutations across healthy human tissues has been limited. This is primarily due to the small proportion of cells harbouring specific somatic variants within an individual, making them more challenging to detect than inherited variants. Here we describe the Somatic Mosaicism across Human Tissues Network, which aims to create a reference catalogue of somatic mutations and their clonal patterns across 19 different tissue sites from 150 non-diseased donors and develop new technologies and computational tools to detect somatic mutations and assess their phenotypic consequences, including clonal expansions. This strategy enables a comprehensive examination of the mutational landscape across the human body, and provides a comparison baseline for somatic mutation in diseases. This will lead to a deep understanding of somatic mutations and clonal expansions across the lifespan, as well as their roles in health, in ageing and, by comparison, in diseases.
    DOI:  https://doi.org/10.1038/s41586-025-09096-7
  33. Int J Biol Macromol. 2025 Jul 01. pii: S0141-8130(25)06261-0. [Epub ahead of print]319(Pt 4): 145706
    Mitochondrial transcription factor a as a guardian of mitochondrial integrity and emerging therapeutic target in human diseases: A review.
    Miao Yang, Le Sun, Xibin Feng, Wei Xu.
      Mitochondrial transcription factor A (TFAM) plays a central role in mtDNA transcription, replication, and nucleoid compaction, thereby maintaining mitochondrial integrity and function. As a highly conserved nuclear-encoded protein, TFAM is indispensable for mitochondrial biogenesis and influences cellular energy metabolism and mitochondrial homeostasis. Given its fundamental role in mitochondrial function, dysfunction of TFAM contributes to the pathogenesis of various diseases and has become a key focus of biomedical research. This review systematically examines recent advances in understanding the diverse biological functions and regulatory mechanisms of TFAM, specifically addresses disease progression through the perspective of TFAM dysfunction. We highlight the therapeutic potential of TFAM, aiming to provide insights into its role as a biomarker and a promising therapeutic target for mitochondrial dysfunction-related diseases, offering promising insights for future therapeutic development in mitochondrial dysfunction-related conditions.
    Keywords:  Mitochondrial homeostasis; Mitochondrial transcription factor A; Therapeutic potential
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145706
  34. Cell Metab. 2025 Jul 01. pii: S1550-4131(25)00296-7. [Epub ahead of print]37(7): 1455-1456
    Muscle needs NAD, but how much?
    David W Frederick, Joseph P McGaunn, Joseph A Baur.
      Supplements that increase nicotinamide adenine dinucleotide (NAD) have become increasingly popular, and much of the attention has focused on potential benefits to skeletal muscle. In this issue of Cell Metabolism, Chubanava et al.1 use an inducible model to lower NAD concentration in the muscles of adult mice, revealing a surprising lack of functional consequences.
    DOI:  https://doi.org/10.1016/j.cmet.2025.06.001
  35. Sci China Life Sci. 2025 Jul 02.
    The mechanisms and functions of mitochondria-encapsulating extracellular vesicles.
    Danli Sheng, Xiangyu Chen, Jing Shi, Hongyun Tang.
      Extracellular vesicles (EVs) are membrane-bound subcellular entities that perform crucial roles in cellular communication and the release of intracellular contents. Traditionally, EVs have been recognized for encapsulating a variety of biomolecules, including DNA, RNA, proteins, and metabolites. However, recent advancements in research have revealed that EVs can also encapsulate organelles, with mitochondria emerging as a significant cargo. This review delves into the burgeoning field of mitochondria-encapsulating EVs, such as mitophers, migrasomes, and exophers, along with other mitochondria-harboring EVs that are less characterized. We explore the discovery, distinctive features, and functional roles of these EVs in regulating mitochondrial quality and quantity, under both physiological and pathological conditions. The mechanisms underlying the generation of these vesicles are also examined. Additionally, we discuss the challenges and future directions in the study of mitochondria-containing EVs. Given their potential to serve as diagnostic biomarkers and therapeutic tools, these mitochondria-embedded vesicles represent a promising frontier in molecular and cell biology, with significant implications for understanding and treating a range of diseases.
    Keywords:  exopher; extracellular vesicles; migrasome; mitochondrial quality control; mitochondrial quantity control; mitocytosis; mitopher
    DOI:  https://doi.org/10.1007/s11427-024-2905-5
  36. Nat Commun. 2025 Jul 01. 16(1): 5442
    Conformational dynamics and membrane insertion mechanism of B4GALNT1 in ganglioside synthesis.
    Jack W J Welland, Henry G Barrow, Phillip J Stansfeld, Janet E Deane.
      Glycosphingolipids (GSLs) are crucial membrane components involved in essential cellular pathways. Complex GSLs, known as gangliosides, are synthesised by glycosyltransferase enzymes and imbalances in GSL metabolism cause severe neurological diseases. B4GALNT1 synthesises the precursors to the major brain gangliosides. Loss of B4GALNT1 function causes hereditary spastic paraplegia, while its overexpression is linked to cancers including childhood neuroblastoma. Here, we present crystal structures of the human homodimeric B4GALNT1 enzyme demonstrating dynamic remodelling of the substrate binding site during catalysis. We show that processing of lipid substrates by B4GALNT1 is severely compromised when surface loops flanking the active site are mutated from hydrophobic residues to polar. Molecular dynamics simulations support that these loops can insert into the lipid bilayer explaining how B4GALNT1 accesses and processes lipid substrates. By combining structure prediction and molecular simulations we propose that this mechanism of dynamic membrane insertion is exploited by other, structurally distinct GSL synthesising enzymes.
    DOI:  https://doi.org/10.1038/s41467-025-60593-9
  37. J Mol Cell Cardiol Plus. 2025 Sep;13 100459
    Genetic deletion or pharmacological inhibition of acetyl-CoA carboxylase 2 enhances fatty acid oxidation and improves cardiac function and survival in the murine ATGL knockout model of severe heart failure.
    Mai Usui, Yu Tsurekawa, Tatsuya Ikehara, Atsuyuki Shimazaki, Archana Vijayakumar, Robert P Myers, G Mani Subramanian, Eisuke Murakami.
