bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–04–06
forty-five papers selected by
Catalina Vasilescu, Helmholz Munich
  1. An engineered mitoCBE facilitates efficient mitochondrial DNA editing and modified mitochondrial transfer.
  2. Understanding mitochondrial protein import: a revised model of the presequence translocase.
  3. Diagnosis of Primary Mitochondrial Diseases.
  4. Retromer promotes the lysosomal turnover of mtDNA.
  5. An inherited mtDNA rearrangement, mimicking a single large-scale deletion, associated with MIDD and a primary cardiological phenotype.
  6. α-Synuclein pathology and mitochondrial dysfunction: Toxic partners in Parkinson's disease.
  7. Investigating the safety and efficacy of deoxycytidine/deoxythymidine in mitochondrial DNA depletion disorders: phase 2 open-label trial.
  8. The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation.
  9. Representing Mitochondrial Dynamics with Abstract Algebra.
  10. An updated compendium and reevaluation of the evidence for nuclear transcription factor occupancy over the mitochondrial genome.
  11. FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome: A rare cause of hyperammonemia.
  12. Characterization of a new mutation of mitochondrial ND6 gene in hepatocellular carcinoma and its effects on respiratory complex I.
  13. Mitochondrial heat production: the elephant in the lab….
  14. Mitochondrial fusion protein: a new therapeutic target for lung injury diseases.
  15. PCSK9 Regulates Cardiac Mitochondrial Cholesterol by Promoting TSPO Degradation.
  16. DNM1L-mediated fission governs mitophagy & mitochondrial biogenesis during myogenic differentiation.
  17. What can ATP content tell us about Barth syndrome muscle phenotypes?
  18. Cardiomyopathy in a c.1528G>C Hadha Mouse is associated with Cardiac Tissue Lipotoxicity and Altered Cardiolipin Species.
  19. Method for Detecting Mitochondrial ATP by Hybridization Chain Reaction.
  20. Perceived association of mood and symptom severity in adults with mitochondrial diseases.
  21. The Silent Saboteur: How Mitochondria Shape the Long-Term Fate of the Injured Brain.
  22. PPM1M, a LRRK2-counteracting, phosphoRab12-preferring phosphatase with potential link to Parkinson's disease.
  23. Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms including sleep.
  24. Review: Utility of mass spectrometry in rare disease research and diagnosis.
  25. Detection of liver mitochondrial oxaloacetate by NMR spectroscopy and membrane potential-dependent accumulation.
  26. Profiling mitochondrial DNA variant segregation during human preimplantation development: a prerequisite to preimplantation genetic testing for mitochondrial DNA-related disorders.
  27. Pathogenic mutation impairs functional dynamics of Hsp60 in mono- and oligomeric states.
  28. Atf3 controls transitioning in female mitochondrial cardiomyopathy as identified by spatial and single-cell transcriptomics.
  29. A drug screening platform for protein expression levels in neurological disorders.
  30. Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation.
  31. Restoration of Miro1's N-terminal GTPase function alleviates prenatal stress-induced mitochondrial fission via Drp1 modulation.
  32. Aberrant gene expression prediction across human tissues.
  33. Targeting mitochondria-regulated ferroptosis: A new frontier in Parkinson's Disease therapy.
  34. Mild activation of the mitochondrial unfolded protein response increases lifespan without increasing resistance to stress.
  35. Mpf1 affects the dual distribution of tail-anchored proteins between mitochondria and peroxisomes.
  36. What Is the Role of Inner Membrane Metalloproteases in Mitochondrial Quality Control and Disease?
  37. Structural bioinformatic study of human mitochondrial respiratory integral membrane megacomplex and its AlphaFold3 predicted water-soluble QTY megacomplex analog.
  38. Re-Analysis Yields Diagnosis in Over 500 Patients with Rare Diseases.
  39. Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.
  40. Current Trends in Gene Therapy to Treat Inherited Disorders of the Brain.
  41. Identifying novel drug targets with computational precision.
  42. Medium-Chain Acyl-CoA Dehydrogenase Deficiency Disorder as a Cause of Acute Liver Failure in a 23-Month-Old Baby.
  43. Elucidating neuroepigenetic mechanisms to inform targeted therapeutics for brain disorders.
  44. DNAJC30 Mutation in a Patient with Coexisting Leber's Hereditary Optic Neuropathy and Multiple Sclerosis (Harding's Syndrome): A Case Report.
  45. NLRP10 Cleaves Oxidized DNA inhibited by OGG1 inhibitors: A Newly Identified Role in DNA Damage Processing and Senescence Regulation.
  1. Mol Ther. 2025 Apr 03. pii: S1525-0016(25)00260-6. [Epub ahead of print]
    An engineered mitoCBE facilitates efficient mitochondrial DNA editing and modified mitochondrial transfer.
    Jie Liu, Jun Chen, Shisheng Huang, Junfan Guo, Xiangyang Li, Ying Yan, Ruijing Chen, Guanglei Li, Ming Liu, Jiao Wei, Xingxu Huang, Yunbo Qiao.
      Double-stranded DNA (dsDNA) cytosine deaminase DddA orthologs from multiple types of bacteria have been fused with TALE system for mitochondrial DNA (mtDNA) base editing, while the efficiencies remain limited and its nuclear off-targeting activity cannot be ignored yet. Here we identified a DddA ortholog from Burkholderia gladioli (BgDddA) and generated nuclear or mitochondrial DNA cytosine base editors (mitoCBEs), exhibiting higher C•G-to-T•A editing frequencies compared to canonical DdCBE, and fusion with transactivator Rta remarkably improved editing efficiencies by up to 6.4-fold at non-TC targets. Referring to DddA11, we further introduced six substitutions into BgDddA and generated mitoCBE3.2, which efficiently induced disease-associated mtDNA mutations in mouse and human cell lines at both TC and non-TC targets with efficiency reaching up to 99.2%. Using mitoCBE3.2, single clones containing homoplasmic mtDNA mutations or premature stop codons associated with human diseases were generated, and the functions of these mutations have been evaluated upon the treatment of ROS inducers. Importantly, mitochondria harboring these homoplasmic mutations were transplanted into wildtype cells, enabling precise base conversions, without risk of nuclear gene off-targets. Thus, we have engineered an efficient mitoCBE using BgDddA, facilitating mitochondrial disease modeling and potential mutation correction with the aid of mitochondrial transplantation.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.03.051
  2. Trends Biochem Sci. 2025 Mar 27. pii: S0968-0004(25)00050-7. [Epub ahead of print]
    Understanding mitochondrial protein import: a revised model of the presequence translocase.
    Naintara Jain, Agnieszka Chacinska, Peter Rehling.
      Mitochondrial function relies on the precise targeting and import of cytosolic proteins into mitochondrial subcompartments. Most matrix-targeted proteins follow the presequence pathway, which directs precursor proteins across the outer mitochondrial membrane (OMM) via the Translocase of the Outer Membrane (TOM) complex and into the matrix or inner mitochondrial membrane (IMM) via the Translocase of the Inner Membrane 23 (TIM23) complex. While classical biochemical studies provided detailed mechanistic insights into the composition and mechanism of the TIM23 complex, recent cryogenic-electron microscopy (cryo-EM) data challenge these established models and propose a revised model of translocation in which the TIM17 subunit acts as a 'slide' for precursor proteins, with Tim23 acting as a structural element. In this review, we summarize existing models, highlighting the questions and data needed to reconcile these perspectives, and enhance our understanding of TIM23 complex function.
    Keywords:  inner mitochondrial membrane (IMM); mitochondria; presequence pathway; protein sorting; protein translocation; translocase of the inner membrane 23 (TIM23)
    DOI:  https://doi.org/10.1016/j.tibs.2025.03.001
  3. Muscle Nerve. 2025 Apr 03.
    Diagnosis of Primary Mitochondrial Diseases.
    Salman Bhai, Michio Hirano.
      Primary mitochondrial diseases are clinically heterogeneous and present diagnostic challenges due to the highly variable genotype-phenotype correlation. Clinical symptoms can range from non-specific fatigue, exercise intolerance, and weakness to syndromic phenotypes. Though multiple testing modalities exist to identify mitochondrial diseases, most of these tests are nonspecific, or results are associated with other diseases. Molecular testing can provide an efficient path toward diagnosis, as molecular detection techniques have improved and become less costly. A "genetics first" approach can reduce diagnostic delay and improve management, where the diagnostic pathway can be an invasive or noninvasive combination of targeted or comprehensive molecular testing. Prior to ordering these tests, clinicians must consider the ambiguities and nuances of various testing modalities during the work-up for mitochondrial diseases. Therefore, due to the diagnostic challenges associated with primary mitochondrial diseases, diagnosis should be made in the context of clinical and molecular data, potentially supplemented with histochemical and biochemical evidence. Confirmation of a diagnosis leads to improvements in the management of the disease, decreases unnecessary testing, informs reproductive planning, and improves research pipelines.
    Keywords:  genetic testing; mitochondria; mitochondrial disease; mitochondrial myopathy; primary mitochondrial disease
    DOI:  https://doi.org/10.1002/mus.28387
  4. Sci Adv. 2025 Apr 04. 11(14): eadr6415
    Retromer promotes the lysosomal turnover of mtDNA.
    Parisa Kakanj, Mari Bonse, Arya Kshirsagar, Aylin Gökmen, Felix Gaedke, Ayesha Sen, Belén Mollá, Elisabeth Vogelsang, Astrid Schauss, Andreas Wodarz, David Pla-Martín.
