bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–02–02
sixty-six papers selected by
Catalina Vasilescu, Helmholz Munich
  1. FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.
  2. Correcting a pathogenic mitochondrial DNA mutation by base editing in mice.
  3. Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.
  4. Successful Diagnosis of Sengers Syndrome Using a Comprehensive Genomic Analysis.
  5. NADH Reductive Stress and Its Correlation with Disease Severity in Leigh Syndrome: A Pilot Study Using Patient Fibroblasts and a Mouse Model.
  6. Electrical homeostasis of the inner mitochondrial membrane potential.
  7. Regulation of mitochondrial cristae organization by Myo19, Miro1/2 and Metaxin 3.
  8. Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.
  9. Mechanism of chaperone recruitment and retention on mitochondrial precursors.
  10. Characterization of the putative yeast mitochondrial triacylglycerol lipase Tgl2.
  11. Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells.
  12. SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation.
  13. PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response.
  14. Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
  15. Mitochondria-plasma membrane contact sites regulate the ER-mitochondria encounter structure.
  16. Near Infrared-Mediated Intracellular NADH Delivery Strengthens Mitochondrial Function and Stability in Muscle Dysfunction Model.
  17. Serine phosphorylation facilitates protein degradation by the human mitochondrial ClpXP protease.
  18. Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain.
  19. Mitochondrial base editing: from principle, optimization to application.
  20. Characterization of Factors Associated With Death in Deceased Patients With Mitochondrial Disorders: A Multicenter Cross-Sectional Survey.
  21. SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters.
  22. Comprehensive analysis of GDF15 as a biomarker in primary mitochondrial myopathies.
  23. Generation of induced pluripotent stem cell line ISMMSi060-A from a patient with combined oxidative phosphorylation deficiency 25.
  24. Modelling the human Coenzyme Q deficiency in Drosophila melanogaster.
  25. The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.
  26. An Addendum to the Chemiosmotic Theory of Mitochondrial Activity: The Role of RNA as a Proton Sink.
  27. De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy-Case Report and Literature Review.
  28. The landscape of rare mitochondrial DNA variants in sudden cardiac death: A potential role for ATP synthase.
  29. Atypical Leber Hereditary Optic Neuropathy (LHON) Associated with a Novel MT-CYB:m.15309T>C(Ile188Thr) Variant.
  30. Genome-wide profiling of tRNA modifications by Induro-tRNAseq reveals coordinated changes.
  31. Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth.
  32. Nicotinamide mononucleotide restores impaired metabolism, endothelial cell proliferation and angiogenesis in old sedentary male mice.
  33. Remodeling of Mitochondria-Endoplasmic Reticulum Contact Sites Accompanies LUHMES Differentiation.
  34. Mitochondrial transplantation for the treatment of cardiac and noncardiac diseases: mechanisms, prospective, and challenges.
  35. Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection.
  36. A machine learning decision support tool optimizes WGS utilization in a neonatal intensive care unit.
  37. Revealing mitochondrial architecture and functions with single molecule localization microscopy.
  38. Genome-wide CRISPR screens identify PTPN21 and WDR26 as modulators of the mitochondrial stress-induced ISR.
  39. Nonapoptotic role of EGL-1 in exopher production and neuronal health in Caenorhabditis elegans.
  40. Selection of initiator tRNA and start codon by mammalian mitochondrial initiation factor 3 in leaderless mRNA translation.
  41. Epstein-Barr virus-driven cardiolipin synthesis sustains metabolic remodeling during B cell transformation.
  42. APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes.
  43. Spatial metabolomics to unravel cellular metabolism.
  44. Synchronized long-read genome, methylome, epigenome and transcriptome profiling resolve a Mendelian condition.
  45. Mitochondrial fission and fusion in neurodegenerative diseases:Ca2+ signalling.
  46. Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability.
  47. Novel strategies targeting mitochondria-lysosome contact sites for the treatment of neurological diseases.
  48. The roles of mitochondria in global and local intracellular calcium signalling.
  49. Mitochondrial microRNAs: Key Drivers in Unraveling Neurodegenerative Diseases.
  50. GenVarLoader: An accelerated dataloader for applying deep learning to personalized genomics.
  51. Epigenetic modification increases skeletal muscle resilience to metabolic stress.
  52. Sub-organellar mitochondrial hydrogen peroxide observed using a SNAP tag targeted coumarin-based fluorescent reporter.
  53. WBSCR16 is essential for mitochondrial 16S rRNA processing in mammals.
  54. Cutaneous Manifestations of NAXD or NAXE Deficiency: A Literature Review for the Dermatologist.
  55. Manganese therapy for dyslipidemia and plaque reversal in murine models.
  56. Revealing Molecular Diagnosis With Whole Exome Sequencing in Patients With Inherited Retinal Disorders.
  57. Super-Resolution Mitochondrial Fluorescent Probe for Accurate Monitoring of Drug-Induced Liver Injury.
  58. Norharmane prevents muscle aging via activation of SKN-1/NRF2 stress response pathways.
  59. AI-driven multi-omics integration for multi-scale predictive modeling of genotype-environment-phenotype relationships.