      Impaired myocardial energetics, including fatty acid oxidation (FAO), is a hallmark feature in the pathophysiology of various disorders. Deficiency of adipose triglyceride lipase (ATGL) results in impaired FAO which leads to severe heart failure due to massive triglyceride accumulation in cardiac muscle and coronary vasculature. Acetyl-CoA carboxylase 2 (ACC2) is a mitochondrial enzyme that regulates FAO; ACC2 inhibition increases transport of fatty acids into mitochondria for oxidation. In this study, the murine ATGL knockout (KO) model of severe heart failure was used to evaluate the effects ACC2 inhibition induced by whole body genetic KO (Atgl/Acc2 double KO mice) and pharmacological inhibition with TLC-3595, an oral, selective small molecule inhibitor of ACC2. Both genetic deletion of Acc2 and treatment with TLC-3595 in Atgl KO mice promoted mitochondrial FAO, reduced cardiac lipid accumulation and remodeling, and led to significant improvements in cardiac function, locomotor activity, and survival. Metabolite profiling of cardiac tissue of Atgl/Acc2 double KO mice and Atgl KO mice treated with TLC-3595 revealed ACC2-specific changes, including reduced malonyl-CoA and increased short-, medium-, and long-chain acylcarnitines, consistent with improved FAO. These findings support the therapeutic targeting of ACC2 for the treatment of heart failure associated with impaired FAO.
    Keywords:  ACC2; Cardiac metabolism; Cardiovascular therapeutics; Fatty acid oxidation; Triglycerides
    DOI:  https://doi.org/10.1016/j.jmccpl.2025.100459
  38. Nat Commun. 2025 Jul 02. 16(1): 6079
    Structure and biochemistry-guided engineering of an all-RNA system for DNA insertion with R2 retrotransposons.
    KeHuan K Edmonds, Max E Wilkinson, Daniel Strebinger, Hongyu Chen, Blake Lash, Clarissa C Schaefer, Shiyou Zhu, Dangliang Liu, Shai Zilberzwige-Tal, Alim Ladha, Michelle L Walsh, Chris J Frangieh, Nicholas A Vaz Reay, Rhiannon K Macrae, Xiao Wang, Feng Zhang.
      R2 elements, a class of non-long terminal repeat (non-LTR) retrotransposons, have the potential to be harnessed for transgene insertion. However, efforts to achieve this are limited by our understanding of the retrotransposon mechanisms. Here, we structurally and biochemically characterize R2 from Taeniopygia guttata (R2Tg). We show that R2Tg cleaves both strands of its ribosomal DNA target and binds a pseudoknotted RNA element within the R2 3' UTR to initiate target-primed reverse transcription. Guided by these insights, we engineer and characterize an all-RNA system for transgene insertion. We substantially reduce the system's size and insertion scars by eliminating unnecessary R2 sequences on the donor. We further improve the integration efficiency by chemically modifying the 5' end of the donor RNA and optimizing delivery, creating a compact system that achieves over 80% integration efficiency in several human cell lines. This work expands the genome engineering toolbox and provides mechanistic insights that will facilitate future development of R2-mediated gene insertion tools.
    DOI:  https://doi.org/10.1038/s41467-025-61321-z
  39. Biochim Biophys Acta Bioenerg. 2025 Jun 29. pii: S0005-2728(25)00032-5. [Epub ahead of print] 149566
    Dynamic binding of acetogenin-type inhibitors to mitochondrial complex I revealed by photoaffinity labeling.
    Misaki Nishida, Cristina Pecorilla, Takahiro Masuya, Keitaro Hirano, Masato Abe, Oleksii Zdorevskyi, Vivek Sharma, Hideto Miyoshi, Masatoshi Murai.
      Acetogenins isolated from the Annonaceae plant family are potent inhibitors of mitochondrial NADH-ubiquinone (UQ) oxidoreductase (complex I). Since acetogenins have a markedly different chemical framework from other complex I inhibitors, studying their inhibitory action offers valuable insights into the mechanism of complex I inhibition. A cryo-EM structure of mouse complex I with a bound ~35 Å-long acetogenin derivative suggested that acetogenins bind along the full length of the predicted UQ-accessing tunnel, with their γ-lactone ring orientating toward the iron‑sulfur cluster N2. However, this binding mode does not fully explain the structure-activity relationships of various acetogenin derivatives. To further elucidate their inhibition mechanism, we conducted photoaffinity labeling experiments in bovine heart SMPs using a photoreactive acetogenin derivative DLA-1, containing a small photolabile diazirine near the γ-lactone ring. DLA-1 labeled both the complex I subunits 49-kDa and ND1, which define the architecture of "top" and "bottom" regions of the canonical UQ-accessing tunnel, respectively. Proteomic analysis revealed that the labeled sites in ND1 are not within the tunnel's interior, whereas in the case of 49-kDa subunit, part of the tunnel's inner region is labeled. To investigate the molecular basis of acetogenin binding, we performed atomistic molecular dynamics simulations of DLA-1 and a natural-type acetogenin analog in the UQ-accessing tunnel. The simulation data indicate that DLA-1 is relatively rigid yet adopts multiple conformations and interacts with several regions in the tunnel including the residues identified by photoaffinity labeling. Based on these results, we discuss the binding modes of acetogenin analogs to complex I.
    Keywords:  Acetogenin; MD simulations; Mitochondria; Photoaffinity labeling; Respiratory complex I
    DOI:  https://doi.org/10.1016/j.bbabio.2025.149566
  40. J Appl Physiol (1985). 2025 Jul 03.
    Effect of high-altitude exposure on skeletal muscle mitochondrial subcellular distribution, ultrastructure and respiration in sea-level residents.
    Camilla Tvede Schytz, Joachim Nielsen, Niels Ortenblad, Anne-Kristine Meinild Lundby, Robert A Jacobs, Carsten Lundby.
      The skeletal muscle mitochondrial network, composed of interconnected subsarcolemmal and intermyofibrillar mitochondria, is essential for oxygen-dependent energy transduction. Since high altitude is characterized by tissue hypoxia, this network may adapt by increasing its respiratory efficiency, but little is known about potential adaptations of the mitochondrial network in such an environment. We investigated effects of high-altitude exposure on mitochondrial subcellular distribution, ultrastructure, respiratory control and intrinsic respiratory capacity. Nine healthy and recreationally active sea-level residents (eight males and one female) resided at an altitude of 3454 m with biopsies collected from the vastus lateralis muscle before and after 7 and 28 days at high altitude. Mitochondrial volume per skeletal muscle fiber volume (total fiber mitochondrial volume density) increased after high-altitude exposure, driven by an increase in the intermyofibrillar mitochondrial volume density (n=9). This was, however, accompanied by a decreased cristae surface area per skeletal muscle fiber volume (total fiber cristae density) because of a decline in the cristae surface area per mitochondrial volume (mitochondrial cristae density) (n=7). Despite a reduced total fiber cristae density, mass-specific respiration increased slightly (n=9), and was considerably elevated when normalized to total fiber cristae density (n=7), suggesting intrinsic adjustments. Correcting cristae-specific respiration for an associated cristae-specific leak respiration showed a higher net oxidative phosphorylation capacity meaning an augmented respiratory capacity potentially available for phosphorylation per total fiber cristae density after 7 and 28 days at high altitude (n=7). In conclusion, these findings suggest that high-altitude exposure alters mitochondrial subcellular distribution, ultrastructure and induces intrinsic respiratory adjustments.
