bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–06–01
fifty-two papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Assessment of the respiratory chain enzyme activity in peripheral blood monocytes for the noninvasive diagnostics of mitochondrial disease.
  2. The mitochondrial intermembrane space - a permanently proteostasis-challenged compartment.
  3. Delineating the mechanisms of cerebellar degeneration in paediatric and adult primary mitochondrial disease.
  4. The power of connections: Recent advances in understanding the regulation of mitochondrial dynamics by membrane contact sites.
  5. Exploring the Phenotypic Heterogeneity and Bioenergetic Profile of the m.13513G>A mtDNA Substitution: A Heteroplasmy Perspective.
  6. The Insertion Domain of Mti2 Facilitates the Association of Mitochondrial Initiation Factors with Mitoribosomes in Schizosaccharomyces pombe.
  7. A Multiomic Network Approach to Uncover Disease Modifying Mechanisms of Inborn Errors of Metabolism.
  8. Mitochondrial clonal mosaicism encodes a biphasic molecular clock of aging.
  9. Infant With a Severe Form of GLRX5-Related Atypical Hyperglycinemia Exhibiting Novel Cardiac and Neurologic Disease Manifestations at Autopsy.
  10. Special Issue "Mitochondrial Metabolism Alterations in Health and Disease".
  11. LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.
  12. The crossroads of Leber hereditary optic neuropathy and autosomal dominant optic Atrophy: Clinical profiles of patients with coexisting pathogenic genetic variants.
  13. Immunoproteasome-specific subunit alterations as a potential therapeutic target for mitochondriopathies.
  14. Mechanisms of heme transport in the mitochondria.
  15. Lysine acetylation modulates s-OPA1 GTPase activity and oligomerization in mitochondrial membrane remodeling.
  16. Predicting expression-altering promoter mutations with deep learning.
  17. Imbalanced mitochondrial dynamics in human PD and α-synuclein mouse brains.
  18. Mitochondria-Nuclear Crosstalk: Orchestrating mtDNA Maintenance.
  19. Inhibition of mitochondrial protein import and proteostasis by a pro-apoptotic lipid.
  20. Epimedin C enhances mitochondrial energy supply by regulating the interaction between MIC25 and UBC in rodent model.
  21. Single-cell data combined with phenotypes improves variant interpretation.
  22. Actin in mitochondrial regulation and mechanometabolic crosstalk.
  23. The Mitochondrial Brown Adipose Tissue Maintenance Factor Nipsnap1 Interfaces Directly with the Beta-Oxidation Protein Machinery in Rodents.
  24. Insertion of mNeonGreen into the variable domain of DRP-1 permits visualization of functional endogenous protein.
  25. Exploration of the effects of 66 mitochondria-associated proteins on different cardiomyopathies: A bidirectional 2-sample mendelian randomization study.
  26. MICU1 myopathy revisited: phenotypic variability in a rare mitochondrial calcium disorder.
  27. Deficiency in the conserved ECHS1 gene causes Leigh syndrome by impairing mitochondrial respiration efficiency and suppressing ADRB2-PKA signaling.
  28. The case for including proteomics in routine diagnostic practice for rare disease.
  29. Super-resolution imaging informed scRNA sequencing analysis reveals the critical role of GDF15 in rejuvenating aged hematopoietic stem cells.
  30. Disruption of cTnT-Mediated Sarcomere-Mitochondrial Communication Results in Dilated Cardiomyopathy.
  31. CHCHD4 Oxidoreductase Activity: A Comprehensive Analysis of the Molecular, Functional, and Structural Properties of Its Redox-Regulated Substrates.
  32. Mitochondrial medicine: "from bench to bedside" 3PM-guided concept.
  33. The potential role of mitochondria in age-related health benefits conferred by moderate hypoxia.
  34. Clinical Phenotype and Neuroimaging Findings in Siblings with COX15 Deficiency: Case Report and Review of Previously Reported Cases.
  35. Deep learning-driven automated mitochondrial segmentation for analysis of complex transmission electron microscopy images.
  36. Review of FUNDC1-mediated mitochondrial autophagy in Alzheimer's disease.
  37. Cellular Metabolic Disorders in a Cohort of Patients with Sjogren's Disease.
  38. Tissue-specific differences impacts therapeutic outcomes of mitochondrial transplantation through regulation of bioenergetics in metabolic syndrome.
  39. Impact of Drp1 Loss on Organelle Interaction, Metabolism, and Inflammation in Mouse Liver.
  40. Construction of a mitochondria-targeted NIR probe with large Stokes shift for real-time monitoring viscosity changes during ferroptosis.
  41. Intervention strategies for Parkinson's disease: the role of exercise and mitochondria.
  42. Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.
  43. ACADVL Deep Sequencing in a Case Study: Beyond the Common c.848T>C Pathogenic Variant.
  44. Cardiolipin membranes drive Myosin VI activation, oligomerization, and processive cargo transport.
  45. CoQ imbalance drives reverse electron transport to disrupt liver metabolism.
  46. Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy.
  47. In vivo structure profiling reveals human cytosolic and mitochondrial tRNA structurome and interactome in response to stress.
  48. Multi-organ metabolome biological age implicates cardiometabolic conditions and mortality risk.
  49. From roadmap to a sustainable end-to-end individualized therapy pathway.
  50. Ontology-guided clustering enables proteomic analysis of rare pediatric disorders.
  51. Blood RNA-seq in rare disease diagnostics: a comparative study of cases with and without candidate variants.
  52. LRRK2 interactions with microtubules are independent of LRRK2-mediated Rab phosphorylation.
  1. World J Pediatr. 2025 May 27.
    Assessment of the respiratory chain enzyme activity in peripheral blood monocytes for the noninvasive diagnostics of mitochondrial disease.
    Jing-Jing Liu, Si-Min Wang, Zi-Han Zhang, Xue-Qian Wang, Xiao-Hui Zhang, Hong-Ying Wang, Ting Chen.
       BACKGROUND: Mitochondrial diseases are among the most common metabolic disorders caused by mitochondrial dysfunction. Analyzing mitochondrial respiratory chain enzyme activity is essential for diagnosis. However, clinical laboratories often rely on mitochondria isolated from muscle biopsies or cultured skin fibroblasts, which may be unacceptable for some pediatric patients. This highlights the need for improved blood-based diagnostic methods.
    METHODS: This paper describes spectrophotometric assays to evaluate mitochondrial respiratory chain enzyme activity in peripheral blood monocytes. Sample preparation methods and assays for respiratory complexes I-IV and the mitochondrial matrix enzyme citrate synthase are detailed. The assays were validated via samples from a panel of 28 healthy children and validated in patients with combined and isolated mitochondrial oxidative phosphorylation system (OXPHOS) deficiency.
    RESULTS: The citrate synthase-normalized activities were 0.23 ± 0.08 for complex I, 0.22 ± 0.081 for complex II, 0.16 ± 0.07 for complex III, and 0.22 ± 0.07 for complex IV. All patients with mitochondrial disease exhibited the expected reductions in respiratory complex activity.
    CONCLUSIONS: We established a method to analyze the respiratory complex activities via blood samples. The normal enzymatic activity ranges were established from healthy Chinese pediatric populations. We also validated the assay via samples from patients with mitochondrial disease. By establishing the first pediatric-specific reference ranges for mitochondrial respiratory chain complex activities in a Chinese population and validating this minimally invasive blood-based assay in patients with mitochondrial disease, our study enabled earlier detection, precise monitoring, and personalized management of mitochondrial disorders while avoiding the need for invasive tissue biopsies.
    Keywords:  Mitochondrial disease; Mitochondrial respiratory chain; PBMC; Pediatrics; Spectrophotometric analysis
    DOI:  https://doi.org/10.1007/s12519-025-00918-2
  2. Biol Chem. 2025 May 27.
    The mitochondrial intermembrane space - a permanently proteostasis-challenged compartment.
    Matthias Weith, Konstantin Weiss, Dylan Stobbe, Jan Riemer.
      The mitochondrial intermembrane space (IMS) houses proteins essential for redox regulation, protein import, signaling, and energy metabolism. Protein import into the IMS is mediated by dedicated pathways, including the disulfide relay pathway for oxidative folding. In addition, various IMS-traversing import pathways potentially expose unfolded proteins, representing threats to proteostasis. This trafficking of precursors coincides with unique biophysical challenges in the IMS, including a confined volume, elevated temperature, variable pH and high levels of reactive oxygen species. Ultrastructural properties and import supercomplex formation ameliorate these challenges. Nonetheless, IMS proteostasis requires constant maintenance by chaperones, folding catalysts, and proteases to counteract misfolding and aggregation. The IMS plays a key role in stress signaling, where proteostasis disruptions trigger responses including the integrated stress response (ISR) activated by mitochondrial stress (ISRmt) and responses to cytosolic accumulation of mitochondrial protein precursors. This review explores the biology and mechanisms governing IMS proteostasis, presents models, which have been employed to decipher IMS-specific stress responses, and discusses open questions.
    Keywords:  IMS; mitochondria; protein import; proteostasis; stress responses
    DOI:  https://doi.org/10.1515/hsz-2025-0108
  3. Acta Neuropathol. 2025 May 30. 149(1): 53
    Delineating the mechanisms of cerebellar degeneration in paediatric and adult primary mitochondrial disease.
    Laura A Smith, Elizaveta A Olkhova, Nichola Z Lax, Yi Shiau Ng, Robert W Taylor, Grainne S Gorman, Daniel Erskine, Robert McFarland.
      Cerebellar ataxia is a frequent, debilitating neurological manifestation of primary mitochondrial disease and is associated with extensive neurodegeneration of the cerebellar cortical circuitry. However, the precise neuropathological mechanisms resulting in cerebellar degeneration in paediatric and adult forms of mitochondrial disease remain unclear. We therefore sought to perform a comparative neuropathological study using post-mortem cerebellar tissues from 28 paediatric and adult patients with pathogenic bi-allelic POLG variants and pathogenic mitochondrial DNA variants (m.3243A > G, m.8344A > G, m.13094T > C, and m.14709T > C), in addition to 18 neurologically normal control cases. We also sought to assess the prevalence and progression of cerebellar ataxia in an adult mitochondrial disease patient clinical cohort (n = 310) harbouring the same pathogenic variants as the post-mortem cases. Analysis of the clinical patient cohort revealed that at least 23.5-39.7% of adult patients with primary mitochondrial disease had predominantly cerebellar ataxia, with disease progression evident in 38.8% of patients. In the mitochondrial disease post-mortem tissue cohort, there was clear evidence of selective loss of inhibitory Purkinje cells, with corresponding oxidative phosphorylation protein deficiencies, which were more severe in comparison to mainly excitatory neuronal populations of the granule cell layer and dentate nucleus. Remaining Purkinje cells also demonstrated an increased expression of mitophagy-related proteins, including LC3B and BNIP3. Focal necrotic cerebellar cortical lesions, identified in eight patients, were characterised by decreased parvalbumin immunoreactivity, and sporadic c-Fos immunoreactivity was observed throughout the cerebellar cortices of 14 patients, suggestive of cerebellar cortical hyperactivity. Overall, these neuropathological features were more severe in the early onset POLG-related disease group and patients who had epilepsy. Our findings provide an important insight to the pathological mechanisms contributing to the degeneration of the cerebellar cortex in paediatric and adult forms of primary mitochondrial disease, highlighting an increased burden of pathology in early onset POLG-related disease which may have important prognostic and therapeutic implications.
    Keywords:  Alpers’ syndrome; DNA polymerase gamma (POLG); MELAS; MERRF; Stroke-like episodes; mtDNA
    DOI:  https://doi.org/10.1007/s00401-025-02891-6
  4. Curr Opin Cell Biol. 2025 May 28. pii: S0955-0674(25)00073-0. [Epub ahead of print]95 102535
    The power of connections: Recent advances in understanding the regulation of mitochondrial dynamics by membrane contact sites.