      Mitochondrial DNA (mtDNA) is exposed to multiple insults produced by normal cellular function. Upon mtDNA replication stress, the mitochondrial genome transfers to endosomes for degradation. Using proximity biotinylation, we found that mtDNA stress leads to the rewiring of the mitochondrial proximity proteome, increasing mitochondria's association with lysosomal and vesicle-related proteins. Among these, the retromer complex, particularly VPS35, plays a pivotal role by extracting mitochondrial components. The retromer promotes the formation of mitochondrial-derived vesicles shuttled to lysosomes. The mtDNA, however, directly shuttles to a recycling organelle in a BAX-dependent manner. Moreover, using a Drosophila model carrying a long deletion on the mtDNA (ΔmtDNA), we found that ΔmtDNA activates a specific transcriptome profile to counteract mitochondrial damage. Here, Vps35 expression restores mtDNA homoplasmy and alleviates associated defects. Hence, we demonstrate the existence of a previously unknown quality control mechanism for the mitochondrial matrix and the essential role of lysosomes in mtDNA turnover to relieve mtDNA damage.
    DOI:  https://doi.org/10.1126/sciadv.adr6415
  5. Mitochondrion. 2025 Mar 29. pii: S1567-7249(25)00034-0. [Epub ahead of print]83 102037
    An inherited mtDNA rearrangement, mimicking a single large-scale deletion, associated with MIDD and a primary cardiological phenotype.
    Piervito Lopriore, Andrea Legati, Christiane Michaela Neuhofer, Annalisa Lo Gerfo, Robert Kopajtich, Marco Barresi, Giulia Cecchi, Martin Pavlov, Rossella Izzo, Vincenzo Montano, Maria Adelaide Caligo, Riccardo Berutti, Michelangelo Mancuso, Holger Prokisch, Daniele Ghezzi.
       AIM: To identify the genetic cause in a previously unsolved pedigree, with mother and two daughters suffering of dilated cardiomyopathy with prevailing arrhythmic burden associated with diabetes mellitus and sensorineural hearing loss, without clear evidence of progressive external ophthalmoplegia.
    METHODS: Several genetic tests were performed over the years including single-gene sequencing, mitochondrial DNA (mtDNA) sequencing, NGS panel for mitochondrial diseases and cardiomyopathies, clinical exome sequencing and whole exome sequencing. Specific amplifications and long-read NGS were used to evaluate mtDNA structural alterations.
    RESULTS: By means of whole exome sequencing we found a novel heteroplasmic 12 kb-long single deletion in the mtDNA in all affected family members, confirmed by long-range PCR. However, a deeper investigation by long-read NGS revealed indeed the presence of rearranged mtDNA species, formed by a wild-type plus a deleted molecule. This mtDNA duplication turned out to be inherited in our pedigree and present in all tested specimens.
    CONCLUSION: While mtDNA single large-scale deletions are generally considered sporadic, few old reports described maternally inherited mtDNA duplication We suggest that mtDNA large rearrangements should be considered as possible disease causes in familial cases with unusual mitochondrial phenotypes. Long-read sequencing is useful for the detection of these variants, particularly mtDNA duplications.
    Keywords:  MIDD (Maternally Inherited Diabetes and Deafness); Mitochondrial DNA; Single large-scale deletion; Structural rearrangement; mtDNA; mtDNA duplication
    DOI:  https://doi.org/10.1016/j.mito.2025.102037
  6. Neurobiol Dis. 2025 Mar 27. pii: S0969-9961(25)00105-6. [Epub ahead of print]209 106889
    α-Synuclein pathology and mitochondrial dysfunction: Toxic partners in Parkinson's disease.
    Yakum B Mingo, Martha L Escobar Galvis, Michael X Henderson.
      Two major neuropathological features of Parkinson's disease (PD) are α-synuclein Lewy pathology and mitochondrial dysfunction. Although both α-synuclein pathology and mitochondrial dysfunction may independently contribute to PD pathogenesis, the interaction between these two factors is not yet fully understood. In this review, we discuss the physiological functions of α-synuclein and mitochondrial homeostasis in neurons as well as the pathological defects that ensue when these functions are disturbed in PD. Recent studies have highlighted that dysfunctional mitochondria can become sequestered within Lewy bodies, and cell biology studies have suggested that α-synuclein can directly impair mitochondrial function. There are also PD cases caused by genetic or environmental perturbation of mitochondrial homeostasis. Together, these studies suggest that mitochondrial dysfunction may be a common pathway to neurodegeneration in PD, triggered by multiple insults. We review the literature surrounding the interaction between α-synuclein and mitochondria and highlight open questions in the field that may be explored to advance our understanding of PD and develop novel, disease-modifying therapies.
    Keywords:  Cell death; Mitochondrial complex I; PINK1; Parkin; mtDNA; α-Synuclein
    DOI:  https://doi.org/10.1016/j.nbd.2025.106889
  7. J Neurol. 2025 Apr 02. 272(4): 307
    Investigating the safety and efficacy of deoxycytidine/deoxythymidine in mitochondrial DNA depletion disorders: phase 2 open-label trial.
    Saoussen Berrahmoune, Christelle Dassi, Heather Pekeles, Anthony C T Cheung, Tommy Gagnon, Paula J Waters, Daniela Buhas, Kenneth A Myers.
       OBJECTIVE: Mitochondrial DNA depletion disorders are rare genetic disorders involving mitochondrial dysfunction. These diseases are genetically and clinically heterogeneous but share the common feature of progressively degenerative courses. At present, there are no approved treatments for mitochondrial DNA depletion disorders, though recent reports have suggested that treatment with deoxycytidine/deoxythymidine could be effective for subtypes caused by pathogenic variants in two specific genes, POLG and TK2. We investigated the therapeutic potential of deoxycytidine/deoxythymidine for people with mitochondrial DNA depletion disorders due to pathogenic variants in genes other than POLG and TK2.
    METHODS: We analyzed interim data from an open-label clinical trial of deoxycytidine/deoxythymidine for treatment of mitochondrial DNA depletion disorders, specifically examining disorders due to pathogenic variants in genes other than POLG and TK2. Outcome measures included Newcastle Mitochondrial Disease Scale score and serum growth differentiation factor 15, a mitochondrial function biomarker.
    RESULTS: Data were available from eight individuals having pathogenic variants in FBXL4, SUCLG1, SUCLA2, or RRM2B. Newcastle Mitochondrial Disease Scale score improved in all individuals except for one who withdrew before the first follow-up visit; group level analysis was significant at 1-month and 6-month timepoints. Five patients had elevated growth differentiation factor 15 at baseline; of these, levels improved in four, including three whose values normalized.
    CONCLUSION: These data suggest deoxycytidine/deoxythymidine is a safe and therapeutically promising intervention for a broad range of mitochondrial DNA depletion disorders.
    Keywords:  Deoxycytidine; Deoxynucleoside; Deoxythymidine; FBXL4; Pyrimidine; SUCLG1
    DOI:  https://doi.org/10.1007/s00415-025-13060-w
  8. Life Sci Alliance. 2025 Jun;pii: e202402921. [Epub ahead of print]8(6):
    The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation.
    Mashiat Zaman, Govinda Sharma, Walaa Almutawa, Tyler Gb Soule, Rasha Sabouny, Matt Joel, Armaan Mohan, Cole Chute, Jeffrey T Joseph, Gerald Pfeffer, Timothy E Shutt.
      Pathogenic variants in the mitochondrial protein MFN2 are typically associated with a peripheral neuropathy phenotype, but can also cause a variety of additional pathologies including myopathy. Here, we identified an uncharacterized MFN2 variant, Q367H, in a patient diagnosed with late-onset distal myopathy, but without peripheral neuropathy. Supporting the hypothesis that this variant contributes to the patient's pathology, patient fibroblasts and transdifferentiated myoblasts showed changes consistent with impairment of several MFN2 functions. We also observed mtDNA outside of the mitochondrial network that colocalized with early endosomes, and measured activation of both TLR9 and cGAS-STING inflammation pathways that sense mtDNA. Re-expressing the Q367H variant in MFN2 KO cells also induced mtDNA release, demonstrating this phenotype is a direct result of the variant. As elevated inflammation can cause myopathy, our findings linking the Q367H MFN2 variant with elevated TLR9 and cGAS-STING signalling can explain the patient's myopathy. Thus, we characterize a novel MFN2 variant in a patient with an atypical presentation that separates peripheral neuropathy and myopathy phenotypes, and establish a potential pathomechanism connecting MFN2 dysfunction to mtDNA-mediated inflammation.
    DOI:  https://doi.org/10.26508/lsa.202402921
  9. bioRxiv. 2025 Mar 28. pii: 2025.03.17.643721. [Epub ahead of print]
    Representing Mitochondrial Dynamics with Abstract Algebra.
    Raphael Mostov, Greyson R Lewis, Gabriel Sturm, Wallace F Marshall.
      This paper addresses the increasing need for comprehensive mathematical descriptions of cell organization by examining the algebraic structure of mitochondrial network dynamics. Mitochondria are cellular structures involved in metabolism that take the form of a network of membrane-based tubes that undergo continuous re-arrangement by a set of morphological processes, including fission and fusion, carried out by protein-based machinery. Because of their network structure, mitochondria can be represented as graphs, and the morphological operations that take place in the cell, referred to as mitochondrial dynamics, can be represented by changes to the graphs. Prior studies have classified mitochondrial graphs based on graph-theoretic features, but an alternative approach is to focus not on the graphs themselves but on the set of morphological operations inducing mitochondrial dynamics, since this may provide a simpler representation. Moreover, the operations are what determine the graphs that will be generated in a biological system. Here we show that mitochondrial dynamics on a single connected mitochondrion constitute a groupoid that includes the automorphism group of each mitochondria graph. For multi-component mitochondria we define a graph structure that encapsulates the structure of mitochondrial dynamics. Using these formalisms we define a distance metric for similarity between mitochondrial structures based on an edit distance. In the course of defining these structures we provide a mathematical motivation for new experimental questions regarding mitochondrial fusion and the impacts of cell division on mitochondrial morphology. This work points to a general strategy for formulating a cell structure state-space, based not on the shapes of cellular structures, but on relations between the dynamic operations that produce them.