    Keywords:  high altitude; mitochondria; mitochondrial cristae density; skeletal muscle fibers; transmission electron microscopy
    DOI:  https://doi.org/10.1152/japplphysiol.00042.2025
  41. Biochim Biophys Acta Mol Cell Res. 2025 Jun 28. pii: S0167-4889(25)00119-3. [Epub ahead of print]1872(7): 120014
    AAV9-mediated gene therapy restores liver function in the MEGDHEL mouse model.
    Ting Wei, Yuyan Lin, Wenhui Ouyang, Yu Lei, Xiali Yang, Linjie Chen, Xiaobai He, Quan Fang, Xiaoguang Zheng, Hang Tong, Binggang Tu, Jia Zeng, Jianxin Lyu, Miaomiao Du, Shanying Gui.
      MEGDHEL syndrome is a severe mitochondrial disorder caused by mutations in the SERAC1 gene, characterized by sensorineural deafness, encephalopathy, hepatopathy, and Leigh-like syndrome. A hallmark feature is neonatal liver failure, often leading to high mortality. There is currently no effective treatment. In this study, we used AAV9-SERAC1 gene therapy to address liver dysfunction and mitochondrial impairments in the Serac1-/- mouse model. Treatment with 4 × 1011 viral genomes led to improvements in liver histology, including reduced fatty degeneration and cholesterol accumulation, as well as enhanced mitochondrial morphology and function. Transmission electron microscopy revealed restored mitochondrial cristae and an increased number of mitochondria in treated mice. Respiratory complex showed activity recovery and mitochondrial DNA content was increased. Behavioral assessments also demonstrated significant improvements in motor coordination, with treated mice showing enhanced grasping strength and balance compared to controls. These findings suggest that AAV9-SERAC1 gene therapy can improve liver function and locomotor abilities in Serac1-/- mice, offering a promising therapeutic strategy for MEGDHEL syndrome.
    Keywords:  MEGDHEL AAV9 gene therapy liver function
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.120014
  42. Trends Biochem Sci. 2025 Jun 27. pii: S0968-0004(25)00140-9. [Epub ahead of print]
    Cell-specific mitoproteomics reveals mitochondrial plasticity and applications.
    Domingos F M Neto, Rita de Cassia Monteiro-Batista, Adriano Nunes-Nesi, Wagner L Araújo.
      Understanding the tissue-specific mitochondrial proteome is essential for advancing understanding of plant biology. In a recent study, Boussardon et al. applied Isolation of Mitochondria Tagged in Specific Cell Types (IMTACT) to investigate mitoproteome dynamics during pollen development. Here, we explore the broader potential of high-purity mitochondrial isolation in elucidating specific roles across tissues and developmental stages.
    Keywords:  mitochondrial proteomics; plant stress; single cell mitochondria
    DOI:  https://doi.org/10.1016/j.tibs.2025.06.010
  43. Circ Res. 2025 Jul 01.
    Mitochondrial Calcium Uniporter Regulates ITAM-Dependent Platelet Activation.
    Abigail Ajanel, Izabella Andrianova, Mia Kowalczyk, Javier Menéndez Pérez, Sradha R Bhatt, Irina Portier, Taylor Boone, Abigail Ballard-Kordeliski, Yasuhiro Kosaka, Dipayan Chaudhuri, David S Paul, Wolfgang Bergmeier, Frederik Denorme, Robert A Campbell.
       BACKGROUND: Platelet activation relies on changes in cytoplasmic calcium flux. However, little is known about the role mitochondrial calcium flux plays in platelet activation. Activation induces release of calcium from intracellular stores, which enters the mitochondrial matrix through the MCU (mitochondrial calcium uniporter) to regulate bioenergetics and reactive oxygen species (ROS) formation, as demonstrated in other cells. However, whether MCU contributes to platelet function is unclear.
    METHODS: We generated platelet-specific Mcu-deficient mice (Mcuplt-/-) and compared them to littermate wild-type controls (Mcuplt+/+). In vitro approaches assessed mitochondrial calcium flux and platelet activation responses to stimulation of immunoreceptor tyrosine-based activation motif (ITAM) receptors and GPCRs (G protein-coupled receptors). In addition, we examined in vivo hemostasis and thrombosis. We also treated human platelets with MCU inhibitors, and platelet function was assessed.
    RESULTS: Mcuplt-/- platelets had significantly reduced mitochondrial calcium flux in response to activation of ITAM receptors, whereas mitochondrial calcium flux in response to GPCR activation was unchanged. Platelet aggregation was significantly reduced by ITAM activation in Mcuplt-/- platelets, but GPCR-induced aggregation was unchanged. Similar findings were observed when MCU was inhibited in human platelets. In vivo, Mcuplt-/- mice had reduced arterial thrombosis and less ischemic stroke brain injury. Hemostasis was mildly altered in Mcuplt-/- mice. Mechanistically, mitochondrial ROS generation was significantly reduced in Mcuplt-/- platelets compared with Mcuplt+/+ platelets after ITAM-dependent activation, but not GPCR activation. Reduced mitochondrial ROS was associated with decreased ITAM signaling based on p-Syk (phospho-spleen tyrosine kinase) and p-PLCγ2 (phospho-phospholipase C-gamma 2) in Mcuplt-/- platelets. Inhibiting mitochondrial ROS decreased aggregation as well as downstream ITAM signaling in Mcuplt+/+ platelets. Conversely, treating Mcuplt-/- platelets with MitoParaquat to induce mitochondrial ROS increased platelet ITAM-dependent aggregation and signaling.
    CONCLUSIONS: Our data support a role for mitochondrial calcium flux in regulating ITAM-dependent platelet activation through the generation of mitochondrial ROS.
    Keywords:  ITAM; mitochondria; platelet; thrombosis
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326443
  44. Int J Biol Sci. 2025 ;21(9): 4252-4269
    Coupling of glucose metabolism with mitophagy via O-GlcNAcylation of PINK1.
    Zhiwei Xu, Xiangzheng Gao, Dade Rong, Jingyao Wang, Liangliang Gao, Mingzhu Tang, Yiguan Chen, Yichi Zhang, Liming Xie, Liming Wang, Guang Lu, Jia-Hong Lu, Wei Liu, Han-Ming Shen.