    Jason C Casler, Laura L Lackner.
      The continuous remodeling of the mitochondrial network through fusion, fission, transport, and turnover events, collectively known as mitochondrial dynamics, is essential for the maintenance of mitochondrial metabolic and genomic health. While the primary molecular machines that mediate these processes were discovered decades ago, the regulation of mitochondrial dynamics clearly involves additional factors. A major breakthrough came from the discovery that sites of close apposition between organelles, known as membrane contact sites (MCSs), serve as critical regulators of organelle function. MCSs between mitochondria and the ER are now universally recognized as important regulatory hubs of mitochondrial dynamics. Despite this, there are still many unknowns pertaining to the mechanisms by which MCSs influence mitochondrial dynamics. In this review, we describe recent progress identifying novel protein and lipid components that regulate mitochondrial dynamics and emphasize clear gaps in our understanding of how mitochondrial dynamics are coordinated at MCSs. Finally, we conclude by discussing progress towards defining the highly biomedically relevant, but enigmatic, role of mitochondrial dynamics in the preservation of mitochondrial DNA integrity.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102535
  5. Int J Mol Sci. 2025 May 10. pii: 4565. [Epub ahead of print]26(10):
    Exploring the Phenotypic Heterogeneity and Bioenergetic Profile of the m.13513G>A mtDNA Substitution: A Heteroplasmy Perspective.
    Tatiana Krylova, Yulia Itkis, Polina Tsygankova, Denis Chistol, Konstantin Lyamzaev, Vyacheslav Tabakov, Svetlana Mikhaylova, Natalia Nikitina, Galina Rudenskaya, Aysylu Murtazina, Tatiana Markova, Natalia Semenova, Natalia Buchinskaya, Elena Saifullina, Hasyanya Aksyanova, Peter Sparber, Natalia Andreeva, Natalia Venediktova, Alina Ivanushkina, Daria Eliseeva, Yulia Murakhovskaya, Natalia Sheremet, Ekaterina Zakharova.
      The m.13513G>A (p.Asp393Asn) substitution in the MT-ND5 (Mitochondrially Encoded NADH/Ubiquinone Oxidoreductase Core Subunit 5) gene is a common pathogenic variant associated with primary mitochondrial disorders. It frequently causes Leigh syndrome and mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS). In this study, we present clinical data, heteroplasmy levels in various tissues (blood, urine, and skin fibroblasts), and bioenergetic characteristics from a cohort of 20 unrelated patients carrying the m.13513G>A mutation, classified according to the following phenotypes: Leigh syndrome (n = 12), MELAS (n = 2), and Leber's hereditary optic neuropathy (LHON, n = 6). We observed a significant correlation between high respiratory ratios and heteroplasmy levels in fibroblast cell lines of the patients. Furthermore, fibroblast cell lines with heteroplasmy levels exceeding 55% exhibited markedly reduced mitochondrial membrane potential. These findings contribute to a better understanding of the clinical and bioenergetic profiles of patients with m.13513G>A-variant-related phenotypes across different heteroplasmy levels, based on data from a single genetic center. Our data suggest that even a slight shift in heteroplasmy can improve cellular function and, consequently, the patients' phenotype, providing a solid foundation for the development of future gene therapies for mtDNA diseases.
    Keywords:  LHON; Leigh; MELAS; heteroplasmy; mtDNA; respirometry
    DOI:  https://doi.org/10.3390/ijms26104565
  6. Biomolecules. 2025 May 10. pii: 695. [Epub ahead of print]15(5):
    The Insertion Domain of Mti2 Facilitates the Association of Mitochondrial Initiation Factors with Mitoribosomes in Schizosaccharomyces pombe.
    Ying Luo, Jürg Bähler, Ying Huang.
      Translation initiation in mitochondria involves unique mechanisms distinct from those in the cytosol or in bacteria. The Schizosaccharomyces pombe mitochondrial translation initiation factor 2 (Mti2) is the ortholog of human MTIF2, which plays a vital role in synthesizing proteins in mitochondria. Here, we investigate the insertion domain of Mti2, which stabilizes its interaction with the ribosome and is crucial for efficient translation initiation. Our results show that the insertion domain is critical for the proper folding and function of Mti2. The absence of the insertion domain disrupts cell growth and affects the expression of genes encoded by mitochondrial DNA. Additionally, we show that Mti2 physically interacts with the small subunits of mitoribosomes (mtSSU), and deletion of the insertion domain dissociates mitochondrial initiation factors from the mitoribosome, reducing the efficiency of mitochondrial translation. Altogether, these findings highlight the conserved role of the insertion domain in facilitating translation initiation in fission yeast and thus reveal shared principles of mitochondrial translation initiation in both fission yeast and humans.
    Keywords:  fission yeast; insertion domain; mitochondrial translation; translation initiation factor
    DOI:  https://doi.org/10.3390/biom15050695
  7. J Inherit Metab Dis. 2025 Jul;48(4): e70045
    A Multiomic Network Approach to Uncover Disease Modifying Mechanisms of Inborn Errors of Metabolism.
    Aaron Bender, Pablo Ranea-Robles, Evan G Williams, Mina Mirzaian, J Alexander Heimel, Christiaan N Levelt, Ronald J Wanders, Johannes M Aerts, Jun Zhu, Johan Auwerx, Sander M Houten, Carmen A Argmann.
      For many inborn errors of metabolism (IEM) the understanding of disease mechanisms remains limited, in part explaining their unmet medical needs. The expressivity of IEM disease phenotypes is affected by disease-modifying factors, including rare and common polygenic variation. We hypothesize that we can identify these modulating pathways using molecular signatures of IEM in combination with multiomic data and gene regulatory networks generated from non-IEM animal and human populations. We tested this approach by identifying and subsequently validating glucocorticoid signaling as a candidate modifier of mitochondrial fatty acid oxidation disorders, and recapitulating complement signaling as a modifier of inflammation in Gaucher disease. Our work describes a novel approach that can overcome the rare disease-rare data dilemma and reveal new IEM pathophysiology and potential drug targets using multiomics data in seemingly healthy populations.
    Keywords:  Bayesian gene regulatory networks; QTL mapping; genetic reference population; metabolomics; mouse models; transcriptomics
    DOI:  https://doi.org/10.1002/jimd.70045
  8. Nat Aging. 2025 May 27.
    Mitochondrial clonal mosaicism encodes a biphasic molecular clock of aging.
    Zhenguo Wang, Zhe Li, Hongyu Liu, Chenghua Yang, Xin Li.
      Mitochondria rapidly accumulate mutations throughout a lifetime, potentially acting as a molecular clock for aging and disease. We profiled mitochondrial RNA across 47 human tissues from 838 individuals, revealing rapid development of clonal mosaicism with two distinct tissue-specific aging signatures. Tissues with constant cellular turnover such as the gastrointestinal tract or skin exhibit accelerated accumulation of sporadic mutations and clonal expansions, implicating increased susceptibility to age-related tumorigenesis and dysfunction. By contrast, post-mitotic tissues, such as the heart and brain, accumulate mutations at deterministic hotspots (tissue-specific, recurrently mutated sites), reflecting the cumulative burden of high energy demand and mitochondrial turnover independent of cell division. These findings support a biphasic model of the mitochondrial clock: stochastic clonal expansion of sporadic replication errors in proliferative tissues, versus age-dependent heteroplasmy increases at hotspots in high-metabolic tissues. This mutational landscape provides a map of tissue-specific vulnerabilities during aging and offers potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s43587-025-00890-6
  9. Pediatr Dev Pathol. 2025 May 26. 10935266251335065
    Infant With a Severe Form of GLRX5-Related Atypical Hyperglycinemia Exhibiting Novel Cardiac and Neurologic Disease Manifestations at Autopsy.
    Elizabeth O Ferreira, Marc R Del Bigio, Jason Morin, Patrick Frosk.
      Glutaredoxin 5 (GLRX5) is a mitochondrial protein encoded by the GLRX5 gene, which is essential for cellular redox homoeostasis, lipoic acid synthesis, and iron-sulfur cluster transfer. Rare cases of pathogenic GLRX5 mutations have been associated with sideroblastic anemia and non-ketotic hyperglycinemia with progressive spasticity and cavitating leukoencephalopathy. We report an 11-month-old child, who died following aspiration, with severe cardiomyocyte mitochondrial abnormalities and cerebral white matter degeneration in the context of a homozygous GLRX5 variant (c.208A>G, p.S70G).
    Keywords:  GLRX5 (glutaredoxin-5); cardiomyopathy; metabolic acidosis; mitochondrial disease; non-ketotic hyperglycinemia; progressive spasticity
    DOI:  https://doi.org/10.1177/10935266251335065
  10. Int J Mol Sci. 2025 May 18. pii: 4826. [Epub ahead of print]26(10):
    Special Issue "Mitochondrial Metabolism Alterations in Health and Disease".
    Graziantonio Lauria, Rosita Curcio.
      Mitochondria are central hubs of cellular metabolism and signaling that play key roles in stress response, inflammation, calcium homeostasis, mitochondrial quality control, and cell death, with mitochondrial impairment potentially being the underlying cause of several conditions, including metabolic, neurodegenerative, and cardiovascular diseases [...].
    DOI:  https://doi.org/10.3390/ijms26104826
  11. Biochem J. 2025 May 28. pii: BCJ20253062. [Epub ahead of print]482(11):
    LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.
    Silas A Buck, Laurie H Sanders.
      Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor, rigidity, and bradykinesia as well as degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). A minority of PD cases are familial and are caused by a single genetic mutation. One of the most common PD-causing genes is leucine-rich repeat kinase 2 (LRRK2), which causes an autosomal dominant PD that presents very similarly to sporadic PD. Pathogenic mutations in LRRK2 increase its kinase activity, indicated by both LRRK2 autophosphorylation and phosphorylation of its substrates. To date, the mechanism(s) by which elevated LRRK2 kinase activity induces DA neuron degeneration and PD has not been fully elucidated. One potential mechanism may involve the role of LRRK2 on mitochondria, as mitochondrial dysfunction has been linked to PD pathogenesis, and exciting recent evidence has connected PD pathogenic mutations in LRRK2 to multiple aspects of mitochondrial dysfunction associated with the disease. In this review, we discuss the current knowledge implicating LRRK2 in mitochondrial energetics, oxidative stress, genome integrity, fission/fusion, mitophagy, and ion/protein transport in PD, as well as examine the potential role LRRK2 may play in mediating the effects of mitochondrial therapeutics being investigated for treatment of PD.
    Keywords:  LRRK2; Parkinson’s disease; mitochondria; mitochondrial DNA; mitophagy
    DOI:  https://doi.org/10.1042/BCJ20253062
  12. Am J Ophthalmol Case Rep. 2025 Jun;38 102346
    The crossroads of Leber hereditary optic neuropathy and autosomal dominant optic Atrophy: Clinical profiles of patients with coexisting pathogenic genetic variants.
    Mohammed A Halawani, Nooran O Badeeb.
       Purpose: Leber Hereditary Optic Neuropathy (LHON) and Autosomal Dominant Optic Atrophy (ADOA) are hereditary optic neuropathies characterized by mitochondrial dysfunctions causing destruction to the retinal ganglion cells and their axons, painless bilateral vision loss and symmetrical temporal pallor of the optic nerve. We present six intrafamilial cases with different manifestations of LHON and/or ADOA and their genetic variant profiles.