    DOI:  https://doi.org/10.1101/2025.03.17.643721
  10. PLoS One. 2025 ;20(3): e0318796
    An updated compendium and reevaluation of the evidence for nuclear transcription factor occupancy over the mitochondrial genome.
    Georgi K Marinov, Vivekanandan Ramalingam, William J Greenleaf, Anshul Kundaje.
      In most eukaryotes, mitochondrial organelles contain their own genome, usually circular, which is the remnant of the genome of the ancestral bacterial endosymbiont that gave rise to modern mitochondria. Mitochondrial genomes are dramatically reduced in their gene content due to the process of endosymbiotic gene transfer to the nucleus; as a result most mitochondrial proteins are encoded in the nucleus and imported into mitochondria. This includes the components of the dedicated mitochondrial transcription and replication systems and regulatory factors, which are entirely distinct from the information processing systems in the nucleus. However, since the 1990s several nuclear transcription factors have been reported to act in mitochondria, and previously we identified 8 human and 3 mouse transcription factors (TFs) with strong localized enrichment over the mitochondrial genome using ChIP-seq (Chromatin Immunoprecipitation) datasets from the second phase of the ENCODE (Encyclopedia of DNA Elements) Project Consortium. Here, we analyze the greatly expanded in the intervening decade ENCODE compendium of TF ChIP-seq datasets (a total of 6,153 ChIP experiments for 942 proteins, of which 763 are sequence-specific TFs) combined with interpretative deep learning models of TF occupancy to create a comprehensive compendium of nuclear TFs that show evidence of association with the mitochondrial genome. We find some evidence for chrM occupancy for 50 nuclear TFs and two other proteins, with bZIP TFs emerging as most likely to be playing a role in mitochondria. However, we also observe that in cases where the same TF has been assayed with multiple antibodies and ChIP protocols, evidence for its chrM occupancy is not always reproducible. In the light of these findings, we discuss the evidential criteria for establishing chrM occupancy and reevaluate the overall compendium of putative mitochondrial-acting nuclear TFs.
    DOI:  https://doi.org/10.1371/journal.pone.0318796
  11. Mol Genet Metab Rep. 2025 Jun;43 101206
    FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome: A rare cause of hyperammonemia.
    Ayça Burcu Kahraman, Halil Çelik, Zafer Bagci, Abdullah Sezer, Mustafa Kılıç.
       Introduction: FBXL4- related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is caused by pathogenic variants in the FBXL4 gene, resulting in mitochondrial dysfunction and multisystem involvement. Hyperammonemia is reported in 45 % of cases but extremely elevated ammonia levels are rare.
    Case presentation: A male infant presented with dysmorphic features, hypotonia, failure to thrive, and lactic acidosis and severe hyperammonemia (ammonia: 1495 μmol/L). Genetic testing identified a homozygous FBXL4 pathogenic variant.
    Conclusion: To our knowledge, this report presents a neonatal case of FBXL4-related mtDNA depletion syndrome with the highest hyperammonemia level. This case emphasizes the importance of FBXL4 genetic testing in neonates with multisystem involvement, hyperammonemia, and dysmorphic features.
    Keywords:  Encephalopathy; FBXL4 gene; Hyperammonemia; Lactic acidosis; Mitochondrial DNA depletion syndromes
    DOI:  https://doi.org/10.1016/j.ymgmr.2025.101206
  12. Sci Rep. 2025 Mar 29. 15(1): 10925
    Characterization of a new mutation of mitochondrial ND6 gene in hepatocellular carcinoma and its effects on respiratory complex I.
    Veronica Bazzani, Deepali L Kundnani, Mara Equisoain Redin, Francesca Agostini, Kirti Chhatlani, Angelo Corso Faini, Jakub Poziemski, Umberto Baccarani, Pawel Siedlecki, Silvia Deaglio, Francesca Storici, Carlo Vascotto.
      Hepatocellular carcinoma (HCC) is the most common form of liver cancer, which often arises from previous liver pathologies such as HBV, HCV, and alcohol abuse. It is typically associated with an enlarged cirrhotic organ. In this study, we analyzed tumor and distal tissues from a patient who underwent liver resection for HCC with no previous pathologies and whose liver showed normal function without signs of cirrhosis. Genetic analysis of mitochondrial DNA (mtDNA) revealed a novel variant of the gene encoding the NADH dehydrogenase subunit 6 (ND6) protein in the tumor tissue. The deletion of a thymidine generated an early stop codon, resulting in a truncated form of the protein (ΔND6) with 50% of the C-terminal primary sequence missing. ND6 is a subunit of the NADH dehydrogenase complex, also known as Complex I, the largest complex in the electron transport chain. Previous studies have linked mtDNA Complex I mutations to mitochondrial disorders and cancer. Through biochemical analyses, we characterized this new mutation and showed that the expression of ΔND6 negatively affects the stability and functionality of Complex I. Data were confirmed by molecular dynamics simulations suggesting conformational rearrangements, overall revealing a leading role of ND6 in the assembly of Complex I.
    Keywords:  Hepatocellular carcinoma; Mitochondria; Mitochondrial DNA; Molecular dynamics simulations.; ND6 gene mutation; Respiratory complex I assembly
    DOI:  https://doi.org/10.1038/s41598-025-91746-x
  13. Trends Biochem Sci. 2025 Mar 31. pii: S0968-0004(25)00051-9. [Epub ahead of print]
    Mitochondrial heat production: the elephant in the lab….
    Pierre Rustin, Howard T Jacobs, Mügen Terzioglu, Paule Bénit.
      It has long been established that heat represents a major part of the energy released during the oxidation of mitochondrial substrates. However, with a few exceptions, the release of heat is rarely mentioned other than as being produced at the expense of ATP, without having any specific function. Here, after briefly surveying the literature on mitochondrial heat production, we argue for its cellular and organismal importance, sharing our opinions as to what could account for this unbalanced portrayal of mitochondrial energy transactions.
    Keywords:  ATP; H(+)-ATPase; heat diffusion; mitochondria; nanoscale; respiratory chain
    DOI:  https://doi.org/10.1016/j.tibs.2025.03.002
  14. Front Physiol. 2025 ;16 1500247
    Mitochondrial fusion protein: a new therapeutic target for lung injury diseases.
    Guiyang Jia, Erqin Song, Qianxia Huang, Miao Chen, Guoyue Liu.
      Mitochondria are essential organelles responsible for cellular energy supply. The maintenance of mitochondrial structure and function relies heavily on quality control systems, including biogenesis, fission, and fusion. Mitochondrial fusion refers to the interconnection of two similar mitochondria, facilitating the exchange of mitochondrial DNA, metabolic substrates, proteins, and other components. This process is crucial for rescuing damaged mitochondria and maintaining their normal function. In mammals, mitochondrial fusion involves two sequential steps: outer membrane fusion, regulated by mitofusin 1 and 2 (MFN1/2), and inner membrane fusion, mediated by optic atrophy 1 (OPA1). Dysfunction in mitochondrial fusion has been implicated in the development of various acute and chronic lung injuries. Regulating mitochondrial fusion, maintaining mitochondrial dynamics, and improving mitochondrial function are effective strategies for mitigating lung tissue and cellular damage. This study reviews the expression and regulatory mechanisms of mitochondrial fusion proteins in lung injuries of different etiologies, explores their relationship with lung injury diseases, and offers a theoretical foundation for developing novel therapeutic approaches targeting mitochondrial fusion proteins in lung injury.
    Keywords:  lung injury; mitochondria; mitochondrial fusion; mitofusin 1/2; optic atrophy 1
    DOI:  https://doi.org/10.3389/fphys.2025.1500247
  15. Circ Res. 2025 Apr 02.
    PCSK9 Regulates Cardiac Mitochondrial Cholesterol by Promoting TSPO Degradation.
    Marion Laudette, Malin Lindbom, Mathieu Cinato, Per-Olof Bergh, Kristina Skålén, Arif Muhammad, Azra Miljanovic, Tomasz Czuba, Rosie Perkins, J Gustav Smith, Frank Lezoualc'h, Malin C Levin, Jan Borén.
       BACKGROUND: Cholesterol is critical for mitochondrial membrane structure and function. Given the emergence of mitochondria as a key factor in the pathogenesis of heart failure, mitochondrial cholesterol homeostasis may be crucial for maintaining mitochondrial properties and thus cardiac function. We previously showed that CM-Pcsk9-/- mice (mice with cardiomyocyte-specific deletion of PCSK9 [proprotein convertase subtilisin-kexin type 9]) have impaired cardiomyocyte mitochondrial bioenergetics and heart function, paralleled by cardiomyocyte mitochondrial cholesterol accumulation and an increased number of mitochondria-endoplasmic reticulum contacts. However, the mechanisms linking PCSK9 to mitochondrial cholesterol homeostasis remain unclear. We hypothesized that PCSK9 acts on proteins involved in mitochondrial cholesterol trafficking in the heart to maintain cardiac mitochondrial function.
    METHODS: By performing RNA sequencing and immunoblot on CM-Pcsk9-/- and CM-Pcsk9+/+ mouse hearts, we showed that TSPO (translocator protein) was increased by Pcsk9 deficiency. To investigate the relationship between TSPO levels and heart function in humans, we compared the transcriptome of human left ventricles with high versus low TSPO levels. We used H9c2 (a rat cardiomyoblast cell line) cardiomyocytes to explore the mechanism linking PCSK9/TSPO to mitochondrial cholesterol content and function. The impact of reduced TSPO levels on cardiac function and mitochondrial oxidation in CM-Pcsk9-/- mice was tested using adeno-associated virus serotype 9 short hairpin TSPO.