      Mitophagy is a selective form of autophagy for the clearance of damaged and dysfunctional mitochondria via the autophagy-lysosome pathway. As mitochondria are the most important metabolic organelles, the process of mitophagy is tightly regulated by glucose metabolism. At present, it is known that glucose is required for the mitophagy process, while the underlying mechanisms remain to be further elucidated. In this study, we establish a novel regulatory role of glucose metabolism in mitophagy via protein O-GlcNAcylation. First, we found that acute mitochondrial damage enhanced glucose uptake and promoted protein O-GlcNAcylation. Second, we provided evidence that protein O-GlcNAcylation promotes PINK1-Parkin-dependent mitophagy. Next, we attempted to illustrate the molecular mechanisms underlying the regulation of O-GlcNAcylation in mitophagy by focusing on PTEN-induced kinase 1 (PINK1). One important observation is that PINK1 is O-GlcNAcylated upon acute mitochondrial damage, and suppression of O-GlcNAcylation impairs PINK1 protein stability and its phosphorylated ubiquitin, leading to impaired mitophagy. More importantly, we found that glucose metabolism promotes mitophagy via regulating O-GlcNAcylation. Taken together, this study demonstrates a novel regulatory mechanism connecting glucose metabolism with mitophagy via O-GlcNAcylation of PINK1. Therefore, targeting the O-GlcNAcylation may provide new strategies for the modulation of mitophagy and mitophagy-related human diseases.
    Keywords:  HBP; O-GlcNAcylation; PINK1; glucose metabolism; mitophagy
    DOI:  https://doi.org/10.7150/ijbs.112672
  45. Cell Death Dis. 2025 Jul 01. 16(1): 473
    Mitochondrial transplantation: adaptive bio-enhancement.
    Xiaomeng Lu.
      Mitochondria, often referred to the powerhouse of the cell, are essential for cellular energy production, and their dysfunction can profoundly affect various organs. Transplantation of healthy mitochondria can restore the bioenergetics in diseased cells and address multiple conditions, but more potentials of this approach remain unclear. In this study, I demonstrated that the source of transplanted mitochondria is not limited by species, as exhibit no significant responses to mitochondria derived from different germlines. Moreover, I identified that metabolic compatibility between the recipient and exogenous mitochondria as a crucial factor in mitochondrial transplantation, which confers unique metabolic properties to recipient cells, enabling them to combat different diseases. Additionally, my findings indicated competitive interactions among mitochondria with varying functions, with more bioenergetic-active mitochondria yielded superior therapeutic benefits. Notably, no upper limit for the bioenhancement provided by exogenous mitochondria has been identified. Based on these insights, I proposes a novel therapeutic approach-adaptive bioenhancement through mitochondrial transplantation.
    DOI:  https://doi.org/10.1038/s41419-025-07643-8
  46. npj metabolic health and disease... 2025 Jul 02. 3(1): 30
    Skeletal muscle proteomics: considerations and opportunities.
    Julian P H Wong, Yaan-Kit Ng, Jeppe Kjærgaard, Ronnie Blazev, Atul S Deshmukh, Benjamin L Parker.
      Skeletal muscle accounts for 30-40% of body weight and plays an indispensable role in maintaining movement and is also a central regulator of whole-body metabolism. As such, understanding the molecular mechanisms of skeletal muscle health and disease is vital. Proteomics has been revolutionized in recent years and provided new insights into skeletal muscle. In this review, we first highlight important considerations unique to the field which make skeletal muscle one of the most challenging tissues to analyse by mass spectrometry. We then highlight recent advances using the latest case studies and how this has allowed coverage of the skeletal muscle temporal, fibre type and stem cells proteome. We also discuss how exercise and metabolic dysfunction can remodel the muscle proteome. Finally, we discuss the future directions of the field and how they can be best leveraged to increase understanding of human biology.
    DOI:  https://doi.org/10.1038/s44324-025-00073-2
  47. Nat Med. 2025 Jul 03.
    From one to many gene therapies.
    Mike May.
      
    DOI:  https://doi.org/10.1038/d41591-025-00043-7
  48. Dalton Trans. 2025 Jul 04.
    A subcellularly targeted photocaged inhibitor for mitochondrial carbonic anhydrase V.
    Noushaba Nusrat Mafy, Kanchan Aggarwal, Sky Price, Dorothea B Hudson, Elva Ye, Divya Kolli, Emily L Que.
      We report the first photoactivatable inhibitor specifically targeting mitochondrial CA-V, a promising anti-obesity target. It features a sulfonamide metal-binding group caged with a photoremovable coumarin and guided to mitochondria via a pyridinium moiety. Light exposure removes the cage, enabling precise spatial and temporal inhibition of mitochondrial CA-V activity.
    DOI:  https://doi.org/10.1039/d5dt01161b
  49. J Parkinsons Dis. 2025 Jul 04. 1877718X251354986
    Parkinson's disease associated with LRRK2-R1441C mutation: Characterization and comparison with other LRRK2 mutations.
    Rafi Hadad, Roy N Alcalay, Inna Senderova, Maria Nassar, Andjelika Milicic, Judith Aharon Peretz, Isabel Elaine Allen, Rachel Ben-Hayun, Natalia Chasnyk, Ilham Morani, Nadav Elkoshi, Victor Valcour, Ilana Schlesinger.
      Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene associate with familial and sporadic Parkinson's disease (PD). While various LRRK2 allelic variants have been studied, characteristics of R1441C carriers remain underexplored. We compared PD patients carrying the R1441C mutation (90% Israeli Arabs) to those carrying the G2019S (70% Ashkenazi Jews) and R1441G (42% Basque) variants. R1441C carriers exhibited a distinct clinical phenotype characterized by severe motor and non-motor symptoms and worse scores on the Montreal Cognitive Assessment. These findings highlight the importance of ethnic diversity and genetic stratification in PD research. These results need confirmation in larger, more diverse samples.
    Keywords:  LRRK2 protein; Parkinson’s disease; cognitive dysfunction; genetic variation; human; mutation
    DOI:  https://doi.org/10.1177/1877718X251354986
  50. J Rare Dis (Berlin). 2025 ;4(1): 31
    Disruption of Lrpprc affects B cell development and proliferation in a mouse model of Leigh Syndrome French Canadian type.
    LSFC Consortium
       Purpose: Leigh Syndrome French Canadian (LSFC) is a rare autosomal recessive metabolic disorder characterized by severe lactic acidosis crises and early mortality. LSFC patients carry variants in the Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) nuclear gene, which lead to defects in the respiratory chain complexes and mitochondrial dysfunction. Mitochondrial respiration modulates cellular metabolic activity, which impacts many cell processes, including the differentiation and function of immune cells. The purpose of this study is to define the role of Lrpprc on immune cell function.