    Observations: Two brothers and their father had symptomatic bilateral vision loss, two sisters were asymptomatic, and the mother had left eye vision loss due to solar retinopathy; accompanied with headaches. Five of the patients had normal anterior and posterior segment exam aside from the affected optic nerves. The family pedigree showed an unaffected first generation and an affected male in the second generation. In the third generation, an affected male (the father in this family), diagnosed with optic atrophy due to OPA1 c.2383C > T variant, married a woman (the mother) carrying the LHON MT-ND4 m.11778G > A variant. Their offspring were one unaffected daughter, one affected daughter and two affected sons harboring both LHON and ADOA pathogenic variants inherited from their parents.
    Conclusion and importance: Mitochondrial optic neuropathies, which result in loss of retinal ganglion cells, are a substantial cause of visual impairment. Herein, we report two cases of combined LHON- and ADOA-causing pathogenic variants in two brothers, in addition to the genetic and ophthalmologic profile of their parents and two sisters.
    Keywords:  Autosomal dominant optic atrophy (ADOA); Leber hereditary optic neuropathy (LHON); Pathogenic variants; Vision loss
    DOI:  https://doi.org/10.1016/j.ajoc.2025.102346
  13. J Mol Biol. 2025 May 23. pii: S0022-2836(25)00295-5. [Epub ahead of print] 169229
    Immunoproteasome-specific subunit alterations as a potential therapeutic target for mitochondriopathies.
    Agata Kodroń, Konrad Kowalski, Ben Hur Marins Mussulini, Cem Hazir, Mayra A Borrero-Landazabal, Sonia Ngati, Michal Wasilewski, Agnieszka Chacinska.
      Mitochondria are double-membrane organelles crucial for eukaryotic cells due to their role in ATP production by oxidative phosphorylation (OXPHOS). Most of the ∼1500 proteins of the mitochondrial proteome are encoded in the nuclear genome, synthesized in the cytosol, and actively transported into mitochondria. The proteasome, a major cellular proteolytic machinery, plays an important role in the quality control of their transport by degradation of inefficiently imported mitochondrial proteins in the cytosol. Proteasome inhibition by bortezomib was described as a strategy to alleviate deficiencies stemming from an inefficient import of proteins into the mitochondria. Notably, an impairment of the respiratory complexes was shown to induce a rearrangement of the proteasome composition to incorporate some of the immunoproteasome catalytic subunits, such as PSMB9. In this study, we demonstrated that targeting immunoproteasome inhibited degradation, and thus restored the abundance of inefficiently imported respiratory complex IV proteins in the patient derived fibroblasts. Furthermore, we demonstrated that the immunoproteasome-specific inhibitors displayed a decreased toxicity compared to bortezomib. Our results indicate that immunoproteasome subunits present a novel molecular target for future therapies of mitochondriopathies.
    Keywords:  PSMB9; immunoproteasome inhibitors; immunoproteasome subunits; mitochondria; mitochondrial diseases
    DOI:  https://doi.org/10.1016/j.jmb.2025.169229
  14. Biochem Soc Trans. 2025 May 29. pii: BST20253013. [Epub ahead of print]
    Mechanisms of heme transport in the mitochondria.
    Saieeda Fabia Ali, Adrianna E White, Amy Medlock, Oleh Khalimonchuk.
      Heme is a vital but highly reactive compound that is synthesized in mitochondria and subsequently distributed to a variety of subcellular compartments for utilization. The transport of heme is essential for normal cellular metabolism, growth, and development. Despite the vital importance of heme transport within the cell, data are lacking about how newly synthesized heme is shuttled within the mitochondrion or exported from the organelle. Here, we briefly summarize current knowledge about the process of mitochondrial heme distribution and discuss the current unresolved questions pertinent to this process.
    Keywords:  heme; heme biosynthesis; hemoproteins; membrane transporters; mitochondria
    DOI:  https://doi.org/10.1042/BST20253013
  15. Protein Sci. 2025 Jun;34(6): e70179
    Lysine acetylation modulates s-OPA1 GTPase activity and oligomerization in mitochondrial membrane remodeling.
    Javaid Jabbar, Bakht Afroze, Naomi X Y Ling, Jonathan S Oakhill, Isabelle Rouiller.
      Mitochondrial dynamics are regulated by coordinated fission and fusion events that rely on key proteins and lipids organized spatially within the mitochondria. The dynamin-related GTPase Optic Atrophy 1 (OPA1) is essential for inner mitochondrial membrane fusion and cristae structure maintenance. While post-translational modifications, particularly lysine acetylation, are emerging as critical regulators of mitochondrial protein function, their impact on OPA1 remains poorly characterized. In this study, we explored the effects of lysine acetylation on the short form of OPA1 (s-OPA1) using acetylation and deacetylation mimetic mutations. Through a combination of in silico analyses and functional assays, we identified lysine residues in s-OPA1 that are conserved across species and significantly influence protein stability, GTPase activity, and oligomeric assembly upon acetylation or deacetylation. Our findings reveal that acetylation at K328 and deacetylation at K342 within the G domain enhance the GTPase activity of s-OPA1 upon lipid membrane binding, whereas deacetylation at K772 abolishes membrane binding-induced GTPase activity. Negative-stain transmission electron microscopy indicated that while lysine acetylation does not alter the ability of s-OPA1 to bind and tubulate liposomes, it significantly impacts higher-order filament formation. These findings provide novel insights into how acetylation modulates s-OPA1 function, highlighting a potential mechanism for post-translational regulation of mitochondrial dynamics. Our study contributes to the understanding of how molecular changes influence broader cellular processes, with implications for mitochondrial function and related disorders.
    Keywords:  GTPase activity; OPA1; acetylation; membrane remodeling; oligomeric assembly
    DOI:  https://doi.org/10.1002/pro.70179
  16. Science. 2025 May 29. eads7373
    Predicting expression-altering promoter mutations with deep learning.
    Kishore Jaganathan, Nicole Ersaro, Gherman Novakovsky, Yuchuan Wang, Terena James, Jeremy Schwartzentruber, Petko Fiziev, Irfahan Kassam, Fan Cao, Johann Hawe, Henry Cavanagh, Ashley Lim, Grace Png, Jeremy McRae, Abhimanyu Banerjee, Arvind Kumar, Jacob Ulirsch, Yan Zhang, Francois Aguet, Pierrick Wainschtein, Laksshman Sundaram, Adriana Salcedo, Sofia Kyriazopoulou Panagiotopoulou, Delasa Aghamirzaie, Evin Padhi, Ziming Weng, Shan Dong, Damian Smedley, Mark Caulfield, Anne O'Donnell-Luria, Heidi L Rehm, Stephan J Sanders, Anshul Kundaje, Stephen B Montgomery, Mark T Ross, Kyle Kai-How Farh.
      Only a minority of patients with rare genetic diseases are currently diagnosed by exome sequencing, suggesting that additional unrecognized pathogenic variants may reside in non-coding sequence. Here, we describe PromoterAI, a deep neural network that accurately identifies non-coding promoter variants which dysregulate gene expression. We show that promoter variants with predicted expression-altering consequences produce outlier expression at both RNA and protein levels in thousands of individuals, and that these variants experience strong negative selection in human populations. We observe that clinically relevant genes in rare disease patients are enriched for such variants and validate their functional impact through reporter assays. Our estimates suggest that promoter variation accounts for 6% of the genetic burden associated with rare diseases.
    DOI:  https://doi.org/10.1126/science.ads7373
  17. Neurobiol Dis. 2025 May 26. pii: S0969-9961(25)00192-5. [Epub ahead of print]212 106976
    Imbalanced mitochondrial dynamics in human PD and α-synuclein mouse brains.
    Harry J Brown, Rebecca Z Fan, Riley Bell, Said S Salehe, Carlos Martínez Martínez, Yanhao Lai, Kim Tieu.
      Emerging studies have shown that dysregulation in mitochondrial dynamics has a major negative impact on mitochondria. Partial genetic and pharmacological inhibition of the mitochondrial fission dynamin-related protein 1 (DRP1) has been demonstrated to be beneficial in models of neurodegenerative disorders, including Parkinson's disease (PD). However, the expression of DRP1 and other mitochondrial fission/fusion mediators have not been investigated in the brains of Parkinson's patients. This information is critical to strengthening mitochondrial dynamics as a potential therapeutic target for PD. We report in this study that significant increases in the levels of both DNM1L, which encodes DRP1, as well as the DRP1 protein were detected in Parkinson's patients. Immunostaining revealed increased DRP1 expression in dopamine (DA) neurons, astrocytes, and microglia. In addition to DRP1, the levels of other fission and fusion genes/proteins were also altered. To complement these human studies and given the significant role of α-synuclein in PD pathogenesis, we performed time-course studies using transgenic mice overexpressing human wild-type SNCA. As early as six months old, we detected an upregulation of DRP1 in the nigral DA neurons of the SNCA mice as compared to their wild-type littermates. Furthermore, these mutant animals exhibited more DRP1 phosphorylation at serine 616, which promotes its translocation to mitochondria to induce fragmentation. Together, this study shows an upregulation of DRP1 and alterations in other fission/fusion proteins in both human and mouse PD brains, leading to a pro-fission phenotype, providing additional evidence that blocking mitochondrial fission or promoting fusion is a potential therapeutic strategy for PD.
    Keywords:  Dynamin-related protein 1; Mitochondrial dynamics; Neurodegeneration; Parkinson's disease; Protein aggregation; α-synuclein
    DOI:  https://doi.org/10.1016/j.nbd.2025.106976
  18. Environ Mol Mutagen. 2025 May 26.
    Mitochondria-Nuclear Crosstalk: Orchestrating mtDNA Maintenance.
    Ghazal Darfarin, Janice Pluth.
      The mitochondria (mt) and nucleus engage in a dynamic bidirectional communication to maintain cellular homeostasis, regulating energy production, stress response, and cell fate. Anterograde signaling directs mt function, while retrograde signaling conveys metabolic and stress-related changes from mt to the nucleus. Central to this crosstalk is mitochondrial DNA (mtDNA), which encodes key oxidative phosphorylation components. MtDNA integrity is preserved through quality control mechanisms, including fusion and fission dynamics, mitophagy, and nuclear-encoded DNA repair. Disruption in these pathways contributes to mt dysfunction, oxidative stress, and genetic instability-hallmarks of aging and diseases. Additionally, redox signaling and NAD+ homeostasis integrate mt and nuclear responses, modulating transcriptional programs that support mt biogenesis and stress adaptation. This review explores the molecular mechanisms coordinating mito-nuclear interactions, emphasizing their role in maintaining mtDNA integrity and cellular equilibrium. Understanding these processes provides insights into how mt dysfunction drives aging and disease, paving the way for targeted therapeutic strategies.
    Keywords:  anterograde and retrograde signaling; cellular homeostasis; mitochondrial biogenesis; mitochondrial dynamics; mtDNA maintenance, mitochondrial‐nuclear communication; redox signaling
    DOI:  https://doi.org/10.1002/em.70013
  19. Elife. 2025 May 30. pii: RP93621. [Epub ahead of print]13
    Inhibition of mitochondrial protein import and proteostasis by a pro-apoptotic lipid.
    Josep Fita-Torró, José Luis Garrido-Huarte, Lucía López-Gil, Agnès H Michel, Benoit Kornmann, Amparo Pascual-Ahuir, Markus Proft.