    RESULTS: Both gene and protein levels of TSPO, a mitochondrial protein involved in cholesterol transport, were increased in CM-Pcsk9-/- mouse hearts. Transcriptome analysis showed that high TSPO expression in human left ventricles was associated with impaired mitochondrial and cardiac function. We showed that PCSK9 induced TSPO degradation through a proteasomal mechanism that occurs in cardiomyocytes but not hepatocytes and contributes to maintaining normal mitochondrial cholesterol composition and function. At the molecular level, endoplasmic reticulum-resident PCSK9 interacted with GRP78, reducing GRP78-TSPO interactions and leading to TSPO misfolding and degradation by the ubiquitin-proteasome pathway. Importantly, gene therapy-induced downregulation of TSPO in CM-Pcsk9-/- mice prevented mitochondrial cholesterol accumulation and improved cardiac function.
    CONCLUSIONS: These findings indicate that PCSK9 regulates mitochondrial cholesterol levels by modulating the TSPO degradation in the heart. Modulation of mitochondrial cholesterol by targeting TSPO may be a promising therapeutic approach for heart failure.
    Keywords:  heart failure; homeostasis; mitochondria; myocytes, cardiac; proprotein convertase 9
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325629
  16. Cell Commun Signal. 2025 Apr 01. 23(1): 158
    DNM1L-mediated fission governs mitophagy & mitochondrial biogenesis during myogenic differentiation.
    Fasih A Rahman, Jasmine M Friedrich Yap, Tyler M Joseph, Amanda M Adam, Sarah M Chapman, Joe Quadrilatero.
       BACKGROUND: Remodeling of the mitochondrial network is implicated in myogenesis. Remodeling processes including mitochondrial fission, mitophagy, and biogenesis are important as they finetune the mitochondrial network to meet the increased energetic demand of myotubes. Evidence suggests that mitochondrial fission governs other mitochondrial remodeling processes; however, this relationship is unclear in the context of myogenesis.
    METHODS: We used C2C12 myoblasts to study changes in mitochondrial remodeling processes and their role in regulating myogenesis. To investigate this, we employed genetic manipulation with adenoviruses to modify the levels of key molecules involved in mitochondrial remodeling, including DNM1L, BNIP3, and PPARGC1A.
    RESULTS: We demonstrate that overexpression of fission protein DNM1L accelerated mitophagic flux, but reduced myotube size without affecting mitochondrial biogenesis. Conversely, DNM1L knockdown reduced mitophagic flux, impaired myoblast differentiation, and suppressed mitochondrial biogenesis signaling. Additionally, DNM1L knockdown increased mitochondrial apoptotic signaling through CASP9 and CASP3 activation. Attempts to rescue myogenesis through overexpression of the mitophagy receptor BNIP3 or the biogenesis regulator PPARGC1A were unsuccessful in the absence of proper mitochondrial fission. Furthermore, DNM1L overexpression in BNIP3-deficient cells enhanced mitophagic flux, but did not promote myogenesis.
    CONCLUSION: These results underscore the complex interdependencies among mitochondrial remodeling processes and highlight the necessity for sequential activation of mitochondrial fission, mitophagy, and biogenesis.
    Keywords:  Apoptosis; Mitochondrial biogenesis; Mitochondrial fission; Mitophagy; Myogenesis; Skeletal muscle
    DOI:  https://doi.org/10.1186/s12964-025-02142-x
  17. J Transl Genet Genom. 2025 ;9(1): 1-10
    What can ATP content tell us about Barth syndrome muscle phenotypes?
    Jeffrey J Brault, Simon J Conway.
      Adenosine triphosphate (ATP) is the energy currency within all living cells and is involved in many vital biochemical reactions, including cell viability, metabolic status, cell death, intracellular signaling, DNA and RNA synthesis, purinergic signaling, synaptic signaling, active transport, and muscle contraction. Consequently, altered ATP production is frequently viewed as a contributor to both disease pathogenesis and subsequent progression of organ failure. Barth syndrome (BTHS) is an X-linked mitochondrial disease characterized by fatigue, skeletal muscle weakness, cardiomyopathy, neutropenia, and growth delay due to inherited TAFAZZIN enzyme mutations. BTHS is widely hypothesized in the literature to be a model of defective mitochondrial ATP production leading to energy deficits. Prior patient data have linked both impaired ATP production and reduced phosphocreatine to ATP ratios (PCr/ATP) in BTHS children and adult hearts and muscles, suggesting a primary role for perturbed energetics. Moreover, although only limited direct measurements of ATP content and ADP/ATP ratio (an indicator of the energy available from ATP hydrolysis) have so far been carried out, analysis of divergent BTHS animal models, cultured cell types, and diverse organs has failed to uncover a unifying understanding of the molecular mechanisms linking TAFAZZIN deficiency to perturbed muscle energetics. This review mainly focuses on the energetics of striated muscle in BTHS mitochondriopathy.
    Keywords:  Barth syndrome; TAFAZZIN; adenosine triphosphate; cardiolipin; energetics; mitochondria; striated muscle
    DOI:  https://doi.org/10.20517/jtgg.2024.83
  18. J Lipid Res. 2025 Mar 29. pii: S0022-2275(25)00052-5. [Epub ahead of print] 100792
    Cardiomyopathy in a c.1528G>C Hadha Mouse is associated with Cardiac Tissue Lipotoxicity and Altered Cardiolipin Species.
    Chibuike Eke, Shannon Babcock, Garen Gaston, Gabriela Elizondo, Hak Chung, Ayah Asal, Kathryn C Chatfield, Genevieve C Sparagna, Andrea E DeBarber, William Packwood, Jonathan R Lindner, Melanie B Gillingham.
      Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a metabolic disorder caused by the loss of LCHAD enzymatic activity in the α-subunit of the trifunctional protein (TFPα), leading to impaired fatty acid oxidation (FAO). Patients with LCHADD often develop dilated cardiomyopathy. A previously unrecognized enzymatic function of TFPα as monolysocardiolipin acyltransferase (MLCL-AT) has been implicated in cardiolipin remodeling, crucial for mitochondrial cristae integrity. However, it remains unclear whether the common pathogenic variant c.1528G>C in HADHA impairs MLCL-AT activity in TFPα. In this study, we investigated whether cardiac cardiolipin profiles are altered in LCHADD and explored potential pathophysiological mechanisms, including heart lipid accumulation, changes in the cardiolipin synthesis pathway, and mitochondrial dynamics, utilizing a murine model of LCHADD carrying c.1528G>C variant that mimics the cardiomyopathy observed in humans. LCHADD mice developed eccentric hypertrophic cardiomyopathy from 3- to 12-months of age. 12-month-old LCHADD hearts exhibited altered cardiolipin profiles and increased oxidized cardiolipin. LCHADD hearts had higher lipid content and the shift in fatty acid profile mirrored the shift in cardiolipin profile compared to wildtype controls, suggesting altered cardiolipin composition in LCHADD may be a reflection of accumulated lipids caused by lower FAO. No differential expression of cardiolipin synthesis and remodeling pathway enzymes were observed, suggesting minimal impact of the c.1528G>C variant on cardiolipin remodeling pathway. LCHADD hearts showed altered ratio of OPA1 isomers, and mitochondria with swelling and disorganized cristae were present. These findings suggest that altered fatty acid, cardiolipin profiles, and mitochondrial dynamics may contribute to LCHADD cardiomyopathy, warranting further studies.
    Keywords:  Lipids/oxidation; cardiolipin; fatty acid oxidation; lipid droplets; lipolysis and fatty acid metabolism; mitochondria; oxidized lipids; phospholipids
    DOI:  https://doi.org/10.1016/j.jlr.2025.100792
  19. Methods Mol Biol. 2025 ;2901 159-165
    Method for Detecting Mitochondrial ATP by Hybridization Chain Reaction.
    Lei Luo, Xiaohai Yang, Kemin Wang.
      Adenosine triphosphate (ATP) plays a central role in energy transduction and signaling in living cells. For mitochondrial ATP detection, the appropriate probes should include the abilities to enter target cells noninvasively, target mitochondria, and then respond to the ATP reliably. Here, we provide a detailed protocol for imaging mitochondrial ATP in living cells exploiting the hybridization chain reaction (HCR).
    Keywords:  Adenosine triphosphate (ATP); Hybridization chain reaction; Imaging; Mitochondria
    DOI:  https://doi.org/10.1007/978-1-0716-4394-5_12
  20. Mitochondrion. 2025 Mar 29. pii: S1567-7249(25)00030-3. [Epub ahead of print] 102033
    Perceived association of mood and symptom severity in adults with mitochondrial diseases.
    Catherine Kelly, Marissa Cross, Alex Junker, Kris Englestad, Xiomara Rosales, Michio Hirano, Caroline Trumpff, Martin Picard.
      Individuals with genetic mitochondrial diseases suffer from multisystem symptoms that vary in severity and over time, but the factors influencing disease manifestations are poorly understood. Based upon i) patient and family reports that stressful life events trigger or exacerbate symptoms, ii) biologically plausible pathways whereby psychological states and stress hormones influence mitochondrial energy production capacity, and iii) epidemiological literature linking traumatic/stressful life events and multiple neurologic disorders, we hypothesized that mitochondrial disease symptom severity may in part vary with daily mood. To examine patients' perception around potential psycho-biological mechanisms known to operate in other chronic illnesses, we administered the Stress, Health and Emotion Survey (SHES) to 70 adults with self-reported mitochondrial diseases. Participants rated how severe each of their symptom(s) was over the past year, separately for either 'good' (happy, calm) or 'bad' (stress, sad) emotional days. On average, patients reported that most symptoms were better on "good" emotional days (p < 0.0001) and worse on "bad" emotional days (p < 0.0001). Of the 29 symptoms assessed, 27 were associated with daily mood (p < 0.01). Some but not all symptoms were reported to be less or more severe on good and bad days, respectively, including fatigue, exercise intolerance, brain fog, and fine motor coordination (ps < 0.0001). These associative results suggest that on average individuals living with mitochondrial diseases perceive a connection between their mood and symptoms severity. These preliminary findings constitute an initial step towards developing more comprehensive models of the psychobiological factors that influence the course of mitochondrial diseases.