    Methods: As genetic deletion of Lrpprc is not viable, we generated two conditional mouse models: a model for systemic deletion of Lrpprc and a knock-in (KI) model carrying the most common LSFC pathogenic variant in Quebec, NM_133259.4(LRPPRC):c.1061C > T (p.Ala354Val).
    Results: We demonstrate that Lrpprc is an essential gene even in adult mice, as systemic deletion of Lrpprc leads to prominent weight loss and mortality. We also find an increase in lactate levels, a symptom of metabolic crises in LSFC. Lrpprc deletion and pathogenic variant affect various immune cell subsets, with a strong impact on B cell development and proliferation.
    Conclusions: We generated a viable disease-relevant mouse model to study the role of Lrpprc in vivo and find that disruption of Lrpprc strongly impairs B cell development and proliferation.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s44162-025-00094-x.
    Keywords:  B cells; Immune cells; LRPPRC; LSFC; Mitochondria; Proliferation
    DOI:  https://doi.org/10.1007/s44162-025-00094-x
  51. Trends Biochem Sci. 2025 Jun 27. pii: S0968-0004(25)00126-4. [Epub ahead of print]
    Mitochondrial tRNA processing: a neutral evolutionary ratchet innovation.
    Lien B Lai, Jane E Jackman, Charles J Daniels, Venkat Gopalan.
      Mitochondrial tRNA processing is a chronicle of molecular adaptability. The processing of structurally compromised tRNAs is unexpectedly rescued by a multienzyme complex shaped by constructive neutral evolution. This striking example of biological complexity arising from nonadaptive mechanisms showcases how a potential vulnerability is transformed into a robust, if precarious, innovation.
    Keywords:  compensatory coevolution; constructive neutral evolution; mitochondria; tRNA maturation
    DOI:  https://doi.org/10.1016/j.tibs.2025.05.008
  52. Mol Cell. 2025 Jul 03. pii: S1097-2765(25)00505-2. [Epub ahead of print]85(13): 2610-2625.e5
    MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction.
    Zhangcheng Ding, Rui Wang, Yuhua Li, Xiaodong Wang.
      Necroptosis is a pro-inflammatory, lytic cell death executed by a pseudokinase mixed lineage kinase-like protein MLKL. Upon necroptosis induction by various inflammatory signals, MLKL is phosphorylated by receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and translocates from the cytosol to the plasma membrane, causing membrane disruption and the release of damage-associated molecular patterns (DAMPs). We report here that phosphor-MLKL also translocates to mitochondria and induces a microtubule-dependent release of mitochondrial DNA (mtDNA). The released mtDNA activates the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway, resulting in the upregulation of interferon-beta (Ifnb) expression. In a necroptosis-mediated inflammatory bowel disease (IBD) mouse model, interfering with the cGAS-STING pathway reduced inflammation and promoted intestinal recovery. Thus, MLKL induces inflammation not only in a cell non-autonomous fashion by releasing DAMP signals, but also in a cell-autonomous manner by causing mtDNA leakage into the cytosol, thereby activating the cGAS-STING pathway.
    Keywords:  IBD; MLKL; cGAS; mitochondrail DNA; mitochondria; mtDNA; necroptosis
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.005
  53. Sci Rep. 2025 Jul 02. 15(1): 23679
    Tafazzin-deficient zebrafish display mitochondrial dysfunction, neutropenia, and metabolic defects without myopathy.
    Usua Oyarbide, Rebecca A Anderson, Igor Radzikh, Jillian V Kodger, Akshay S Patil, Morgan Staton, Anny Mulya, Genevieve M Crane, Silvio Litovsky, Yana Sandlers, Seth J Corey.
      Barth syndrome is an X-linked syndrome characterized by cardiomyopathy, skeletal myopathy, and neutropenia. This life-threatening disorder results from loss-of-function mutations in TAFAZZIN, which encodes a phospholipid-lysophospholipid transacylase located in the mitochondria inner membrane. Decreased cardiolipin levels and increased monolysocardiolipin levels perturb mitochondrial function. However, the mechanism(s) leading to myopathies and neutropenia are unknown, and no currently effective therapy exists. To address these knowledge gaps, we generated tafazzin-deficient zebrafish. Neutropenia developed 5 days post-fertilization, but surprisingly no cardiac or skeletal myopathies were detected into adulthood. tafazzin mutants displayed multiple metabolic disturbances like those observed in humans with Barth syndrome. These include increased monolysocardiolipin: Cardiolipin ratios, high levels of 3-methylglutaconic acid, decreased ATP production, increased levels of lactic acid, and hypoglycemia. There were also widespread effects on amino acid and unsaturated fatty acid synthesis. Despite these metabolic disturbances, zebrafish displayed a normal lifespan and fertility. Cardiolipin abnormalities were detected in both larvae and adult tissues, specifically in the heart and whole kidney marrow. Surprisingly, adult tafazzin mutants exhibited a higher number of neutrophils compared to wildtype fish. Further investigation revealed signs of inflammation as evidenced by elevated levels of il6 in the whole kidney marrows and hearts of adult fish. Our comprehensive studies demonstrated that while mitochondrial dysfunction and metabolic defects were evident in tafazzin-deficient zebrafish, these disturbances did not significantly affect their development nor survival. These findings suggest that zebrafish may possess salvage pathways which compensate for Tafazzin loss or that humans have a unique vulnerability to the loss of TAFAZZIN.
    DOI:  https://doi.org/10.1038/s41598-025-07843-4
  54. MedComm (2020). 2025 Jul;6(7): e70283
    Phase Separation Regulates Metabolism, Mitochondria, and Diseases.
    Chuan Gao, Peng Ding, Changqing Zhang, Junjie Gao.
      As a physicochemical mechanism, phase separation is a spatial and temporal regulator of specific molecules within a cell, and it provides a new perspective for understanding cellular pathophysiology. Phase separation is closely associated with multiple metabolic processes in the body, including the regulation of key metabolic enzymes and the physiology of mitochondria. Mitochondria also regulate multiple physiological functions through phase separation, including protecting healthy mitochondria and mRNAs in oocytes and regulating crosstalk between nuclear and mitochondrial. Importantly, abnormal phase separation in vivo is associated with the development of diseases, including cancer, neurodegenerative diseases, endocrine disorders, skeletal system diseases, and infectious diseases. This review summarizes the relationship between phase separation and metabolism under both physiological and pathological conditions, as well as the therapeutic potential of phase separation in the treatment of relevant diseases, aiming to explore the possibility of treating diseases by regulating phase separation.