      Mitochondria-mediated cell death is critically regulated by bioactive lipids derived from sphingolipid metabolism. The lipid aldehyde trans-2-hexadecenal (t-2-hex) induces mitochondrial dysfunction from yeast to humans. Here, we apply unbiased transcriptomic, functional genomics, and chemoproteomic approaches in the yeast model to uncover the principal mechanisms and biological targets underlying this lipid-induced mitochondrial inhibition. We find that loss of Hfd1 fatty aldehyde dehydrogenase function efficiently sensitizes cells for t-2-hex inhibition and apoptotic cell death. Excess of t-2-hex causes a profound transcriptomic response with characteristic hallmarks of impaired mitochondrial protein import, like activation of mitochondrial and cytosolic chaperones or proteasomal function and severe repression of translation. We confirm that t-2-hex stress induces rapid accumulation of mitochondrial pre-proteins and protein aggregates and subsequent activation of Hsf1- and Rpn4-dependent gene expression. By saturated transposon mutagenesis, we find that t-2-hex tolerance requires an efficient heat shock response and specific mitochondrial and ER functions and that mutations in ribosome, protein, and amino acid biogenesis are beneficial upon t-2-hex stress. We further show that genetic and pharmacological inhibition of protein translation causes t-2-hex resistance, indicating that loss of proteostasis is the predominant consequence of the pro-apoptotic lipid. Several TOM subunits, including the central Tom40 channel, are lipidated by t-2-hex in vitro and mutation of accessory subunits Tom20 or Tom70 confers t-2-hex tolerance. Moreover, the Hfd1 gene dose determines the strength of t-2-hex mediated inhibition of mitochondrial protein import, and Hfd1 co-purifies with Tom70. Our results indicate that the transport of mitochondrial precursor proteins through the outer mitochondrial membrane is sensitively inhibited by the pro-apoptotic lipid and thus represents a hotspot for pro- and anti-apoptotic signaling.
    Keywords:  S. cerevisiae; apoptosis; biochemistry; chemical biology; genetics; genomics; lipid signaling; mitochondrial protein import; proteostasis; sphingolipid metabolism; yeast
    DOI:  https://doi.org/10.7554/eLife.93621
  20. PLoS One. 2025 ;20(5): e0325031
    Epimedin C enhances mitochondrial energy supply by regulating the interaction between MIC25 and UBC in rodent model.
    Mi Huang, Lei Yu, Zhong Li, Ying Wang, Chunlin Yang.
      The study investigates the molecular mechanisms underlying the skeletal muscle-enhancing effects of Epimedin C, a natural flavonoid, focusing on its interaction with the mitochondrial cristae structural protein MIC25. Using C57BL/6 mice, we demonstrate that Epimedin C enhances exercise performance through preservation of mitochondrial function. Proteomic analysis identified MIC25 as a key protein modulated by Epimedin C, whose stability is regulated via ubiquitin-dependent degradation. Functional experiments revealed that Epimedin C disrupts the interaction between MIC25 and ubiquitin-conjugating enzyme C (UBC), preventing MIC25 degradation and maintaining the integrity of the mitochondrial contact site and cristae organizing system (MICOS). This stabilization preserves mitochondrial cristae structure, improves ATP production, and delays muscle fatigue. Notably, MIC25 overexpression mimicked Epimedin C's effects, while its knockdown abolished these benefits. Our findings establish MIC25 as a critical effector of Epimedin C, elucidating a novel pathway through which flavonoids maintain mitochondrial homeostasis to enhance muscle function. These insights hold promise for developing therapies targeting muscle atrophy and metabolic disorders.
    DOI:  https://doi.org/10.1371/journal.pone.0325031
  21. BMC Genomics. 2025 May 28. 26(1): 540
    Single-cell data combined with phenotypes improves variant interpretation.
    Timothy Chapman, Timo Lassmann.
       BACKGROUND: Whole genome sequencing offers significant potential to improve the diagnosis and treatment of rare diseases by enabling the identification of thousands of rare, potentially pathogenic variants. Existing variant prioritisation tools can be complemented by approaches that incorporate phenotype specificity and provide contextual biological information, such as tissue or cell-type specificity. We hypothesised that integrating single-cell gene expression data into phenotype-specific models would improve the accuracy and interpretability of pathogenic variant prioritisation.
    METHODS: To test this hypothesis, we developed IMPPROVE, a new tool that constructs phenotype-specific ensemble models integrating CADD scores with bulk and single-cell gene expression data. We constructed a total of 1,866 Random Forest models for individual HPO terms, incorporating both bulk and single cell expression data.
    RESULTS: Our phenotype-specific models utilising expression data can better predict pathogenic variants in 90% of the phenotypes (HPO terms) considered. Using single-cell expression data instead of bulk benefited the models, significantly shifting the proportion of pathogenic variants that were correctly identified at a fixed false positive rate (p<10-30 , using an approximate Wilcoxon signed rank test). We found 57 phenotypes' models exhibited a large performance difference, depending on the dataset used. Further analysis revealed biological links between the pathology and the tissues or cell-types used by these 57 models.
    CONCLUSIONS: Phenotype-specific models that integrate gene expression data with CADD scores show great promise in improving variant prioritisation. In addition to improving diagnostic accuracy, these models offer insights into the underlying biological mechanisms of rare diseases. Enriching existing pathogenicity-related scores with gene expression datasets has the potential to advance personalised medicine through more accurate and interpretable variant prioritisation.
    Keywords:  Interpretable models; Machine learning; Random forest; Rare disease; Variant prioritisation; Whole Genome sequencing
    DOI:  https://doi.org/10.1186/s12864-025-11711-w
  22. Curr Opin Cell Biol. 2025 May 26. pii: S0955-0674(25)00077-8. [Epub ahead of print]95 102539
    Actin in mitochondrial regulation and mechanometabolic crosstalk.
    Peng Shi, Yuhan Zhang, Congying Wu.
      Mitochondria undergo dynamic adaptations to cellular energy demands, changing morphology and function, through active interactions with other cellular organelles and the cytoskeletons. With advances in light and electron microscopy, actin probes for live-cell imaging, as well as proximity labeling, subtle and transient actin structures associated with mitochondria have been resolved and examined, which opened a new era for the understanding of architectural and mechanical regulation of organelles and metabolism. Here, we first review the recent findings that elucidate the actin-mitochondrion interactions in regulating mitochondrial dynamics (including fission, fusion and trafficking), and cristae architecture. Further, we discuss the functional consequences accompanying these morphological changes, which link cellular metabolism to the cytoskeleton and mechanotransduction through direct or indirect organelle control. Moreover, we summarize the avant-garde techniques for probing mitochondrion-associated actin, including new ways to visualize mitochondria-actin interaction in the cytosol and within the mitochondria, methods to identify the molecular components mediating actin-mitochondria crosstalk, and techniques for reconstructing the 3D ultrastructure of actin-mitochondrion interaction. Finally, we conclude pressing issues in this exciting field, calling for interdisciplinary efforts in examine actin-mitochondrion interactions at micro and macro levels. The dynamics and structural integrity of mitochondria are essential for energy metabolism and signal transduction, while their abnormalities lead to mitochondrial dysfunction and severe disease. This review aims to provide a comprehensive perspective on the emerging roles of the actin cytoskeleton in shaping mitochondrial morphology, structure, and functions, providing new angles to understand mitochondria-related diseases.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102539
  23. J Nutr. 2025 May 22. pii: S0022-3166(25)00308-6. [Epub ahead of print]
    The Mitochondrial Brown Adipose Tissue Maintenance Factor Nipsnap1 Interfaces Directly with the Beta-Oxidation Protein Machinery in Rodents.
    Pei-Yin Tsai, Yue Qu, Claire Walter, Yang Liu, Chloe Cheng, Joeva J Barrow.
       BACKGROUND: The activation of brown adipose tissue (BAT) is associated with improved metabolic health in humans. We previously identified the mitochondrial protein Nipsnap1 as a novel regulatory factor that integrates with lipid metabolism and is critical to sustain the long-term activation of BAT, but the precise mechanism and function of Nipsnap1 is unknown.
    OBJECTIVES: Define the function of the regulatory factor Nipsnap1 in lipid metabolism by identifying its specific protein-protein interactions and regulatory role in fatty acid beta-oxidation.
    METHODS: We used adeno-associated viral (AAV) vectors to overexpress Nipsnap1 in the thermogenic adipose tissue of male C57BL/6J mice and assessed whole-body energy metabolism using metabolic cages. Mitochondrial respiration in primary brown adipocytes was measured by Seahorse assay following AAV-Nipsnap1 infection. To further investigate molecular mechanisms, an immunoprecipitation assay was performed to identify Nipsnap1-interacting proteins.
    RESULTS: We show that adipose-specific overexpression of Nipsnap1 in mice elicits a 20% increase in energy expenditure through the utilization of lipids as an energy substrate as evidenced by the shift of the respiratory exchange ratio (RER) to 0.7 (P<0.001). Additionally, we show that Nipsnap1 overexpression in primary adipocytes increases lipid beta-oxidation by 39% to increase cellular energy expenditure (P< 0.05). Moreover, we mapped the first protein-protein network of Nipsnap1 in brown adipocytes and show that Nipsnap1 interacts with proteins such as solute carrier family 25 member 20 (Slc25a20) and Enoyl-CoA Hydratase And 3-Hydroxyacyl CoA Dehydrogenase (Ehhadh) that regulate both mitochondrial and peroxisomal fatty acid beta-oxidation respectively.
    CONCLUSION: This study elucidates a mechanistic function of Nipsnap1 in thermogenic fat where Nipsnap1 facilitates a functional connection between peroxisomal and mitochondrial beta-oxidation pathways. By enhancing lipid utilization as energy substrates, Nipsnap1 plays a pivotal role in sustaining thermogenic fat activation to increase energy expenditure. These findings underscore the potential of Nipsnap1 as a therapeutic target for metabolic health.
    Keywords:  BAT; Brown Adipose Tissue; Brown Fat; Lipid Metabolism; Mitochondria; Nipsnap1
    DOI:  https://doi.org/10.1016/j.tjnut.2025.05.026
  24. MicroPubl Biol. 2025 ;2025
    Insertion of mNeonGreen into the variable domain of DRP-1 permits visualization of functional endogenous protein.
    Eric J Lambie, Barbara Conradt.
      We used CRISPR-Cas9 editing of the genomic drp-1 locus in C. elegans to test whether the mitochondrial fission function of DRP-1 was retained following insertion of mNeonGreen into the variable domain. We found that DRP-1 activity remains largely intact despite this large internal insertion. Furthermore, in living cells, the internally tagged protein is readily detectable as discrete puncta associated with mitochondria, which presumably represent prospective mitochondrial scission sites. The internally tagged DRP-1 protein represents a powerful new tool for real time in vivo analyses of mitochondrial fission and DRP-1 function.
    DOI:  https://doi.org/10.17912/micropub.biology.001588
  25. Medicine (Baltimore). 2025 May 30. 104(22): e42556
    Exploration of the effects of 66 mitochondria-associated proteins on different cardiomyopathies: A bidirectional 2-sample mendelian randomization study.
    Zehong Peng, Xin Liu, Xi Zhu, Wenzhuo Zhu, Jianglong Wen, Chao Liu, Conghui Li, Lili Zhu.