    Keywords:  Clinical survey; Disease severity; Emotions; Mitochondrial disease; Patient care; Stress
    DOI:  https://doi.org/10.1016/j.mito.2025.102033
  21. bioRxiv. 2025 Mar 27. pii: 2025.03.19.644244. [Epub ahead of print]
    The Silent Saboteur: How Mitochondria Shape the Long-Term Fate of the Injured Brain.
    Sahan Bs Kansakar, Sydney P Sterben, Charitha C Anamala, Mitchell D Thielen, Volha Liaudanskaya.
      Traumatic brain injury (TBI) is a major risk factor for neurodegenerative diseases, including Alzheimer's disease (AD), yet the mechanistic link remains unclear. Here, we integrated human patient-derived transcriptomics with a 3D in vitro brain injury model to dissect cell-specific mitochondrial dysfunction as a driver of injury-induced neurodegeneration. Comparative transcriptomic analysis at 6 and 48 hours post-injury revealed conserved mitochondrial impairments across excitatory neurons, interneurons, astrocytes, and microglia. Using a novel cell-specific mitochondria tracking system, we demonstrate prolonged neuronal mitochondrial fragmentation, bioenergetic failure, and metabolic instability, coinciding with the emergence of AD markers, including pTau, APP, and Aβ42/40 dysregulation. Glial mitochondria exhibited delayed but distinct metabolic dysfunctions, with astrocytes impaired metabolic support and microglia sustained chronic inflammation. These findings establish neuronal mitochondrial failure as an early trigger of injury-induced neurodegeneration, reinforcing mitochondrial dysfunction as a therapeutic target for preventing TBI-driven AD pathology.
    DOI:  https://doi.org/10.1101/2025.03.19.644244
  22. bioRxiv. 2025 Mar 19. pii: 2025.03.19.644182. [Epub ahead of print]
    PPM1M, a LRRK2-counteracting, phosphoRab12-preferring phosphatase with potential link to Parkinson's disease.
    Claire Y Chiang, Neringa Pratuseviciute, Yu-En Lin, Ayan Adhikari, Wondwossen M Yeshaw, Chloe Flitton, Pemba L Sherpa, Francesca Tonelli, Irena Rektorova, Timothy Lynch, Joanna Siuda, Monika Rudzińska-Bar, Oleksandr Pulyk, Peter Bauer, Christian Beetz, Dennis W Dickson, Owen A Ross, Zbigniew K Wszolek, Christine Klein, Alexander Zimprich, Dario R Alessi, Esther M Sammler, Suzanne R Pfeffer.
      Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking; activating mutations in LRRK2 are linked to Parkinson's disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including PPM1H, that acts on phosphoRab8A and phosphoRab10. Here we report a phosphatome-wide siRNA screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10. Upon knockout from cells or mice, PPM1M displays selectivity for phosphoRab12. As shown previously for mice harboring LRRK2 pathway mutations, knockout of Ppm1m leads to primary cilia loss in striatal cholinergic interneurons. We have also identified a rare PPM1M mutation in patients with Parkinson's disease that is catalytically inactive when tested in vitro and in cells. These findings identify PPM1M as a key player in the LRRK2 signaling pathway and provide a new therapeutic target for the possible benefit of patients with Parkinson's disease.
    Teaser: Parkinson's linked Rab phosphorylation is reversed by PPM1M; the inactive D440N variant is implicated in rare patient cases.
    DOI:  https://doi.org/10.1101/2025.03.19.644182
  23. bioRxiv. 2025 Mar 18. pii: 2025.03.18.643991. [Epub ahead of print]
    Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms including sleep.
    Milan Stoiljkovic, Jae Eun Song, Hee-Kyung Hong, Heiko Endle, Luis Varela, Jonatas Catarino, Xiao-Bing Gao, Zong-Wu Liu, Sabrina Diano, Jonathan Cedernaes, Joseph T Bass, Tamas L Horvath.
      Sustaining the strong rhythmic interactions between cellular adaptations and environmental cues has been posited as essential for preserving the physiological and behavioral alignment of an organism to the proper phase of the daily light/dark cycle. Here, we show that mitochondria and synaptic input organization of suprachiasmatic (SCN) vasoactive intestinal peptide (VIP)-expressing neurons show circadian rhythmicity. Perturbed mitochondrial dynamics achieved by conditional ablation of the fusogenic protein mitofusin 2 (Mfn2) in VIP neurons cause disrupted circadian oscillation in mitochondria and synapses in SCN VIP neurons leading to desynchronization of entrainment to the light/dark cycle in Mfn2 deficient mice that resulted in advanced phase angle of their locomotor activity onset, alterations in core body temperature and sleep-wake amount and architecture. Our data provide direct evidence of circadian SCN clock machinery dependence on high-performance Mfn2-regulated mitochondrial dynamics in VIP neurons for maintaining the coherence in daily biological rhythms of the mammalian organism.
    DOI:  https://doi.org/10.1101/2025.03.18.643991
  24. NPJ Genom Med. 2025 Mar 31. 10(1): 29
    Review: Utility of mass spectrometry in rare disease research and diagnosis.
    Teresa Zhao, Daniella H Hock, James Pitt, David R Thorburn, David A Stroud, John Christodoulou.
      Individuals affected by a rare disease often experience a long and arduous diagnostic odyssey. Delivery of genetic answers in a timely manner is critical to affected individuals and their families. Multi-omics, a term which usually encompasses genomics, transcriptomics, proteomics, metabolomics and lipidomics, has gained increasing popularity in rare disease research and diagnosis over the past decade. Mass spectrometry (MS) is a technique allowing the study of proteins, metabolites and lipids and their fragments at scale, enabling researchers to effectively determine the presence and abundance of thousands of molecules in a single test, accurately quantify their specific levels, identify potential therapeutic biomarkers, detect differentially expressed proteins in patients with rare diseases, and monitor disease progression and treatment response. In this review, we focus on mass spectrometry (MS)-based omics and survey the literature describing the utility of different MS-based omics and how they have transformed rare disease research and diagnosis.
    DOI:  https://doi.org/10.1038/s41525-025-00487-3
  25. FASEB J. 2025 Apr 15. 39(7): e70490
    Detection of liver mitochondrial oxaloacetate by NMR spectroscopy and membrane potential-dependent accumulation.
    Liping Yu, Brian D Fink, William I Sivitz.
      Oxaloacetate (OAA) is a central liver metabolite fundamental to critical metabolic pathways. However, understanding OAA metabolism in the liver has been limited because the compound is very difficult to measure by mass spectroscopy and not abundant enough for detection by other methods. Here we describe a novel approach to quantifying OAA in liver mitochondria. Moreover, we provide evidence for membrane potential-dependent OAA accumulation in mitochondria during complex II-energized respiration consistent with OAA inhibition of succinate dehydrogenase.
    Keywords:  inner membrane potential; liver; metabolites; mitochondria; oxaloacetate; respiration
    DOI:  https://doi.org/10.1096/fj.202500039R
  26. Hum Reprod. 2025 Apr 02. pii: deaf050. [Epub ahead of print]
    Profiling mitochondrial DNA variant segregation during human preimplantation development: a prerequisite to preimplantation genetic testing for mitochondrial DNA-related disorders.
    Paula Rubens, Anne Mayeur, Kalliopi Chatzovoulou, Nadine Gigarel, Sophie Monnot, Agnès Rötig, Arnold Munnich, Nelly Frydman, Julie Steffann.
       STUDY QUESTION: Is preimplantation genetic testing for mitochondrial DNA (mtDNA) disorders (PGT-mt) feasible at early compaction and blastocyst stages?
    SUMMARY ANSWER: Pathogenic mtDNA variants segregate evenly among cell types and various lineages of a given embryo during preimplantation development, supporting the relevance of genetic analyses performed on Day 4 blastomere and on Day 5 or 6 trophectoderm (TE) samples.
    WHAT IS KNOWN ALREADY: PGT-mt is validated at cleavage stage (Day 3 of development). However, its feasibility at later stages is questionable, as little is known regarding the segregation of pathogenic mtDNA variants during preimplantation development. Since mtDNA replication is silenced until the blastocyst stage (Day 5 or 6), uneven mtDNA segregation between preimplantation embryo cellular lineages known as a 'bottleneck' effect, cannot be excluded, posing a challenge for PGT-mt.
    STUDY DESIGN, SIZE, DURATION: We analyzed 112 'mito' embryos carrying pathogenic mtDNA variants and 28 control embryos with mtDNA polymorphism. Heteroplasmy levels were assessed in single cells of the TE, in different parts of blastocysts (inner cell mass and TE), and at three time points of development, namely cleavage (Day 3), early compaction (Day 4), and blastocyst stages (Day 5 or 6).
    PARTICIPANTS/MATERIALS, SETTING, METHODS: As part of clinical PGT, a blastomere biopsy was performed at cleavage or early compaction stages (Day 3 or 4) on 112 'mito' and 21/28 control embryos. Further analysis was carried out at Day 5 or 6 on 51 embryos deemed unsuitable for uterine transfer and donated to research. Heteroplasmy levels were determined by semi-quantitative PCR amplification of (i) the mtDNA pathogenic variants with additional enzymatic digestion or (ii) the mtDNA polymorphic hypervariable region 2.