    Keywords:  diseases; metabolism; mitochondria; phase separation
    DOI:  https://doi.org/10.1002/mco2.70283
  55. Cell Genom. 2025 Jun 26. pii: S2666-979X(25)00201-0. [Epub ahead of print] 100945
    Structural diversity and evolutionary constraints of oxidative phosphorylation.
    José Luis Cabrera-Alarcón, Marina Rosa-Moreno, Lucía Sánchez-García, Pablo Hernansanz Agustín, Maria Concepción Jiménez-Gómez, Fernando Martínez, Fátima Sánchez-Cabo, José Antonio Enríquez.
      The oxidative phosphorylation (OxPhos) system is central to metabolism. The more than 90 structural subunits are encoded by different chromosome categories (autosomal, X, and mtDNA). The system is envisioned as an invariant structure between cells and individuals. However, a comprehensive analysis of the 1,000 Genomes Project data reveals unexpected genetic intra-individual variability resulting from the heterozygosity of diploid autosomal genes, while diversity at the population level is generated by variability in mtDNA. We characterized the different levels of structural constriction at evolutionary and population levels for all OxPhos protein residues. To support this analysis, we developed ConScore, a conservation-based predictor of variant impact within OxPhos proteins (area under the receiver operating characteristic curve [ROC-AUC] = 0.97; area under the precision-recall curve [PR-AUC] = 0.94). Notably, for the nuclear-encoded subunits, we found mechanisms limiting individual variability as allelic imbalance or homozygosity bias. Integrating structural, functional, and genetic data, we highlight the significance of each OxPhos protein position, expanding insights into its role in speciation and disease.
    Keywords:  OxPhos; conservation score; evolutionary drivers; human variability; mitochondrial DNA; mtDNA; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.xgen.2025.100945
  56. Mov Disord. 2025 Jul 01.
    Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis.
    Keit Men Wong, Reza Maroofian, Kolja Meier, Susann Diegmann, Tinatin Tkemaladze, Javeria Raza Alvi, Behnoosh Tasharrofi, Stephanie Efthymiou, Alexander Munchau, G Christoph Korenke, Naif Almontashiri, Wafaa Eyaid, Amna Kashgari, Modhi Alotaibi, Jutta Gärtner, Brenda Huppke, Mostafa Asadollahi, Gocha Chikvinidze, Mohammad Keramatipour, Tipu Sultan, Holger Thiele, Peter Nürnberg, Markus H Gräler, Henry Houlden, Peter Huppke.
       BACKGROUND: Very long chain fatty acids (VLCFAs) are an integral component of myelin and the epidermal water barrier. Variants in genes encoding enzymes responsible for catalyzing the first and rate limiting step in the production of VLCFAs, elongation of VLCFAs (ELOVLs), underlie a novel group of metabolic disorders.
    OBJECTIVES: The goal was to describe the clinical phenotype and disturbance in VLCFA metabolism associated with variants in the ELOV1 gene.
    METHODS: The following methods were employed: Exome sequencing, clinical phenotyping, magnetic resonance imaging (MRI), metabolomics, liquid chromatography-tandem mass spectrometry, fatty acid elongation assay.
    RESULTS: We, here, describe seven patients with autosomal recessive variants in ELOVL1. Common clinical features included ichthyosis (5/7), developmental delay (7/7), progressive spasticity (7/7), nystagmus (5/6), and a complex movement disorder characterized by pronounced head tremor (7/7), myoclonus (6/7), and dysarthria (6/6). Brain MRI revealed non-progressive hypomyelination (6/6) and hypoplasia of the corpus callosum (5/6). Plasma VLCFA analysis in one patient showed reduced concentrations of C24:0 and C26:0. Biochemical analysis of fibroblasts from this patient revealed elongation defects in VLCFA synthesis and dysregulation of other ELOVL enzymes.
    CONCLUSIONS: We show that biallelic variants in ELOVL1 are associated with a unique and recognizable phenotype of hypomyelinating leukodystrophy, ichthyosis, and a complex movement disorder including progressive spasticity, head tremor, and myoclonus. Biochemical analyses confirmed a defect in VLCFA synthesis. Variants in genes encoding enzymes involved in the elongation of VLCFAs are a novel group of metabolic disorders with overlapping symptoms. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  ELOVL1; head tremor; ichthyosis; leukodystrophy; myoclonus
    DOI:  https://doi.org/10.1002/mds.30258
  57. J Chem Theory Comput. 2025 Jul 03.
    Comparison of Magnesium and Manganese Ions on the Structural and Catalytic Properties of Human DNA Polymerase Gamma.
    Arkanil Roy, G Andrés Cisneros.
      DNA polymerases are essential enzymes responsible for accurate genome replication and repair, with divalent metal cofactors playing a crucial role in their catalytic function. Polymerase γ (Pol γ) is the primary DNA polymerase in mitochondria, ensuring the faithful replication of mitochondrial DNA. The choice of metal cofactor, typically magnesium (Mg2+) or manganese (Mn2+), influences its structural stability, enzymatic activity, and fidelity. In this study, we employed molecular dynamics (MD) simulations and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations to investigate how Mg2+ and Mn2+ affect the flexibility, active site stabilization, and catalytic efficiency of Pol γ. Intermolecular interaction analysis of individual residues is consistent with experimental mutagenesis reports and highlights the importance of specific residues, many of which are evolutionarily conserved, and some are involved in pathogenic mutations. It is also observed that Mn2+ enhances catalytic efficiency, exhibiting higher exoergicity (-3.65 kcal mol-1 vs -1.61 kcal mol-1 for Mg2+) and a lower activation barrier. Intermolecular interaction analysis reveals that Mn2+ provides larger stabilization of the transition state and product complex, favoring reaction progression. Investigation of the effects of the electric field in the active site suggests that the O3' atom on the DNA primer base experiences larger polarization in the system with Mn2+ ions when compared to Mg2+, with dipole directions consistent with the catalytic reaction progress. Our findings highlight a trade-off between structural stability and catalytic efficiency, providing insights into the role of metal ions in mitochondrial polymerase function and their implications for mutagenesis and mitochondrial disorders.
    DOI:  https://doi.org/10.1021/acs.jctc.5c00435
  58. FEBS J. 2025 Jul 01.
    Human FASTK preferentially binds single-stranded and G-rich RNA.
    Daria M Dawidziak, Dawid A Dzadz, Mikołaj I Kuska, Madhuri Kanavalli, Maria M Klimecka, Matthew Merski, Katarzyna J Bandyra, Maria W Górna.