      The aim of this study was to apply bidirectional Mendelian randomization (MR) to assess and investigate the causal associations between mitochondrial DNA copy number (mtDNA-CN), mitochondrial-associated proteins and cardiomyopathy. The mtDNA-CN and MAP from the IEU Open GWAS database were screened for strong associations with 4 different cardiomyopathy-associated single nucleotide polymorphisms (SNPs) in the IEU Open GWAS and Finnish databases, respectively, and causal associations were investigated using the inverse variance weighting method, the MR-Egger regression method, the weighted median method, the weighted mode method, and the simple mode method. method to explore causality; meanwhile, we used the Cochran Q test to assess the variability of SNPs. Horizontal pleiotropy of SNPs was examined by MR-Egger regression analysis and MR-PRESSO method. Sensitivity analyses were performed using the "Leave-One-Out (LOO)" method to determine whether the MR results would be interfered by a single SNP. MR analyses of mtDNA-CN, mitochondria-associated proteins, and different cardiomyopathies, respectively, with IVW as the primary analytical method, showed a statistically significant association between mtDNA-CN and pharmacological cardiomyopathy, P < .05. Statistical significance was found between 2 mitochondria-associated proteins (dihydrolipoyl dehydrogenase, mitochondrial apoptosis-inducing factor 1) and hypertrophic cardiomyopathy, both with P < .05. Six mitochondria-associated proteins (mitochondrial 39S ribosomal protein L33, ribosomal recycling factor, mitochondrial leucine-rich pentatricopeptide repeat motif-containing protein, serine protease high-temperature requirement protease A2, mitochondrial peptide methionine sulfoxide reductase, and mitochondrial input endomembrane transporter enzyme subunit translocase of inner mitochondrial membrane 14) and dilated cardiomyopathy were statistically significant, both with P < .05. Screening for 2 mitochondria-associated proteins (nicotinamide adenine dinucleotide dehydrogenase [ubiquinone] flavoprotein 2, and mitochondrial input endomembrane transporter enzyme subunit translocase of inner mitochondrial membrane 14, prot-a-847) and alcoholic cardiomyopathy was statistically significant，P < .05. Statistical significance was found between 1 mitochondria-associated protein (mitochondrial peptide chain release factor 1) screened and pharmacological cardiomyopathy, P < .05. Sensitivity analyses of all MR results: the Cochran Q test, MR-Egger intercept test, MR-Presso global test, and LOO sensitivity test No significant heterogeneity or horizontal pleiotropy was found at any time (all P > .05). There were causal associations between mtDNA-CN, mitochondria-associated proteins and cardiomyopathy, and mtDNA-CN and mitochondria-associated proteins had a certain predictive value for the condition and prognosis of patients with cardiomyopathy.
    Keywords:  Mendelian randomization; cardiomyopathy; causality; genetic epidemiology; mitochondria-associated protein; mitochondrial DNA copy number.
    DOI:  https://doi.org/10.1097/MD.0000000000042556
  26. Acta Neurol Belg. 2025 May 28.
    MICU1 myopathy revisited: phenotypic variability in a rare mitochondrial calcium disorder.
    Pushkar Pazhani, Jayaram Saibaba, Rajeswari Aghoram, Vaibhav Wadwekar, Ankith K Jayan.
      
    Keywords:  Chorea; Extrapyramidal signs; Keloid; Myopathy; Sensory neuropathy
    DOI:  https://doi.org/10.1007/s13760-025-02815-x
  27. Biochim Biophys Acta Mol Basis Dis. 2025 May 28. pii: S0925-4439(25)00278-9. [Epub ahead of print] 167930
    Deficiency in the conserved ECHS1 gene causes Leigh syndrome by impairing mitochondrial respiration efficiency and suppressing ADRB2-PKA signaling.
    Baojiang Wang, Yueyuan Qin, Yantao Bao, Shiguo Chen, Junge Zheng, Sheng Lin, Kaifeng Zheng, Shan Duan.
      Deficiency in the short-chain enoyl-CoA hydratase 1 (ECHS1) gene causes Leigh Syndrome (LS), a rare inherited metabolic disorder. Despite LS that arises as a result of inborn errors of energy metabolism, the specific contributions of ECHS1 deficiency to energy metabolism processes, developmental delay, and its mediated signaling mechanism remain unclear. Here, we identify a novel compound heterozygous variant [c.724G > A (p.Glu242Lys) and c.865G > A (Asp289Asn)] in the ECHS1 gene from a family of Han Chinese descent, with the affected individual displaying typical LS symptoms. The ECHS1 variants exhibit reduced 2-enoyl-CoA hydratase activity, resulting in a restricted ATP production rate, but the cellular ATP levels remains unchanged. ECHS1 deficiency also decreases cell viability and proliferation. Mechanistically, ECHS1 interacts with ADRB2, and its variants suppress the ADRB2/protein kinase A (PKA) signaling. Treatment with PKA signaling agonists or overexpression of PKA subunits in ECHS1-deficient cells can rescue the ATP production rate and restore cell viability. Additionally, the mitochondrial E3 ligase MUL1 mediates the ubiquitylation and degradation of ECHS1 protein variants. In conclusion, our study suggests that ECHS1 deficiency impairs mitochondrial respiratory efficiency, thereby lowering the ATP production rate, and reveals a promising therapeutic approach by targeting ADRB2/PKA signaling to combat ECHS1 deficiency-induced LS.
    Keywords:  ADRB2; Developmental delay; ECHS1 deficiency; Leigh syndrome; Mitochondrial respiration; Neurodegenerative conditions
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167930
  28. Genome Med. 2025 May 26. 17(1): 61
    The case for including proteomics in routine diagnostic practice for rare disease.
    Elizabeth M McCormick.
      Many people with rare diseases cannot access personalized therapies because they do not have a confirmed genetic diagnosis. Promising technologies including proteomics are underutilized in routine diagnostic practice. It is time to incorporate proteomics into the diagnostic workflow to shorten time to diagnosis and expand treatment options for rare disease.
    Keywords:  Diagnostic practice; Precision medicine; Proteomics; Rare disease; Undiagnosed disease
    DOI:  https://doi.org/10.1186/s13073-025-01491-z
  29. Blood Sci. 2025 Jun;7(2): e00236
    Super-resolution imaging informed scRNA sequencing analysis reveals the critical role of GDF15 in rejuvenating aged hematopoietic stem cells.
    Zhongyu Shi, Xuefei Zhang, Huihui Yang, Xiaolu Zheng, Mengxiao Niu, Yongjian Zhang, Pengfei Yuan, Wensheng Wei, Gang Huang, Riguo Fang, Liangyi Chen.
      Although changes in mitochondrial morphology consistently associated with the aging of hematopoietic stem cells (HSCs), the specific molecular and cellular mechanisms involved are partially unclear. Live-cell super-resolution (SR) microscopy has been used to identify distinct HSC subsets that characterized by mitochondria unique morphologies and spatial distributions. The integration of SR microscopy with single-cell RNA sequencing enabled the classification of approximately 200 HSCs from young and aged mice into 5 discrete clusters. These clusters displayed molecular profiles that corresponded to the observed mitochondria states. An integrated approach combining RNA biomarker analysis and potential regulon assessment revealed previously unrecognized roles of GDF15 in mediating mitochondrial signals and morphologies that influence HSC fate. Thus, combining SR imaging with a bioinformatics pipeline provides an effective method for identifying key molecular players in specific phases of cellular transition, even with a relatively small dataset.
    Keywords:  Hematopoietic stem cells; Mitochondria; Super-resolution microscopy; scRNA sequencing
    DOI:  https://doi.org/10.1097/BS9.0000000000000236
  30. Circulation. 2025 May 27.
    Disruption of cTnT-Mediated Sarcomere-Mitochondrial Communication Results in Dilated Cardiomyopathy.
    Lingqun Ye, Junwei Liu, Wei Lei, Baoqiang Ni, Xinglong Han, Yan Zhang, Yong Wang, Kaili Hao, Yuanhui Peng, Hongchun Wu, Miao Yu, Huadong Li, Zhen-Ao Zhao, Zhenya Shen, Jianyi Zhang, Shijun Hu.
       BACKGROUND: Dilated cardiomyopathy (DCM) is substantially influenced by genetic factors. Sarcomere function is intricately associated with other organelles, particularly the reciprocal regulation between sarcomeres and mitochondria. Mitochondrial stress dysregulation is linked to DCM progression, yet mechanisms remain unclear. In this study, we investigated the effects of cTnT (cardiac troponin T) dysregulation on sarcomere-mitochondrial communication in DCM.
    METHODS: Induced pluripotent stem cells (iPSCs) derived from a DCM family cohort were used in this study, and CRISPR-Cas9 genome editing was used to rectify the TNNT2 (c.A553G) sequence variation in iPSCs. A knock-in mouse model harboring the (p.K192E) sequence variation, equivalent to the human cTnT (p.K185E) sequence variation, was subsequently established. The pathological phenotypes were analyzed in iPSC-derived cardiomyocytes, iPSC-derived cardiac organoids, and mice. RNA sequencing, metabolite profiling, and coimmunoprecipitation mass spectrometry were used to elucidate the molecular mechanisms.
    RESULTS: Through whole exome sequencing, we identified a novel pathogenic variant in cTnT (p.K185E) as the causal sequence variation in a familial DCM cohort. In iPSC-derived cardiomyocytes from patients with DCM, we observed sarcomere disarray and mitochondrial fragmentation accompanied by severe mitochondrial dysfunction. The diminished interaction between cTnT (p.K185E) and 14-3-3 proteins resulted in the dissociation of 14-3-3 proteins from sarcomeric structures. The free 14-3-3 proteins aberrantly engaged in the RAS/RAF1 signaling axis, driving aberrant p44/42 kinase activation that culminated in the phosphorylation of mitochondrial fission regulators DRP1 (dynamin-related protein 1) and MFF (mitochondrial fission factor). These observations were replicated in iPSC-derived cardiac organoids. The knock-in mice bearing the orthologous cTnT sequence variation faithfully recapitulated the hallmark features of human DCM, including cardiac dysfunction, ventricular dilatation, sarcomeric disarray, and mitochondrial fragmentation. Mdivi-1, a mitochondrial fission inhibitor, alleviated DCM phenotypes in vivo.
    CONCLUSIONS: Our findings delineate a novel pathogenic mechanism underlying DCM, demonstrating that cTnT (p.K185E) sequence variation disrupts sarcomere-mitochondrial communication by weakening the interaction between cTnT and 14-3-3 proteins, thereby accelerating mitochondrial fragmentation through excessive activation of the 14-3-3 protein-mediated RAS/RAF1-p44/42-DRP1/MFF signaling axis. Therefore, therapeutic targeting of 14-3-3 proteins and p44/42 kinase activity may represent a promising strategy for DCM and other cardiac diseases associated with aberrant mitochondrial dynamics.
    Keywords:  cardiomyopathy, dilated; induced pluripotent stem cells; mitochondria; organoids; sarcomeres
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.071523
  31. Molecules. 2025 May 10. pii: 2117. [Epub ahead of print]30(10):
    CHCHD4 Oxidoreductase Activity: A Comprehensive Analysis of the Molecular, Functional, and Structural Properties of Its Redox-Regulated Substrates.
    Nicole Balasco, Nazanine Modjtahedi, Alessandra Monti, Menotti Ruvo, Luigi Vitagliano, Nunzianna Doti.
      The human CHCHD4 protein, which is a prototypical family member, carries a coiled-coil-helix-coiled-coil-helix motif that is stabilized by two disulfide bonds. Using its CPC sequence motif, CHCHD4 plays a key role in mitochondrial metabolism, cell survival, and response to stress conditions, controlling the mitochondrial import of diversified protein substrates that are specifically recognized through an interplay between covalent and non-covalent interactions. In the present review, we provide an updated and comprehensive analysis of CHCHD4 substrates controlled by its redox activities. A particular emphasis has been placed on the molecular and structural aspects of these partnerships. The literature survey has been integrated with the mining of structural databases reporting either experimental structures (Protein Data Bank) or structures predicted by AlphaFold, which provide protein three-dimensional models using machine learning-based approaches. In providing an updated view of the thirty-four CHCHD4 substrates that have been experimentally validated, our analyses highlight the notion that this protein can operate on a variety of structurally diversified substrates. Although in most cases, CHCHD4 plays a crucial role in the formation of disulfide bridges that stabilize helix-coil-helix motifs of its substrates, significant variations on this common theme are observed, especially for substrates that have been more recently identified.
    Keywords:  p53; protein structure prediction; protein-protein interactions
    DOI:  https://doi.org/10.3390/molecules30102117
  32. EPMA J. 2025 Jun;16(2): 239-264
    Mitochondrial medicine: "from bench to bedside" 3PM-guided concept.
    Qianwen Shao, Marie Louise Ndzie Noah, Olga Golubnitschaja, Xianquan Zhan.