    MAIN RESULTS AND THE ROLE OF CHANCE: Here, we first show that mtDNA variants segregate evenly among blastomeres during early compaction (Day 4), supporting the feasibility of PGT-mt at this stage. We also found that mtDNA ratios remain stable between cleavage and blastocyst stages. Yet, the substantial variation of heteroplasmy levels occurring among single TE cells in 1/8 embryos suggests that PGT is only feasible when at least 5-10 cells are collected by standard TE biopsy.
    LIMITATIONS, REASONS FOR CAUTION: This study sheds light on mtDNA segregation in human preimplantation embryo development. Its limitation lies in the scarcity of the material and the small number of embryos carrying a specific pathogenic mtDNA variant. Furthermore, the study of single cells from TE was performed on control embryos only.
    WIDER IMPLICATIONS OF THE FINDINGS: By supporting the relevance of blastocyst biopsy in the context of PGT for pathogenic mtDNA variants, this study contributes to the general trend of postponing the biopsy to later stages of embryonic development. However, particular attention should be paid to the number of TE cells tested. Due to the potential variation of mutant load during in utero development, a control amniocentesis for evolutive pregnancies following the transfer of heteroplasmic embryos is still recommended.
    STUDY FUNDING/COMPETING INTEREST(S): This work was funded by 'Association Française contre les Myopathies/AFM Téléthon' (22112, 24317, 28525); and EUR G.E.N.E. (No. ANR-17-EURE-0013). The authors have no competing interests to declare.
    TRIAL REGISTRATION NUMBER: N/A.
    Keywords:  heteroplasmy; human preimplantation embryo; mitochondria; mitochondrial DNA; morula biopsy; mtDNA segregation; pathogenic mtDNA variants; preimplantation genetic testing; trophectoderm biopsy
    DOI:  https://doi.org/10.1093/humrep/deaf050
  27. Nat Commun. 2025 Apr 03. 16(1): 3158
    Pathogenic mutation impairs functional dynamics of Hsp60 in mono- and oligomeric states.
    Luca Torielli, Federica Guarra, Hao Shao, Jason E Gestwicki, Stefano A Serapian, Giorgio Colombo.
      Mitochondrial chaperonin Heat Shock Protein 60 kDa (Hsp60) oversees the correct folding of client proteins in cooperation with Hsp10. Hsp60 monomers M first form 7-meric Single rings (S), which then pair into 14-meric Double rings (D) that accommodate clients in their lumen. Recruitment of 7 Hsp10 molecules per pole yields a sealed 28-meric Football-shaped complex (F). ATP hydrolysis in each Hsp60 unit drives client folding and F disassembly. The V72I mutation in hereditary spastic paraplegia form SPG13 impairs Hsp60 function despite being distant from the active site. We here investigate this impairment with atomistic molecular dynamics (MD) simulations of M, S, D, and F for both WT and mutant Hsp60, considering catalytic aspartates in D and F in different protonation states (even simulating one such state of D post-hydrolysis). Our findings show that-as observed experimentally-V72I rigidifies Hsp60 assemblies, significantly impacting internal dynamics. In monomers, V72I introduces a new allosteric route that bypasses the ATP binding site and affects mechanisms driving reactivity. These insights highlight a multiscale complexity of Hsp60 that could inspire the design of experiments to better understand both its WT and V72I variants.
    DOI:  https://doi.org/10.1038/s41467-025-57958-5
  28. Sci Adv. 2025 Apr 04. 11(14): eadq1575
    Atf3 controls transitioning in female mitochondrial cardiomyopathy as identified by spatial and single-cell transcriptomics.
    Tasneem Qaqorh, Yusuke Takahashi, Kohei Sameshima, Kentaro Otani, Issei Yazawa, Yuya Nishida, Kohei Tonai, Yoshitaka Fujihara, Mizuki Honda, Shinya Oki, Yasuyuki Ohkawa, David R Thorburn, Ann E Frazier, Atsuhito Takeda, Yoshihiko Ikeda, Heima Sakaguchi, Takuya Watanabe, Norihide Fukushima, Yasumasa Tsukamoto, Naomasa Makita, Osamu Yamaguchi, Kei Murayama, Akira Ohtake, Yasushi Okazaki, Takanari Kimura, Hisakazu Kato, Hijiri Inoue, Ken Matsuoka, Seiji Takashima, Yasunori Shintani.
      Oxidative phosphorylation defects result in now intractable mitochondrial diseases (MD) with cardiac involvement markedly affecting prognosis. The mechanisms underlying the transition from compensation to dysfunction in response to metabolic deficiency remain unclear. Here, we used spatially resolved transcriptomics and single-nucleus RNA sequencing (snRNA-seq) on the heart of a patient with mitochondrial cardiomyopathy (MCM), combined with an MCM mouse model with cardiac-specific Ndufs6 knockdown (FS6KD). Cardiomyocytes demonstrated the most heterogeneous expression landscape among cell types caused by metabolic perturbation, and pseudotime trajectory analysis revealed dynamic cellular states transitioning from compensation to severe compromise. This progression coincided with the transient up-regulation of a transcription factor, ATF3. Genetic ablation of Atf3 in FS6KD corroborated its pivotal role, effectively delaying cardiomyopathy progression in a female-specific manner. Our findings highlight a fate-determining role of ATF3 in female MCM progression and that the latest transcriptomic analysis will help decipher the mechanisms underlying MD progression.
    DOI:  https://doi.org/10.1126/sciadv.adq1575
  29. Biotechniques. 2025 Apr 03. 1-12
    A drug screening platform for protein expression levels in neurological disorders.
    Farida Emran, Ibrahim Kays, Chiu-An Lo, Yueyang Li, Brian E Chen.
      Neurological and psychiatric diseases and disorders affect more than half of the population. Many of these diseases are caused by the malfunctioning of protein synthesis, where too little or too much production of a protein harms a cell and its functions within the brain. We developed a drug screening platform to identify compounds that target the primary cause of these diseases, namely protein expression amounts. This cellular assay monitors protein expression of a target disease gene along with the protein expression of a control gene using the Protein Quantitation Ratioing (PQR) technique. PQR tracks protein concentration using fluorescence. We used human cells and CRISPR-Cas9 genome editing to insert the Protein Quantitation Reporter into target genes. These cells are used in high-throughput drug screening measuring the fluorescence as the assay. Drug hits can be validated using the same PQR technique or animal models of the disease.
    Keywords:  CRISPR-Cas9 genome editing; High-throughput drug screening; genetic disorders; human cell lines; induced pluripotent stem cells; protein expression; protein quantitation ratioing; time-lapse imaging
    DOI:  https://doi.org/10.1080/07366205.2025.2484094
  30. Aging (Albany NY). 2025 Apr 02. null
    Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation.
    Sofie Lautrup, Shi-Qi Zhang, Shinichiro Funayama, Lisa Lirussi, Tina Visnovska, Hoi-Hung Cheung, Marc Niere, Yuyao Tian, Hilde Loge Nilsen, Geir Selbæk, Janna Saarela, Yoshiro Maezawa, Koutaro Yokote, Per Nilsson, Wai-Yee Chan, Hisaya Kato, Mathias Ziegler, Vilhelm A Bohr, Evandro F Fang.
      Werner syndrome (WS), caused by mutations in the RecQ helicase WERNER (WRN) gene, is a classical accelerated aging disease with patients suffering from several metabolic dysfunctions without a cure. While, as we previously reported, depleted NAD+ causes accumulation of damaged mitochondria, leading to compromised metabolism, how mitochondrial NAD+ changes in WS and the impact on WS pathologies were unknown. We show that loss of WRN increases senescence in mesenchymal stem cells (MSCs) likely related to dysregulation of metabolic and aging pathways. In line with this, NAD+ augmentation, via supplementation with nicotinamide riboside, reduces senescence and improves mitochondrial metabolic profiles in MSCs with WRN knockout (WRN-/-) and in primary fibroblasts derived from WS patients compared to controls. Moreover, WRN deficiency results in decreased mitochondrial NAD+ (measured indirectly via mitochondrially-expressed PARP activity), and altered expression of key salvage pathway enzymes, including NMNAT1 and NAMPT; ChIP-seq data analysis unveils a potential co-regulatory axis between WRN and the NMNATs, likely important for chromatin stability and DNA metabolism. However, restoration of mitochondrial or cellular NAD+ is not sufficient to reinstall cellular proliferation in immortalized cells with siRNA-mediated knockdown of WRN, highlighting an indispensable role of WRN in proliferation even in an NAD+ affluent environment. Further cell and animal studies are needed to deepen our understanding of the underlying mechanisms, facilitating related drug development.
    Keywords:  NAD+; Werner syndrome; mitochondria; premature aging; proliferation
    DOI:  https://doi.org/10.18632/aging.206236
  31. Cell Commun Signal. 2025 Apr 02. 23(1): 166
    Restoration of Miro1's N-terminal GTPase function alleviates prenatal stress-induced mitochondrial fission via Drp1 modulation.
    Gee Euhn Choi, Ji Yong Park, Mo Ran Park, Chang Woo Chae, Young Hyun Jung, Jae Ryong Lim, Jee Hyeon Yoon, Ji Hyeon Cho, Ho Jae Han.
       BACKGROUND: Prenatal stress exposure irreversibly impairs mitochondrial dynamics, including mitochondrial trafficking and morphology in offspring, leading to neurodevelopmental and neuropsychiatric disorders in adulthood. Thus, understanding the molecular mechanism controlling mitochondrial dynamics in differentiating neurons is crucial to prevent the prenatal stress-induced impairments in behavior. We investigated the interplay between mitochondrial transport and fusion/fission in differentiating neurons exposed to prenatal stress, leading to ensuing behavior impairments, and then tried to identify the primary regulator that modulates both phenomena.