      Fas-activated serine/threonine kinase (FASTK) is the founding member of the FASTKD protein family, which was shown to regulate the fate of mRNA molecules on multiple levels. The mitochondrial variant of FASTK co-localizes with mitochondrial RNA granules and regulates the degradation of mitochondrial mRNAs, whereas the cytoplasmic and nuclear forms of FASTK are involved in the regulation of alternative splicing, cytoplasmic RNA granule formation, and mRNA translation. Despite these multiple roles of FASTK in mRNA biology, the exact rules of RNA recognition by this protein remained undetermined. Here, we demonstrate direct RNA binding by purified human FASTK and show its preference for single-stranded G-rich oligonucleotides, including those with a tendency to form RNA G-quadruplexes. Addition of FASTK alone was sufficient to achieve protection of mitochondrial mRNAs from degradation by the degradosome. Structural characterization by SAXS (Small-Angle X-ray Scattering) showed that FASTK in solution is a monomer with an extended conformation. Point mutagenesis studies supported the structural predictions of an exposed RNA-binding interface in the central helical region, preceded by a smaller, flexibly attached helical N-terminal domain. We provide the first such extensive in vitro characterization of the RNA binding properties for a representative of the FASTKD protein family and suggest how these intrinsic properties may underlie FASTK function in mRNA metabolism.
    Keywords:  FASTK; G‐rich RNA; RNA degradation; RNA‐binding proteins
    DOI:  https://doi.org/10.1111/febs.70155
  59. J Biol Chem. 2025 Jun 26. pii: S0021-9258(25)02280-X. [Epub ahead of print] 110430
    The ability of SAMHD1-deficient monocytes to trigger the type I IFN response depends on cGAS and mitochondrial DNA.
    Jesse Rabinowitz, Isabelle K Vila, Charlotte Luchsinger, Cinzia Bertelli, Moritz Schüssler, Clara Taffoni, Bin Cui, Annie Zhi Dai, Mohammad M Rashid, William J Cisneros, Daphne Cornish, Juan Redondo, Kathryn A Jackson-Jones, Lacy M Simons, Ramon Lorenzo-Redondo, Nadine Laguette, Judd F Hultquist, Felipe Diaz-Griffero.
      In humans, mutations in sterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) lead to the development of a type I interferonopathy known as Aicardi-Goutières syndrome (AGS). AGS can present with a variety of severe phenotypes in patients, and a hallmark of this disease is chronic activation of type I interferon (IFN) signaling. However, the mechanism through which type I IFN signaling is activated in the absence of functional SAMHD1 is not known. Here, we investigated the molecular pathways that lead to type I IFN signaling activation in the absence of SAMHD1. Our investigations revealed that chronic activation of type I IFN signaling in SAMHD1-knockout(KO) monocytes is cyclic GMP-AMP synthase (cGAS)-dependent. Analysis of other nucleic acid sensors showed that type I IFN signaling in SAMHD1-KO cells is not dependent on melanoma differentiation-associated protein 5 (MDA5) or retinoic acid-inducible gene I (RIG-I). In agreement with our observation that type I IFN signaling is dependent on cGAS, two inhibitors of the cGAS-stimulator of IFN genes pathway, G140 and H151, effectively prevented type I IFN activation in SAMHD1-KO monocytes. We also found that type I IFN signaling in SAMHD1-KO monocytes is dependent on type I IFN receptor expression. Further exploration revealed mitochondrial malfunction in SAMHD1-KO monocytes that is likely to leak mitochondrial components into the cytoplasm. Overall, our work suggests that genetic knock out of SAMHD1 leads to mitochondrial disfunction, resulting in the presence of mitochondrial DNA in the cytoplasm, which triggers cGAS and the type I IFN response.
    Keywords:  Aicardi–Goutières syndrome; THP-1; cGAS; mitochondria; type I IFN response
    DOI:  https://doi.org/10.1016/j.jbc.2025.110430
  60. Nat Commun. 2025 Jul 01. 16(1): 5676
    Multidimensional third-generation sequencing of modified DNA bases allows interrogation of complex biological systems.
    Serena S David, Brendan A Pacheco, Kensei Kishimoto, Sam Vantine, Kai Hu, Haibo Liu, Diana L Davis, Hoang Tran, Benjamin F Sallis, Levi Ali, Cole M Haynes, Beth A McCormick, Lihua Julie Zhu, William A Flavahan.
      DNA exists biologically as a highly dynamic macromolecular complex subject to myriad chemical modifications that alter its physiological interpretation, yet most sequencing technologies only measure Watson-Crick base pairing interactions. Third-generation sequencing technologies can directly detect novel and modified bases, yet the difficulty and cost of training these techniques for each novel base has so far limited this potential. Here, we present a method based on barcoded split-pool synthesis to generate reference standard oligonucleotides allowing novel base sequencing. Using novel base detection, we perform multidimensional sequencing to retrieve information, both physiologically stored and experimentally encoded, from DNA, allowing us to characterize the preferential replication of deleterious mitochondrial genome mutations, the infection dynamics of a host-pathogen model, and the effect of chemotherapy on cancer cell DNA at the single molecule level. The low cost and experimental simplicity of this method make this approach widely accessible to the research community, enabling complex experimental interrogation across the biological sciences.
    DOI:  https://doi.org/10.1038/s41467-025-60896-x
  61. Nat Commun. 2025 Jul 01. 16(1): 5454
    Deficits in mitochondrial dynamics and iron balance result in templated insertions.
    Jordan Fox, Yang Yu, Yang Yu, Pilendra Thakre, Chloe Fox, Qian Li, Yunxia Wang, Adam Hughes, Xin Wang, Kaifu Chen, Grzegorz Ira.
      Mitochondrial membrane dynamics control the shape, number, and distribution of mitochondria and regulate energy production and cell health. In a screen for yeast mutants with increased levels of templated insertions (~10-1000 bp) in the nuclear genome, we identified mitochondrial fusion deficient mutants (mgm1Δ, ugo1Δ, fzo1Δ). We found that fusion mutants activate the iron regulon, have decreased iron-sulfur clusters (ISCs), and increased DNA damage, suggesting a role of iron homeostasis in preventing insertions. Consistently, a secondary screen found mutants affecting iron-sulfur cluster production (yfh1Δ, grx5Δ), vacuolar iron storage (ccc1Δ) or general iron homeostasis (aft1Δ) to exhibit high insertion levels. Treatment with iron chelators or hydrogen peroxide also increased insertions. We propose that iron dysregulation leading to oxidative DNA damage and compromised DNA repair drives insertions. These studies suggest that severe iron imbalance, associated with many human diseases and pharmacological treatments, can trigger genome instability in the form of templated insertions.