      Mitochondria are the primary sites for aerobic respiration and play a vital role in maintaining physiologic function at the cellular and organismal levels. Physiologic mitochondrial homeostasis, functions, health, and any kind of mitochondrial impairments are associated with systemic effects that are linked to the human health and pathologies. Contextually, mitochondria are acting as a natural vital biosensor in humans controlling status of physical and mental health in a holistic manner. So far, no any disorder is known as happening to humans independently from a compromised mitochondrial health as the cause (primary mitochondrial dysfunction) or a target of collateral damage (secondary mitochondrial injury). This certainty makes mitochondrial medicine be the superior instrument to reach highly ambitious objectives of predictive, preventive, and personalized medicine (PPPM/3PM). 3PM effectively implements the paradigm change from the economically ineffective reactive medical services to a predictive approach, targeted prevention and treatments tailored to individualized patient profiles in primary (protection against health-to-disease transition) and secondary (protection against disease progression) healthcare. Mitochondrial DNA (mtDNA) properties differ significantly from those of nuclear DNA (nDNA). For example, mtDNA as the cell-free DNA molecule is much more stable compared to nDNA, which makes mtDNA be an attractive diagnostic target circulating in human body fluids such as blood and tear fluid. Further, genetic variations in mtDNA contribute to substantial individual differences in disease susceptibility and treatment response. To this end, the current gene editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas, are still immature in mtDNA modification, and cannot be effectively applied in clinical practice posing a challenge for mtDNA-based therapies. In contrast, comprehensive multiomics technologies offer new insights into mitochondrial homeostasis, health, and functions, which enables to develop more effective multi-level diagnostics and targeted treatment strategies. This review article highlights health- and disease-relevant mitochondrial particularities and assesses involvement of mitochondrial medicine into implementing the 3PM objectives. By discussing the interrelationship between 3PM and mitochondrial medicine, we aim to provide a foundation for advancing early and predictive diagnostics, cost-effective targeted prevention in primary and secondary care, and exemplify personalized treatments creating proof-of-concept approaches for 3PM-guided clinical applications.
    Keywords:  Autophagy and mitophagy; Cancer; Cardio-vascular disease; Chronic Fatigue; Cost-effective tailored treatments; Environment; Health policy; Health-to-disease transition; Individualized patient profile; Metabolic disease; Mitochondrial medicine; Neurodegeneration; Predictive Preventive Personalized Medicine (PPPM / 3PM / 3P medicine); Signaling; Stress; Vital biosensor
    DOI:  https://doi.org/10.1007/s13167-025-00409-4
  33. Gerontology. 2025 May 26. 1-14
    The potential role of mitochondria in age-related health benefits conferred by moderate hypoxia.
    Johannes Burtscher, Kamilla Woznica Miskowiak, Katharina Hüfner, Hannelore Ehrenreich, Martin Kopp.
      Background Mitochondrial integrity and efficiency deteriorate with age and are linked to cellular senescence. Mitochondria are highly responsive to reduced oxygen availability (hypoxia), which for example occurs when exposed to altitude. We hypothesize that mitochondria are involved in the observed health benefits at moderate altitude. Because the experimental evidence on mitochondrial changes at moderate altitude is limited, we also evaluate dose-response associations of oxygen transport and mitochondrial functions derived from measurements at normoxia and severe hypoxia. Summary We summarize the effects of environmental oxygen availability and changes in cellular oxygen demand/supply on mitochondrial functions and assess, how this may influence aging. Hypotheses are presented how mild hypoxia at moderate altitude (1000 - 2500 m) could improve mitochondrial function and possibly explain the reported lower levels of mortality from several age-related diseases. Key messages It is unknown, whether continuous or intermittent types of hypoxia exposure are more effective in improving mitochondrial functions and promoting healthy aging. The combination of tissue-specific oxygen demand (for example during physical exercise) with mild reductions of ambient oxygen availability may enable the reported health benefits associated with moderate altitude residence.
    DOI:  https://doi.org/10.1159/000546478
  34. Mov Disord Clin Pract. 2025 May 29.
    Clinical Phenotype and Neuroimaging Findings in Siblings with COX15 Deficiency: Case Report and Review of Previously Reported Cases.
    Haya S AlFaris, Sangeetha Yoganathan, Marcus N Callister, Liali Aljouda, Vivek Pai, Pradeep Krishnan, Andrea LeBlanc-Millar, Christos Ganos, Carolina Gorodetsky.
      
    Keywords:  COX15 deficiency; Leigh syndrome; dystonia; mitochondrial disorders
    DOI:  https://doi.org/10.1002/mdc3.70135
  35. Sci Rep. 2025 May 30. 15(1): 19076
    Deep learning-driven automated mitochondrial segmentation for analysis of complex transmission electron microscopy images.
    Chan Jang, Hojun Lee, Jaejun Yoo, Haejin Yoon.
      Mitochondria are central to cellular energy production and regulation, with their morphology tightly linked to functional performance. Precise analysis of mitochondrial ultrastructure is crucial for understanding cellular bioenergetics and pathology. While transmission electron microscopy (TEM) remains the gold standard for such analyses, traditional manual segmentation methods are time-consuming and prone to error. In this study, we introduce a novel deep learning framework that combines probabilistic interactive segmentation with automated quantification of mitochondrial morphology. Leveraging uncertainty analysis and real-time user feedback, the model achieves comparable segmentation accuracy while reducing analysis time by 90% compared to manual methods. Evaluated on both benchmark Lucchi++ datasets and real-world TEM images of mouse skeletal muscle, the pipeline not only improved efficiency but also identified key pathological differences in mitochondrial morphology between wild-type and mdx mouse models of Duchenne muscular dystrophy. This automated approach offers a powerful, scalable tool for mitochondrial analysis, enabling high-throughput and reproducible insights into cellular function and disease mechanisms.
    Keywords:  Automated quantification; Deep learning segmentation; Interactive segmentation; Mitochondrial morphology; Transmission electron microscopy imaging; Uncertainty analysis
    DOI:  https://doi.org/10.1038/s41598-025-03311-1
  36. Front Aging Neurosci. 2025 ;17 1544241
    Review of FUNDC1-mediated mitochondrial autophagy in Alzheimer's disease.
    Dandan Shi, Xiaochen Guo, Ziqi Ning, Yaoyao Zhang, Fang Liu, Meixia Liu, Yun Wei.
      Mitochondrial autophagy is a critical quality control mechanism that eliminates dysfunctional mitochondria to maintain cellular homeostasis. Among receptor-dependent mitophagy pathways, FUN14 domain-containing 1 (FUNDC1)-a mitochondrial outer membrane protein harboring an LC3-interacting region (LIR)-plays a central role by directly binding to LC3 under stress conditions, thereby initiating autophagosome encapsulation of damaged organelles. Emerging evidence implicates FUNDC1 dysregulation in neurodegenerative diseases, particularly Alzheimer's disease (AD), where defective mitophagy exacerbates hallmark pathologies including Aβ plaque deposition and hyperphosphorylated Tau-driven neurofibrillary tangles. Despite advances, the molecular interplay between FUNDC1 phosphorylation states (e.g., Ser13/Ser17/Tyr18) and AD progression remains poorly defined. This review systematically examines FUNDC1's dual regulatory role in mitophagy, its mechanistic links to Aβ and Tau pathologies, and the therapeutic potential of targeting FUNDC1-associated kinases (e.g., ULK1, CK2) or downstream effectors (e.g., DRP1, OPA1) to counteract mitochondrial dysfunction in AD. By synthesizing recent preclinical and clinical findings, we aim to bridge the gap between FUNDC1 biology and AD therapeutics, highlighting actionable nodes for drug development.
    Keywords:  Alzheimer’s disease; FUNDC1 signaling pathway; mitochondrial autophagy; neurodegenerative diseases; signaling molecules
    DOI:  https://doi.org/10.3389/fnagi.2025.1544241
  37. Int J Mol Sci. 2025 May 13. pii: 4668. [Epub ahead of print]26(10):
    Cellular Metabolic Disorders in a Cohort of Patients with Sjogren's Disease.
    Julian L Ambrus, Alexander Jacob, Abhay A Shukla.
      Metabolism disorders have been seen in multiple autoimmune diseases, including SLE and Sjogren's disease. The current studies were designed to evaluate mutations in genes involved in metabolism in a cohort of patients with Sjogren's disease, diagnosed from clinical criteria and the presence of antibodies to salivary gland antigens. Patients were from an Immunology clinic that follows a large population of patients with autoimmune and metabolic disorders. The patients included in these studies were patients who met the criteria for Sjogren's disease and for whom we were able to obtain genetic studies, sequencing of the mitochondrial DNA, and whole exome sequencing. There were 194 of these patients, and 192 had mutations in one or more gene involved in metabolism: 188 patients had mutations in mitochondrial respiratory chain genes, 17 patients had mutations in mitochondrial tRNA genes, 10 patients had mutations in mitochondrial DLOOP regions, 6 patients had mutations involved in carnitine transport, 6 patients had mutations in genes causing mitochondrial depletion, and 7 patients had glycogen storage diseases. In all cases, the treatment of the metabolic disorder led to symptomatic improvement in energy, exercise tolerance, gastrointestinal dysmotility, and the management of infections. In conclusion, metabolic disorders are common in patients with Sjogren's disease and may be one of the factors leading to the initiation of the disease. The treatment of patients with Sjogren's disease should include the treatment of the underlying/associated metabolic disorder.
    Keywords:  Sjogren’s disease; autoantibodies; metabolism
    DOI:  https://doi.org/10.3390/ijms26104668
  38. Cell Tissue Res. 2025 May 26.
    Tissue-specific differences impacts therapeutic outcomes of mitochondrial transplantation through regulation of bioenergetics in metabolic syndrome.
    Jyotsna Pareek, Pallavi Mudgal, Nitika Sindhu, Vaibhav Tiwari, Dinesh Mani Tripathi, Swati Paliwal.
      Mitochondria transplantation is an emerging therapeutic strategy with remarkable potential in treating various diseases associated with mitochondrial dysfunction. Despite the known differences in tissue-specific mitochondria, the therapeutic outcomes of mitochondria isolated from various sources, after their transplantation in a specific disease model has remained elusive. In this study, we investigated the tissue-dependent therapeutic differences after transplantation of mitochondria isolated from heart, muscle, and liver tissues in a high-fat diet and streptozotocin, 35 mg/Kg (HFD + STZ) induced metabolic syndrome (MetS) in Wistar rats. We found striking differences in lowering of blood glucose levels, blood pressure, cholesterol, ALT, and AST levels in MetS after transplantation of mitochondria obtained from heart, muscle, and liver tissues (P < 0.01). Liver mitochondria transplantation demonstrated the most effective upregulation of mitochondrial complex activities, enhanced anti-oxidant enzyme levels in recipient liver tissues (P < 0.01). It also upregulated gene expression of genes associated with mitochondrial biogenesis and bioenergetics and reduced apoptosis and inflammation associated genes in HFD + STZ rats. In addition, GC-MS metabolite analysis revealed differential blood serum concentrations of key tri-carboxylic acid metabolites such as succinic acid, malic acid, alpha-ketoglutarate, citric acid, and pyruvate after mitochondrial transplantation in HFD + STZ rats. This study supports the idea that mitochondria source tissue should be considered to provide better clinical outcomes for mitochondrial transplantation.
    Keywords:  Metabolic syndrome; Mitochondrial transplantation; Therapeutic potential; Tissue source
    DOI:  https://doi.org/10.1007/s00441-025-03977-z
  39. Cells. 2025 05 08. pii: 679. [Epub ahead of print]14(10):
    Impact of Drp1 Loss on Organelle Interaction, Metabolism, and Inflammation in Mouse Liver.