    METHODS: We used primary hippocampal neurons of mice exposed to prenatal stress and human induced-pluripotent stem cell (hiPSC)-derived neurons, for investigating the impact of glucocorticoid on mitochondrial dynamics during differentiation. For constructing mouse models, we used AAV vectors into mouse pups exposed to prenatal stress to regulate protein expressions in hippocampal regions.
    RESULTS: We first observed that prenatal exposure to glucocorticoids induced motility arrest and fragmentation of mitochondria in differentiating neurons derived from mouse fetuses (E18) and human induced pluripotent stem cells (hiPSCs). Further, glucocorticoid exposure during neurogenesis selectively downregulated Miro1 and increased Drp1 phosphorylation (Ser616). MIRO1 overexpression restored mitochondrial motility and increased intramitochondrial calcium influx through ER-mitochondria contact (ERMC) formation. Furthermore, we determined that the N-terminal GTPase domain of Miro1 plays a critical role in ERMC formation, which then decreased Drp1 phosphorylation (Ser616). Similarly, prenatal corticosterone exposure led to impaired neuropsychiatric and cognitive function in the offspring by affecting mitochondrial distribution and synaptogenesis, rescued by Miro1WT, but not N-terminal GTPase active form Miro1P26V, expression.
    CONCLUSION: Prenatal glucocorticoid-mediated Miro1 downregulation contributes to dysfunction in mitochondrial dynamics through Drp1 phosphorylation (Ser616) in differentiating neurons.
    Keywords:  ER-mitochondria contacts; Miro; Mitochondrial dynamics; Neurodegeneration; Prenatal glucocorticoid
    DOI:  https://doi.org/10.1186/s12964-025-02172-5
  32. Nat Commun. 2025 Mar 29. 16(1): 3061
    Aberrant gene expression prediction across human tissues.
    Florian R Hölzlwimmer, Jonas Lindner, Georgios Tsitsiridis, Nils Wagner, Francesco Paolo Casale, Vicente A Yépez, Julien Gagneur.
      Despite the frequent implication of aberrant gene expression in diseases, algorithms predicting aberrantly expressed genes of an individual are lacking. To address this need, we compile an aberrant expression prediction benchmark covering 8.2 million rare variants from 633 individuals across 49 tissues. While not geared toward aberrant expression, the deleteriousness score CADD and the loss-of-function predictor LOFTEE show mild predictive ability (1-1.6% average precision). Leveraging these and further variant annotations, we next train AbExp, a model that yields 12% average precision by combining in a tissue-specific fashion expression variability with variant effects on isoforms and on aberrant splicing. Integrating expression measurements from clinically accessible tissues leads to another two-fold improvement. Furthermore, we show on UK Biobank blood traits that performing rare variant association testing using the continuous and tissue-specific AbExp variant scores instead of LOFTEE variant burden increases gene discovery sensitivity and enables improved phenotype predictions.
    DOI:  https://doi.org/10.1038/s41467-025-58210-w
  33. Neuropharmacology. 2025 Mar 31. pii: S0028-3908(25)00145-5. [Epub ahead of print] 110439
    Targeting mitochondria-regulated ferroptosis: A new frontier in Parkinson's Disease therapy.
    Wenjun Wang, Elizabeth Rosalind Thomas, Ruyue Xiao, Tianshun Chen, Shiting Xia, Qulian Guo, Kezhi Liu, You Yang, Xiang Li.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantial nigra. Mitochondrial dysfunction and mitochondrial oxidative stress are central to the pathogenesis of PD, with recent evidence highlighting the role of ferroptosis - a type of regulated cell death dependent on iron metabolism and lipid peroxidation. Mitochondria, the central organelles for cellular energy metabolism, play a pivotal role in PD pathogenesis through the production of Reactive oxygen species (ROS) and the disruption of iron homeostasis. This review explores the intricate interplay between mitochondrial dysfunction and ferroptosis in PD, focusing on key processes such as impaired electron transport chain function, tricarboxylic acid (TCA) cycle dysregulation, disruption of iron metabolism, and altered lipid peroxidation. We discuss key pathways, including the role of glutathione (GSH), mitochondrial ferritin, and the regulation of the mitochondrial labile iron pool (mLIP), which collectively influence the susceptibility of neurons to ferroptosis. Furthermore, this review emphasizes the importance of mitochondrial quality control mechanisms, such as mitophagy and mitochondrial biogenesis, in mitigating ferroptosis-induced neuronal death. Understanding these mechanisms linking the interplay between mitochondrial dysfunction and ferroptosis may pave the way for novel therapeutic approaches aimed at preserving mitochondrial integrity and preventing neuronal loss in PD.
    Keywords:  Ferroptosis; Mitochondria; Parkinson's disease; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.neuropharm.2025.110439
  34. Open Biol. 2025 Apr;15(4): 240358
    Mild activation of the mitochondrial unfolded protein response increases lifespan without increasing resistance to stress.
    Alexa Di Pede, Bokang Ko, Abdelrahman AlOkda, Aura A Tamez González, Shusen Zhu, Jeremy M Van Raamsdonk.
      The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway that responds to mitochondrial insults by altering gene expression to recover mitochondrial homeostasis. The mitoUPR is mediated by the stress-activated transcription factor ATFS-1 (activating transcription factor associated with stress 1). Constitutive activation of ATFS-1 increases resistance to exogenous stressors but paradoxically decreases lifespan. In this work, we determined the optimal levels of expression of activated ATFS-1 with respect to lifespan and resistance to stress by treating constitutively active atfs-1(et17) worms with different concentrations of RNA interference (RNAi) bacteria targeting atfs-1. We observed the maximum lifespan of atfs-1(et17) worms at full-strength atfs-1 RNAi, which was significantly longer than wild-type lifespan. Under the conditions of maximum lifespan, atfs-1(et17) worms did not show enhanced resistance to stress, suggesting a trade-off between stress resistance and longevity. The maximum resistance to stress in atfs-1(et17) worms occurred on empty vector. Under these conditions, atfs-1(et17) worms are short-lived. This indicates that constitutive activation of ATFS-1 can increase lifespan or enhance resistance to stress but not both, at the same time. Overall, these results demonstrate that constitutively active ATFS-1 can extend lifespan when expressed at low levels and that this lifespan extension is not dependent on the ability of ATFS-1 to enhance resistance to stress.
    Keywords:  ATFS-1; Caenorhabditis elegans; ageing; genetics; mitochondrial unfolded protein response; stress resistance
    DOI:  https://doi.org/10.1098/rsob.240358
  35. EMBO Rep. 2025 Apr 02.
    Mpf1 affects the dual distribution of tail-anchored proteins between mitochondria and peroxisomes.
    Nitya Aravindan, Daniela G Vitali, Julia Breuer, Jessica Oberst, Einat Zalckvar, Maya Schuldiner, Doron Rapaport.
      Most cellular proteins require targeting to a distinct cellular compartment to function properly. A subset of proteins is distributed to two or more destinations in the cell and little is known about the mechanisms controlling the process of dual/multiple targeting. Here, we provide insight into the mechanism of dual targeting of proteins between mitochondria and peroxisomes. We perform a high throughput microscopy screen in which we visualize the location of the model tail-anchored proteins Fis1 and Gem1 in the background of mutants in virtually all yeast genes. This screen identifies three proteins, whose absence results in a higher portion of the tail-anchored proteins in peroxisomes: the two paralogues Tom70, Tom71, and the uncharacterized gene YNL144C that we rename mitochondria and peroxisomes factor 1 (Mpf1). We characterize Mpf1 to be an unstable protein that associates with the cytosolic face of the mitochondrial outer membrane. Furthermore, our study uncovers a unique contribution of Tom71 to the regulation of dual targeting. Collectively, our study reveals, for the first time, factors that influence the dual targeting of proteins between mitochondria and peroxisomes.
    Keywords:  Dual Targeting; Fis1; Mitochondria; Peroxisomes; Tail-anchored Proteins
    DOI:  https://doi.org/10.1038/s44319-025-00440-6
  36. Neurology. 2025 Apr 22. 104(8): e213532
    What Is the Role of Inner Membrane Metalloproteases in Mitochondrial Quality Control and Disease?
    Eduardo Benarroch.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000213532
  37. QRB Discov. 2025 ;6 e12
    Structural bioinformatic study of human mitochondrial respiratory integral membrane megacomplex and its AlphaFold3 predicted water-soluble QTY megacomplex analog.
    Edward Chen, Shuguang Zhang.
      Human mitochondrial Complex I is one of the largest multi-subunit membrane protein megacomplexes, which plays a critical role in oxidative phosphorylation and ATP production. It is also involved in many neurodegenerative diseases. However, studying its structure and the mechanisms underlying proton translocation remains challenging due to the hydrophobic nature of its transmembrane parts. In this structural bioinformatic study, we used the QTY code to reduce the hydrophobicity of megacomplex I, while preserving its structure and function. We carried out the structural bioinformatics analysis of 20 key enzymes in the integral membrane parts. We compare their native structure, experimentally determined using Cryo-electron microscopy (CryoEM), with their water-soluble QTY analogs predicted using AlphaFold 3. Leveraging AlphaFold 3's advanced capabilities in predicting protein-protein complex interactions, we further explore whether the QTY-code integral membrane proteins maintain their protein-protein interactions necessary to form the functional megacomplex. Our structural bioinformatics analysis not only demonstrates the feasibility of engineering water-soluble integral membrane proteins using the QTY code, but also highlights the potential to use the water-soluble membrane protein QTY analogs as soluble antigens for discovery of therapeutic monoclonal antibodies, thus offering promising implications for the treatment of various neurodegenerative diseases.