    DOI:  https://doi.org/10.1038/s41467-025-60546-2
  62. Hepatobiliary Pancreat Dis Int. 2025 Jun 18. pii: S1499-3872(25)00099-2. [Epub ahead of print]
    Acute liver failure caused by amino acid or organic acid related inborn errors of metabolism.
    Ying Zhou, Chi Chen, Xin Yang.
      
    DOI:  https://doi.org/10.1016/j.hbpd.2025.06.003
  63. Cold Spring Harb Perspect Med. 2025 Jun 30. pii: a041620. [Epub ahead of print]
    Leucine-Rich Repeat Kinase 2: Pathways to Parkinson's Disease.
    Suzanne R Pfeffer, Dario R Alessi.
      The past 10 years have seen tremendous progress in our understanding of leucine-rich repeat kinase 2 (LRRK2) and how mutations activate the kinase and trigger downstream pathology, contributing to Parkinson's disease. A breakthrough came from the identification of key LRRK2 substrates-a subset of small guanosine triphosphatases (GTPases) called Rab proteins. Cryoelectron microscopy has revealed structures of LRRK2 and showed how inhibitors engage and inhibit the kinase. Biochemical experiments have revealed how LRRK2 is recruited to membranes to phosphorylate Rab substrates. LRRK2 activation during lysosomal stress triggers Rab phosphorylation, altering the repertoire of Rab-binding partners. Resulting phospho-Rab-effector complexes have prominent effects in specific cell types, disrupting primary cilia and impairing Hedgehog signaling-effects that can be reversed by LRRK2 inhibitors. This disruption in Hedgehog signaling represents a convergence point linking genetic and idiopathic forms of Parkinson's. Together, these findings support the therapeutic potential of LRRK2 inhibitors in Parkinson's disease.
    DOI:  https://doi.org/10.1101/cshperspect.a041620
  64. Adv Exp Med Biol. 2025 ;1480 131-143
    Diagnosis and Management of Non-HFE Hemochromatosis, Ferroportin Disease, and Rare Hereditary Iron-Loading Disorders.
    Antonello Pietrangelo.
      Beyond the classic HFE-hemochromatosis, several genetic iron-loading disorders arise from mutations in genes regulating iron homeostasis, such as TFR2, HAMP, HJV, and the SLC40A1 (ferroportin) gene, as well as those involved in iron transport and mitochondrial function. These disorders lead to systemic or localized iron overload, resulting in complications such as liver disease, cardiomyopathy, endocrine dysfunction, and neurodegeneration. This chapter reviews the genetic basis, clinical presentations, and therapeutic approaches, emphasizing the importance of early diagnosis and intervention to mitigate organ damage and improve outcomes.
    Keywords:  Ferroportin disease; Iron overload; Juvenile hemochromatosis; Mitochondrial iron genes; Non-HFE Hemochromatosis
    DOI:  https://doi.org/10.1007/978-3-031-92033-2_10
  65. Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(24)00131-7. [Epub ahead of print]146 1-34
    Proteostasis imbalance: Unraveling protein aggregation in neurodegenerative diseases and emerging therapeutic strategies.
    Chandrabose Selvaraj, Periyasamy Vijayalakshmi, Dipali Desai, Jayakumar Manoharan.
      Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are defined by the accumulation of misfolded and aggregated proteins, which impair cellular function and result in progressive neuronal death. This chapter examines the critical function of proteostasis-cellular protein homeostasis-in sustaining neuronal health and its disruption as a key factor in disease progression. Proteostasis is upheld by a complex array of mechanisms, which encompass molecular chaperones, the ubiquitin-proteasome system, autophagy-lysosomal pathways, and mitochondrial quality control. Impairment of these systems leads to protein misfolding and aggregation, resulting in toxic cellular environments that promote neurodegeneration. Novel therapeutic approaches focus on restoring proteostasis through the enhancement of cellular protein folding, degradation, and clearance mechanisms. This encompasses small molecule chaperones, gene therapy, RNA-based treatments, immunotherapy, autophagy inducers, and stem cell-based approaches, each addressing distinct components of the proteostasis network to mitigate or prevent disease progression. While these therapies show potential, challenges persist, such as possible side effects, selective targeting, and the efficacy of blood-brain barrier penetration. Personalized medicine and combination therapies customized to specific disease profiles are increasingly recognized for their potential to improve efficacy and safety. This chapter consolidates recent developments in therapies aimed at proteostasis, addresses the challenges encountered in clinical applications, and outlines potential future directions for transformative treatments. Ongoing research indicates that proteostasis modulation may significantly alter the course of neurodegenerative disease treatment, potentially enhancing patient outcomes and quality of life.
    Keywords:  Alzheimer’s and Parkinson’s therapies; Autophagy induction; Gene therapy; Molecular chaperones; Neurodegenerative diseases; Protein aggregation; Proteostasis
    DOI:  https://doi.org/10.1016/bs.apcsb.2024.11.008
  66. Nat Med. 2025 Jul 01.
    AI-enabled drug discovery reaches clinical milestone.
    Marinka Zitnik.
      
    DOI:  https://doi.org/10.1038/s41591-025-03832-2
  67. Nat Commun. 2025 Jul 01. 16(1): 5557
    Projection-TAGs enable multiplex projection tracing and multi-modal profiling of projection neurons.
    Lite Yang, Fang Liu, Hannah Hahm, Takao Okuda, Xiaoyue Li, Yufen Zhang, Vani Kalyanaraman, Monique R Heitmeier, Vijay K Samineni.
      Single-cell multiomic techniques have sparked immense interest in developing a comprehensive multi-modal map of diverse neuronal cell types and their brain-wide projections. However, investigating the complex wiring diagram, spatial organization, transcriptional, and epigenetic landscapes of brain-wide projection neurons is hampered by the lack of efficient and easily adoptable tools. Here we introduce Projection-TAGs, a retrograde AAV platform that allows multiplex tagging of projection neurons using RNA barcodes. By using Projection-TAGs, we performed multiplex projection tracing of the cortex and high-throughput single-cell profiling of the transcriptional and epigenetic landscapes of the cortical projection neurons in female mice. Projection-TAGs can be leveraged to obtain a snapshot of activity-dependent recruitment of distinct projection neurons and their molecular features in the context of a specific stimulus. Given its flexibility, usability, and compatibility, we envision that Projection-TAGs can be readily applied to build a comprehensive multi-modal map of brain neuronal cell types and their projections.
    DOI:  https://doi.org/10.1038/s41467-025-60360-w
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