    Lixiang Wang, Seiji Nomura, Nao Hasuzawa, Sadaki Yokota, Ayako Nagayama, Kenji Ashida, Junjiro Rikitake, Yoshinori Moriyama, Masatoshi Nomura, Ken Yamamoto.
      Dynamin-related protein 1 (Drp1) is a crucial player in mitochondrial fission and liver function. The interactions between mitochondria, endoplasmic reticulum (ER), and lipid droplets (LDs) are fundamental for lipid metabolism. This study utilized liver-specific Drp1 knockout (Drp1LiKO) mice to investigate the effects of Drp1 deficiency on organelle interactions, metabolism, and inflammation. Our analysis revealed disrupted interactions between mitochondria and LDs, as well as altered interactions among ER, mitochondria, and LDs in Drp1LiKO mice. Through mass spectrometry and microarray analysis, we identified changes in lipid profiles and perturbed expression of lipid metabolism genes in the livers of Drp1LiKO mice. Further in vitro experiments using primary hepatocytes from Drp1LiKO mice confirmed disturbances in lipid metabolism and increased inflammation. These findings highlight the critical involvement of Drp1 in regulating organelle interactions for efficient lipid metabolism and overall liver health. Targeting Drp1-mediated organelle interactions may offer potential for developing therapies for liver diseases associated with disrupted lipid metabolism.
    Keywords:  dynamin-related protein 1; lipid metabolism; liver inflammation; organelle interaction
    DOI:  https://doi.org/10.3390/cells14100679
  40. Spectrochim Acta A Mol Biomol Spectrosc. 2025 May 27. pii: S1386-1425(25)00794-2. [Epub ahead of print]342 126488
    Construction of a mitochondria-targeted NIR probe with large Stokes shift for real-time monitoring viscosity changes during ferroptosis.
    Yongfei Huang, Zifan Gao, Zhefeng Fan.
      Ferroptosis, an iron-dependent form of apoptosis, differs from the caspase-dependent apoptosis. Mitochondria plays an irreplaceable role in the ferroptosis processes. Compared with normal mitochondria, mitochondria of ferroptosis process are characterized by smaller mitochondrial membrane densities, mitochondrial crista may be reduced. The microenvironmental parameter viscosity is active in the physiological processes of mitochondrial respiration and metabolism. Abnormal mitochondrial viscosity concentration have been linked to many diseases, including diabetes, inflammation, atherosclerosis, and even cancer. Monitoring the change of mitochondrial viscosity is of great significance for understanding the occurrence of ferroptosis disease. So far, some fluorescent probes reported have short absorption and emission wavelengths and small Stokes shifts, which will affect its application in living tissues. In our work, we reported four novel mitochondria-targeted NIR fluorescent probes for viscosity detection. These probes contain different electron-donating groups, among which Mito-Vis-4 with large Stokes shift (200 nm) and mitochondrial targetable can be used image the viscosity changes during ferroptosis process. The results indicated that Mito-Vis-4 is a promising noninvasive and sensitive tool for monitor the viscosity changes in vivo.
    Keywords:  Ferroptosis; Large Stokes shift; Mitochondria-targeted; Near-infrared; Viscosity
    DOI:  https://doi.org/10.1016/j.saa.2025.126488
  41. Front Aging Neurosci. 2025 ;17 1519672
    Intervention strategies for Parkinson's disease: the role of exercise and mitochondria.
    Ganggang Xu, Chunlian Ma, Yi Yang.
      Parkinson's disease (PD), a progressive neurodegenerative disorder with complex pathogenic mechanisms, exhibiting rising prevalence alongside global population aging. Its pathological hallmarks include substantial loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor symptoms (e.g., bradykinesia, rigidity) and non-motor manifestations (e.g., cognitive impairment, sleep disorders). Accumulating evidence underscores mitochondrial dysfunction-encompassing reactive oxygen species (ROS) overproduction, defective mitophagy, and impaired biogenesis-as an important contributor to PD pathogenesis. Exercise, endorsed by leading medical and sports authorities as a non-pharmacological therapeutic strategy. While mitochondrial dysfunction impairs cellular energetics in PD patients, exercise can re-establish mitochondrial homeostasis through multiple pathways: stimulating neuroprotective exerkines, regulating mitochondrial ROS balance, modulating mitochondrial biogenesis and mitophagy, and enhancing brain-derived neurotrophic factor production. Many studies demonstrate that aerobic, resistance, and mind-body exercises demonstrably improve gait stability, postural control, and cognitive function in PD patients. However, standardized exercise prescriptions for PD prevention and treatment remain underutilized in clinical practice. This review synthesizes mitochondrial pathophysiology in PD progression, exercise-mediated regulatory mechanisms, and evidence-based exercise protocols, proposing accessible exercise regimens to support PD management. By integrating molecular insights with practical strategies, this work provides foundational evidence for utilizing exercise as a non-medical intervention against PD.
    Keywords:  PINK1; Parkinson’s disease; dopamine; exercise; mitochondria
    DOI:  https://doi.org/10.3389/fnagi.2025.1519672
  42. Nat Commun. 2025 May 27. 16(1): 4909
    Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.
    Yao Zhang, Peng Ma, Saifei Wang, Shuxin Chen, Hansong Deng.
      Breakdown of calcium network is closely associated with cellular aging. Previously, we found that cytosolic calcium (CytoCa2+) levels were elevated while mitochondrial calcium (MitoCa2+) levels were decreased and associated with metabolic shift in aged intestinal stem cells (ISCs) of Drosophila. How MitoCa2+ was decoupled from the intracellular calcium network and whether the reduction of MitoCa2+ drives ISC aging, however, remains unresolved. Here, we show that genetically restoring MitoCa2+ can reverse ISC functional decline and promote intestinal homeostasis by activating autophagy in aged flies. Further studies indicate that MitoCa2+ and Mitochondria-ER contacts (MERCs) form a positive feedback loop via IP3R to regulate autophagy independent of AMPK. Breakdown of this loop is responsible for MitoCa2+ reduction and ISC dysfunction in aged flies. Our results identify a regulatory module for autophagy initiation involving calcium crosstalk between the ER and mitochondria, providing a strategy to treat aging and age-related diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60196-4
  43. Genes (Basel). 2025 Apr 30. pii: 538. [Epub ahead of print]16(5):
    ACADVL Deep Sequencing in a Case Study: Beyond the Common c.848T>C Pathogenic Variant.
    Francesco Baldo, Luisa Zupin, Andrea Magnolato, Valeria Capaci, Maria Teresa Bonati.
      Background: Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is caused by biallelic pathogenic variants in ACADVL (acyl-CoA dehydrogenase very-long-chain), leading to impaired fatty acid oxidation and the accumulation of long-chain acylcarnitine. We report a single case of a two-year-old girl, whose neonatal metabolic screening revealed an acylcarnitine profile suggestive of VLCADD, with residual enzymatic activity of 19.8%. Methods: We performed ACADVL whole-gene sequencing. We then carried out an in silico analysis of the potential effects of the variants with dedicated tools, assessing splicing, RNA structure, RNA binding factors, and protein structure. We also conducted gene expression analysis. Results: Genetic testing identified her as compound heterozygous for the pathogenic ACADVL variant (NM_000018.3):c.848T>C, inherited from her mother, and for the two paternal variants, c.-64T>C in the basal promoter and c.957G>A, a synonymous substitution in exon 10. Gene expression analysis revealed reduced ACADVL mRNA levels in the proband's blood cells but without abnormal isoform production. A decreased expression of the paternal allele carrying the 957A was also observed. Despite this significant reduction in mRNA levels, the underlying mechanism remains unclear. Conclusions: Although currently healthy, due to the VLCAD residual activity within the range associated with the mild form of the disease, the child might be at potential risk for metabolic decompensation or late-onset VLCADD. Our results indicated an allelic imbalance in mRNA expression and c.957G>A is identified as a hypomorphic allele. This suggests that deep ACADVL sequencing is a valuable tool for correlating genetic variants with enzymatic activity levels.
    Keywords:  ACADVL; gene expression; metabolic newborn screening; plasma acetylcarnitine profile; synonymous hypomorphic variants; white blood cell VLCAD assay
    DOI:  https://doi.org/10.3390/genes16050538
  44. Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2501022122
    Cardiolipin membranes drive Myosin VI activation, oligomerization, and processive cargo transport.
    Antonino F Montanarella, Nikolas Hundt, Dominik Keim, Aron Venczel, Felix Zierhut, Simon Langnickel, Andreas Graw, Markus Kröss, Johannes Dietrich, Dario Saczko-Brack, Claudia Veigel.
      Mitochondrial damage determines cell fate, leading to mitochondrial autophagy or cellular apoptosis in health and disease. The molecular mechanisms and role of the acto-myosin cytoskeleton regulating mitochondrial clearance and membrane remodeling are critical in neurodegenerative disease progression including Alzheimer, but remain unclear. To investigate the potential link between full-length Myosin VI (FL-Myo6) recruitment and exposure of the mitochondria-specific lipid cardiolipin (CL), here we adapted a combination of molecular biology, biochemical, high-resolution fluorescence and interferometric light-scattering techniques. We developed analysis tools to reveal the structural Myo6-CL interaction sites, Myo6-oligomerization interfaces and mechanical properties. We found that CL activates backfolded FL-Myo6 and induces Myo6-oligomerization. Myo6 bound to CL cargo-vesicles in vitro mediates processive runs over >500 nm at >90 nm s-1. We propose a model how CL-interaction regulates backfolded Myo6 activation into a highly processive cargo-bound motor.
    Keywords:  cardiolipin; cytoskeleton; iSCAT; membranes; motility
    DOI:  https://doi.org/10.1073/pnas.2501022122
  45. Nature. 2025 May 28.
    CoQ imbalance drives reverse electron transport to disrupt liver metabolism.
    Renata L S Goncalves, Zeqiu Branden Wang, Jillian K Riveros, Güneş Parlakgül, Karen E Inouye, Grace Yankun Lee, Xiaorong Fu, Jani Saksi, Clement Rosique, Sheng Tony Hui, Mar Coll, Ana Paula Arruda, Shawn C Burgess, Isabel Graupera, Gökhan S Hotamışlıgil.
      Mitochondrial reactive oxygen species (mROS) are central to physiology1,2. Excess mROS production has been associated with several disease states2,3; however, the precise sources, regulation and mechanism of generation in vivo remain unclear, which limits translational efforts. Here we show that in obesity, hepatic coenzyme Q (CoQ) synthesis is impaired, which increases the CoQH2 to CoQ (CoQH2/CoQ) ratio and drives excessive mROS production through reverse electron transport (RET) from site IQ in complex I. Using multiple complementary genetic and pharmacological models in vivo, we demonstrate that RET is crucial for metabolic health. In patients with steatosis, the hepatic CoQ biosynthetic program is also suppressed, and the CoQH2/CoQ ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s41586-025-09072-1
  46. Cell Death Discov. 2025 May 30. 11(1): 259
    Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy.
    Shi-Qi Yao, Jia-Jian Liang, Hui Zhou, Shaoying Tan, Yingjie Cao, Chong-Bo Chen, Ciyan Xu, Ruixi Wang, Tai-Ping Li, Fang-Fang Zhao, Yun Wang, Han-Jie He, Dan Zhang, Meng Wang, Lifang Liu, Patrick Yu-Wai-Man, Shihui Wei, Ling-Ping Cen.