    Keywords:  Convert hydrophobic alpha-helix to hydrophilic alpha-helix:Protein engineering; QTY code; Water-soluble transmembrane protein megacomplex
    DOI:  https://doi.org/10.1017/qrd.2025.2
  38. Am J Med Genet A. 2025 May;197(5): e63744
    Re-Analysis Yields Diagnosis in Over 500 Patients with Rare Diseases.
      
    DOI:  https://doi.org/10.1002/ajmg.a.63744
  39. Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 31.
    Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.
    Al-Hassan Soliman Wadan, Ahmed H Shaaban, Mohamed Z El-Sadek, Salah Abdelfatah Mostafa, Ahmed Sherief Moshref, Ahmed El-Hussein, Doha El-Sayed Ellakwa, Samah S Mehanny.
      Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.
    Keywords:  Mitochondria-focused therapies; Mitochondrial dysfunction; Neurodegenerative diseases; Oxidative stress; Therapeutic strategies
    DOI:  https://doi.org/10.1007/s00210-025-04014-0
  40. Mol Ther. 2025 Apr 02. pii: S1525-0016(25)00266-7. [Epub ahead of print]
    Current Trends in Gene Therapy to Treat Inherited Disorders of the Brain.
    Zaneta Matuszek, Brandon L Brown, Carolyn M Yrigollen, Megan S Keiser, Beverly L Davidson.
      Gene therapy development, re-engineering, and application to patients hold promise to revolutionize medicine, including therapies for disorders of the brain. Advances in delivery modalities, expression regulation, and improving safety profiles are of critical importance. Additionally, each inherited disorder has its own unique characteristics as to regions and cell types impacted, and the temporal dynamics of that impact, that are essential for the design of therapeutic design strategies. Here, we review the current state of the art in gene therapies for inherited brain disorders, summarizing key considerations for vector delivery, gene addition, gene silencing, gene editing, and epigenetic editing. We provide examples from animal models, human cell lines, and where possible, clinical trials. This review also highlights the various tools available to researchers for basic research questions and discusses our views on the current limitations in the field.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.03.057
  41. Adv Pharmacol. 2025 ;pii: S1054-3589(25)00003-1. [Epub ahead of print]103 231-263
    Identifying novel drug targets with computational precision.
    Riya Dave, Pierpaolo Giordano, Sakshi Roy, Hiba Imran.
      Computational precision in drug discovery integrates algorithms and high-performance computing to analyze complex biological data with unprecedented accuracy, revolutionizing the identification of therapeutic targets. This process encompasses diverse computational and experimental approaches that enhance drug discovery's speed and precision. Advanced techniques like next-generation sequencing enable rapid genetic characterization, while proteomics explores protein expression and interactions driving disease progression. In-silico methods, including molecular docking, virtual screening, and pharmacophore modeling, predict interactions between small molecules and biological targets, accelerating early drug candidate identification. Structure-based drug design and molecular dynamics simulations refine drug designs by elucidating target structures and molecular behaviors. Ligand-based methods utilize known chemical properties to anticipate new compound activities. AI and machine learning optimizes data analysis, offering novel insights and improving predictive accuracy. Systems biology and network pharmacology provide a holistic view of biological networks, identifying critical nodes as potential drug targets, which traditional methods might overlook. Computational tools synergize with experimental techniques, enhancing the treatment of complex diseases with personalized medicine by tailoring therapies to individual patients. Ethical and regulatory compliance ensures clinical applicability, bridging computational predictions to effective therapies. This multi-dimensional approach marks a paradigm shift in modern medicine, delivering safer, more effective treatments with precision. By integrating bioinformatics, genomics, and proteomics, computational drug discovery has transformed how therapeutic interventions are developed, ensuring an era of personalized, efficient healthcare.
    Keywords:  Bioinformatics; Computational drug discovery; Drug target identification; Ethical considerations; Machine learning; Precision medicine
    DOI:  https://doi.org/10.1016/bs.apha.2025.01.003
  42. J Med Cases. 2025 Mar;16(3): 114-119
    Medium-Chain Acyl-CoA Dehydrogenase Deficiency Disorder as a Cause of Acute Liver Failure in a 23-Month-Old Baby.
    Inva Gjeta, Ilirjana Bakalli, Durim Sala, Ermela Celaj, Marsela Biqiku, Vladimir Hoxha, Virtut Velmishi, Elmira Kola.
      Fatty acid oxidation disorders are inborn metabolic defects caused by impaired beta-oxidation of fats within the mitochondria. This occurs due to a deficiency in the pathway of fatty acids into the mitochondria via carnitine. Although their incidence is not frequent, the clinical presence of this disorder often leads to morbidity and high mortality. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is part of the large group of fatty acid oxidation disorders which has a high variability in clinical manifestations and in daily medical practice can be challenging to early and correctly diagnose. In this article, we present a 23-month-old boy with drowsiness, mild hypoglycemia, and rapid progression to acute liver failure as a consequence of this metabolic disorder. Once the diagnosis was confirmed, treatment was conducted following the guideline of hypoglycemia of the metabolic disorder of MCAD deficiency and its complications. The child was discharged in good condition and the follow-up after 6 months was successful. Further, we review the literature on this genetic condition and check on how they connect to our case. The article aims to focus on the early evaluation of the clinical signs that present from the underlying of this rare metabolic disorder and the importance of aggressive treatment to prevent complications that can be fatal for the patient.
    Keywords:  Acyl-CoA dehydrogenase; Fatty oxidation; Hypoglycemia; Liver failure
    DOI:  https://doi.org/10.14740/jmc5093
  43. iScience. 2025 Mar 21. 28(3): 112092
    Elucidating neuroepigenetic mechanisms to inform targeted therapeutics for brain disorders.
    Benjamin H Weekley, Newaz I Ahmed, Ian Maze.
      The evolving field of neuroepigenetics provides important insights into the molecular foundations of brain function. Novel sequencing technologies have identified patient-specific mutations and gene expression profiles involved in shaping the epigenetic landscape during neurodevelopment and in disease. Traditional methods to investigate the consequences of chromatin-related mutations provide valuable phenotypic insights but often lack information on the biochemical mechanisms underlying these processes. Recent studies, however, are beginning to elucidate how structural and/or functional aspects of histone, DNA, and RNA post-translational modifications affect transcriptional landscapes and neurological phenotypes. Here, we review the identification of epigenetic regulators from genomic studies of brain disease, as well as mechanistic findings that reveal the intricacies of neuronal chromatin regulation. We then discuss how these mechanistic studies serve as a guideline for future neuroepigenetics investigations. We end by proposing a roadmap to future therapies that exploit these findings by coupling them to recent advances in targeted therapeutics.
    Keywords:  Epigenetics; Neuroscience; Therapeutics
    DOI:  https://doi.org/10.1016/j.isci.2025.112092
  44. Case Rep Ophthalmol. 2025 Jan-Dec;16(1):16(1): 246-253
    DNAJC30 Mutation in a Patient with Coexisting Leber's Hereditary Optic Neuropathy and Multiple Sclerosis (Harding's Syndrome): A Case Report.
    Sara KamaliZonouzi, Jonathan Micieli.
       Introduction: Patients with Leber's hereditary optic neuropathy (LHON) have a higher risk of developing multiple sclerosis (MS) than the general population. The coexistence of LHON and MS, also known as Harding's syndrome complicates the diagnosis of optic neuropathy, particularly when the underlying genetic mutation is a rare cause of LHON like DNAJC30.
    Case Presentation: We present a 26-year-old woman with progressive, sequential, painless, bilateral visual loss which was unresponsive to steroids, and two temporally distinct episodes of neurological disturbance suggestive of central nervous system demyelination. Thorough investigations including serological tests ruled out other causes, including negative neuromyelitis optica and myelin oligodendrocyte protein (MOG) antibodies and nutritional deficiencies. MRI detected areas of demyelination within the spinal cord and brain (infratentorial and periventricular areas). After genetic analysis revealing c.152A>G (p.Tyr51Cys) mutation at the DNAJC30 gene, LHON was suggested. She was prescribed with idebenone and her visual acuity resolved to normal at 4-year follow-up.
    Conclusion: This case further expands the clinical presentations of DNAJC30-related LHON and underscores the importance of considering LHON in patients with demyelinating syndrome presenting with severe bilateral visual loss and presumed optic neuritis unresponsive to steroids.
    Keywords:  DNAJC30; Harding’s syndrome; Leber’s hereditary optic neuropathy; Multiple sclerosis
    DOI:  https://doi.org/10.1159/000545079
  45. bioRxiv. 2025 Mar 12. pii: 2025.03.07.642110. [Epub ahead of print]
    NLRP10 Cleaves Oxidized DNA inhibited by OGG1 inhibitors: A Newly Identified Role in DNA Damage Processing and Senescence Regulation.
    Julia Elise Cabral, Sophia Lin, Haitian Zhou, Anna Wu, Angie Lackner, Minh Anh Pham, Feixuan Chi, Reginald McNulty.
      Mitochondrial DNA (mtDNA) release into the cytosol is a critical event in innate immune activation, often acting as a damage-associated molecular pattern (DAMP) that triggers inflammasome assembly. Here, we demonstrate that NLRP3 plays a direct role in cleaving and facilitating the release of D-loop mtDNA into the cytosol. We further show that NLRP3 interacts with NLRP10. NLRP10-mediated ox-DNA cleavage involves a Schiff base intermediate and is inhibited by small molecules known to inhibit glycosylases. These findings support a model where NLRP10 interaction with oxidized DNA may contribute to long-term senescence secretory phenotype and modulate inflammasome activation. Our study highlights a novel mechanism by which NLRP10 can respond to mitochondrial stress signals to influence innate immunity and suggests therapeutic potential for targeting these interactions in inflammatory diseases.
    DOI:  https://doi.org/10.1101/2025.03.07.642110
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