      Autosomal dominant optic atrophy (ADOA) caused by mutations in the nuclear-encoded OPA1 gene result in the preferential loss of retinal ganglion cells (RGCs) and progressive optic nerve degeneration. The severity of ADOA can be highly variable. This study compared the pathophysiological consequences of the c.1034 G > A OPA1 missense mutation and the c.1305+2delGT OPA1 deletion. There was a significant correlation between the severity of visual loss and the extent of macular RGC loss as determined by optical coherence tomography imaging. In cells transfected with the c.1034 G > A mutant, the percentage of fragmented mitochondria was greater than 60% with cytochrome c (cyt c) overflow, and significantly elevated levels of reactive oxygen species (ROS) and apoptosis. In contrast, the c.1305+2delGT mutant caused mitochondrial fragmentation in ~ 20% of HeLa cells, resulting in less cyt c overflow and apoptosis. The extent of mitochondrial network fragmentation and apoptosis increased with decreasing WT OPA1 mRNA expression levels. The c.1034 G > A OPA1 missense mutation is likely to induce a dominant-negative effect compared with haploinsufficiency with the c.1305+2delGT OPA1 deletion. These contrasting pathophysiological mechanisms could influence disease severity in ADOA through their differential consequences on mitochondrial structure and function. The small drug molecule Paromomycin was able to rescue the mitochondrial fragmentation induced by the c.1034 G > A mutation, providing proof-of-concept for further therapeutic validation in ADOA.
    DOI:  https://doi.org/10.1038/s41420-025-02442-8
  47. Nat Commun. 2025 May 30. 16(1): 5041
    In vivo structure profiling reveals human cytosolic and mitochondrial tRNA structurome and interactome in response to stress.
    Noah Peña, Yichen Hou, Christopher P Watkins, Sihao Huang, Wen Zhang, Christopher D Katanski, Tao Pan.
      Transfer RNA (tRNA) is the most abundant cellular RNA family in terms of copy numbers. It not only folds into defined structures but also has complex cellular interaction networks involving aminoacyl-tRNA synthetases, translation factors, and ribosomes. The human tRNAome is comprised of chromosomal-encoded tRNAs with a large sequence diversity and mitochondrial-encoded tRNAs with A/U-rich sequences and noncanonical tertiary interactions. How tRNA folding and interactions in a eukaryotic cell respond to stress is poorly understood. Here, we develop DM-DMS-MaPseq, which utilizes in vivo dimethyl-sulfate (DMS) chemical probing and mutational profiling (MaP) coupled with demethylase (DM) treatment in transcriptome-wide tRNA sequencing to profile structures and the cellular interactions of human chromosomal and mitochondrial-encoded tRNAs. We found that tRNAs maintain stable structures in vivo, but the in vivo DMS profiles are vastly different from those in vitro, which can be explained by their interactions with cellular proteins and the ribosome. We also identify cytosolic and mitochondrial tRNA structure and interaction changes upon arsenite treatment, a type of oxidative stress that induces translational reprogramming, which is consistent with global translation repression in both compartments. Our results reveal variations of tRNA structurome and dynamic interactome that have functional consequences in translational regulation.
    DOI:  https://doi.org/10.1038/s41467-025-59435-5
  48. Nat Commun. 2025 May 26. 16(1): 4871
    Multi-organ metabolome biological age implicates cardiometabolic conditions and mortality risk.
    MULTI consortium
      Multi-organ biological aging clocks across different organ systems have been shown to predict human disease and mortality. Here, we extend this multi-organ framework to plasma metabolomics, developing five organ-specific metabolome-based biological age gaps (MetBAGs) using 107 plasma non-derivatized metabolites from 274,247 UK Biobank participants. Our age prediction models achieve a mean absolute error of approximately 6 years (0.25<r < 0.42). Crucially, including composite metabolites (e.g. sums or ratios of raw metabolites) results in poor generalizability to independent test data due to multicollinearity. Genome-wide associations identify 405 MetBAG-locus pairs (P < 5 × 10-8/5). Using SBayesS, we estimate the SNP-based heritability (0.09< hSNP2  < 0.18), negative selection signatures (-0.93 < S < -0.76), and polygenicity (0.001<Pi < 0.003) for the 5 MetBAGs. Genetic correlation and Mendelian randomization analyses reveal potential causal links between the 5 MetBAGs and cardiometabolic conditions (e.g., metabolic disorders and hypertension). Integrating multi-organ and multi-omics features improves disease category and mortality predictions. The 5 MetBAGs extend existing biological aging clocks to study human aging and disease across multiple biological scales. All results are publicly available at https://labs-laboratory.com/medicine/ .
    DOI:  https://doi.org/10.1038/s41467-025-59964-z
  49. Ther Adv Rare Dis. 2025 Jan-Dec;6:6 26330040251339204
    From roadmap to a sustainable end-to-end individualized therapy pathway.
    Anneliene H Jonker, Elena-Alexandra Tataru, David P Dimmock, Alison Bateman-House, Holm Graessner, Gareth Baynam, Erika F Augustine, Adam Jaffe, Anna M G Pasmooij, Oxana Iliach, Richard Horgan, James Davies, Shruti Mitkus, Larissa Lapteva, Matthis Synofzik, Timothy W Yu, Daniel O'Connor, Annemieke Aartsma-Rus.
      The field of individualized, or N-of-1, therapy development is growing and increasingly gaining attention as a novel option for people with serious diseases, caused by unique genetic variants for whom approved therapies are not available. The N-of-1 taskforce of the International Rare Disease Research Consortium previously outlined a roadmap of aspects involved in N-of-1 therapy development and implementation. Here, this follow-up paper looks forward and reflects on how to address existing gaps to advance the current state of individualized interventions toward an integrated and sustainable treatment development model. It discusses what needs to be established for N-of-1 therapies to be developed and utilized at a larger scale, which involves features like sustainability; safety; efficacy; regulatory aspects; dedicated registries and data sharing; tools; long-term treatment monitoring; partnering with patient advocates; and reimbursement models. It closes with recommendations to shape the future of individualized therapies, focusing on ethical implications, education, creation of tools, incentives for data sharing, and innovative payment models.
    Keywords:  N-of-1 therapy; data sharing; education; individualized therapies; patient engagement; payment models
    DOI:  https://doi.org/10.1177/26330040251339204
  50. EMBO Mol Med. 2025 May 27.
    Ontology-guided clustering enables proteomic analysis of rare pediatric disorders.
    Ericka C M Itang, Vincent Albrecht, Alicia-Sophie Schebesta, Marvin Thielert, Anna-Lisa Lanz, Katharina Danhauser, Jessica Jin, Tobias Prell, Sophie Strobel, Christoph Klein, Matthias Mann, Susanne Pangratz-Fuehrer, Johannes Mueller-Reif.
      The study of rare pediatric disorders is fundamentally limited by small patient numbers, making it challenging to draw meaningful biological conclusions. To address this, we developed a framework integrating clinical ontologies with proteomic profiling, enabling the systematic analysis of rare conditions in aggregate. We applied this approach to urine and plasma samples from 1140 children and adolescents, encompassing 394 distinct disease conditions and healthy controls. Using advanced mass spectrometry workflows, we quantified over 5000 proteins in urine, 900 in undepleted (neat) plasma, and 1900 in perchloric acid-depleted plasma. Embedding SNOMED CT clinical terminology in a network structure allowed us to group rare conditions based on their clinical relationships, enabling statistical analysis even for diseases with as few as two patients. This approach revealed molecular signatures across developmental stages and disease clusters while accounting for age- and sex-specific variation. Our framework provides a generalizable solution for studying heterogeneous patient populations where traditional case-control studies are impractical, bridging the gap between clinical classification and molecular profiling of rare diseases.
    Keywords:  Pediatrics; Plasma; Proteomics; SNOMED CT; Urine
    DOI:  https://doi.org/10.1038/s44321-025-00253-z
  51. J Transl Med. 2025 May 26. 23(1): 586
    Blood RNA-seq in rare disease diagnostics: a comparative study of cases with and without candidate variants.
    Xiaomei Luo, Bing Xiao, Lili Liang, Kaichuang Zhang, Ting Xu, Huili Liu, Yi Liu, Yongguo Yu, Yanjie Fan.
       BACKGROUND: Approximately 60% of rare disease cases remain unsolved after exome and genome sequencing (ES/GS). Blood RNA sequencing (RNA-seq) complements DNA-level diagnosis by revealing the functional impact of variants on gene expression and splicing, but to what extent RNA-driven approaches offer diagnostic benefits across different scenarios-with and without pre-existing candidate variants-remains uncertain.
    METHODS: 128 unrelated probands with suspected Mendelian disorders who had previously undergone ES/GS were recruited. A validation cohort (n = 7, with variants expected to alter RNA) and a test cohort (n = 121, including 10 with variants of uncertain significance (VUS) and 111 with no previously identified candidate variants) were analyzed. Blood RNA-seq was performed, and aberrant splicing (AS) and aberrant expression (AE) were detected using the DROP pipeline. SpliceAI predictions were compared with RNA-seq results for splicing-related VUS variants, and pathogenicity was re-evaluated. AS/AE outliers were evaluated for diagnostic potential in cases without candidate variants. The feasibility of an RNA-driven approach was assessed by ranking causal variant-associated aberrant events.
    RESULTS: The pipeline correctly identified all expected AS/AE events in the validation cohort. In the test cohort with candidate VUS, RNA-seq provided a 60% (6/10) diagnostic uplift. Notably, SpliceAI predictions matched RNA-seq observations perfectly only in 40% of these VUS. A 2.7% (3/111) diagnostic uplift was achieved in the test cohort with no prior candidates. Overall, target AS and AE events ranked among the top eight in 14 of the 16 diagnosed cases using a purely RNA-driven approach; however, two cases would have been missed without prior candidate identification from DNA sequencing.
    CONCLUSION: Blood RNA-seq is highly effective in refining the interpretation of splicing VUS, frequently leading to reclassification and diagnosis. Meanwhile, RNA-driven identification of causal variants shows a more modest yield in cases without prior candidates. This study supports an RNA-complementary approach as the preferred strategy for clinical utility.
    Keywords:  Clinical practice; Genome sequencing; RNA sequencing; Undiagnosed rare disease; Variant interpretation
    DOI:  https://doi.org/10.1186/s12967-025-06609-w
  52. EMBO Rep. 2025 May 27.
    LRRK2 interactions with microtubules are independent of LRRK2-mediated Rab phosphorylation.
    Tuyana Malankhanova, Zhiyong Liu, Enquan Xu, Nicole Bryant, Ki Woon Sung, Huizhong Li, Samuel Strader, Andrew B West.
      Deregulated microtubules are common defects associated with neurodegenerative diseases. Recent cryo-electron microscopy studies in cell lines overexpressing Parkinson's disease-associated LRRK2 suggest microtubule surfaces may regulate kinase activity by stabilizing different LRRK2 conformations. In macrophages with high endogenous LRRK2 expression, we find that nocodazole treatment destabilizes microtubules and impairs LRRK2-mediated Rab phosphorylation. GTP supplementation restores nocodazole-reduced Rab phosphorylation, linking LRRK2 kinase action to cellular GTP levels. Chemical microtubule stabilization, and kinetically trapping LRRK2 to microtubule surfaces, has negligible effects on Rab phosphorylation. In contrast, trapping LRRK2 to LAMP1-positive membranes upregulates LRRK2-mediated Rab phosphorylation. Proximity-labeling proteomics and colocalization studies show that LRRK2 robustly interacts with both polymerized and free tubulin transiently and independently of LRRK2 kinase activity. Endogenous LRRK2 complexed with type I inhibitors in neurons and macrophages fails to stably interact with microtubules, whereas bulky N-terminal tags fused to LRRK2 promotes stable microtubule binding in cell lines. Collectively, these results show that tubulin isoforms and microtubules are transient LRRK2-interacting proteins non-essential for LRRK2-mediated Rab phosphorylation.
    Keywords:  Cell Signaling; Cytoskeleton; GTPase; Parkinson’s Disease; Protein Kinase
    DOI:  https://doi.org/10.1038/s44319-025-00486-6
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