  60. Biotin mitigates the development of manganese-induced, Parkinson's disease-related neurotoxicity in Drosophila and human neurons.
  61. The Characteristics of the Metabolomic Profile in Patients with Parkinson's Disease and Vascular Parkinsonism.
  62. Genetic and neurochemical profiles underlying cortical morphometric vulnerability to Parkinson's disease.
  63. Structural and Dynamic Assessment of Disease-Causing Mutations for the Carnitine Transporter OCTN2.
  64. NAD World 3.0: the importance of the NMN transporter and eNAMPT in mammalian aging and longevity control.
  65. An augmented transformer model trained on protein family specific variant data leads to improved prediction of variants of uncertain significance.
  66. A genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells.
  1. J Cell Biol. 2025 Mar 03. pii: e202311082. [Epub ahead of print]224(3):
    FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.
    Alva G Sainz, Gladys R Rojas, Alexandra G Moyzis, Matthew P Donnelly, Kailash C Mangalhara, Melissa A Johnson, Pau B Esparza-Moltó, Kym J Grae, Reuben J Shaw, Gerald S Shadel.
      Mitochondrial retrograde signaling (MRS) pathways relay the functional status of mitochondria to elicit homeostatic or adaptive changes in nuclear gene expression. Budding yeast have "intergenomic signaling" pathways that sense the amount of mitochondrial DNA (mtDNA) independently of oxidative phosphorylation (OXPHOS), the primary function of genes encoded by mtDNA. However, MRS pathways that sense the amount of mtDNA in mammalian cells remain poorly understood. We found that mtDNA-depleted IMR90 cells can sustain OXPHOS for a significant amount of time, providing a robust model system to interrogate human intergenomic signaling. We identified FAM43A, a largely uncharacterized protein, as a CHK2-dependent early responder to mtDNA depletion. Depletion of FAM43A activates a mitochondrial biogenesis program, resulting in an increase in mitochondrial mass and mtDNA copy number via CHK2-mediated upregulation of the p53R2 form of ribonucleotide reductase. We propose that FAM43A performs a checkpoint-like function to limit mitochondrial biogenesis and turnover under conditions of mtDNA depletion or replication stress.
    DOI:  https://doi.org/10.1083/jcb.202311082
  2. Sci Transl Med. 2025 Jan 29. 17(783): eadr0792
    Correcting a pathogenic mitochondrial DNA mutation by base editing in mice.
    Jose D Barrera-Paez, Sandra R Bacman, Till Balla, Derek Van Booven, Durga P Gannamedi, James B Stewart, Beverly Mok, David R Liu, David B Lombard, Anthony J Griswold, Danny D Nedialkova, Carlos T Moraes.
      Primary mitochondrial disorders are most often caused by deleterious mutations in the mitochondrial DNA (mtDNA). Here, we used a mitochondrial DddA-derived cytosine base editor (DdCBE) to introduce a compensatory edit in a mouse model that carries the pathological mutation in the mitochondrial transfer RNA (tRNA) alanine (mt-tRNAAla) gene. Because the original m.5024C→T mutation (G→A in the mt-tRNAAla) destabilizes the mt-tRNAAla aminoacyl stem, we designed a compensatory m.5081G→A edit (C→T in the mt-tRNAAla) that could restore the secondary structure of the tRNAAla aminoacyl stem. For this, the DdCBE gene construct was initially tested in an m.5024C→T mutant cell line. The reduced mt-tRNAAla amounts in these cells were increased after editing up to 78% of the mtDNA. Then, DdCBE was packaged in recombinant adeno-associated virus 9 (AAV9) and intravenously administered by retro-orbital injections into mice. Expression of the transduced DdCBE was observed in the heart and skeletal muscle. Total mt-tRNAAla amounts were restored in heart and muscle by the m.5081G→A edit in a dose-dependent manner. Lactate amounts, which were increased in the heart, were also decreased in treated mice. However, the highest dose tested of AAV9-DdCBE also induced severe adverse effects in vivo because of the extensive mtDNA off-target editing that it generated. These results show that although DdCBE is a promising gene therapy tool for mitochondrial disorders, the doses of the therapeutic constructs must be carefully monitored to avoid deleterious off-target editing.
    DOI:  https://doi.org/10.1126/scitranslmed.adr0792
  3. Nat Cell Biol. 2025 Jan 24.
    Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.
      
    DOI:  https://doi.org/10.1038/s41556-024-01603-8
  4. Mol Genet Genomic Med. 2025 Jan;13(1): e70048
    Successful Diagnosis of Sengers Syndrome Using a Comprehensive Genomic Analysis.
    Kohta Nakamura, Yukiko Yatsuka, Sachie Naito, Akira Hasegawa, Takeya Kasukawa, Atsushi Kondo, Yoshihito Kishita, Yohei Sugiyama, Takanori Onuki, Tomohiro Ebihara, Tomoko Tsuruoka, Takuya Fushimi, Akira Ohtake, Kei Murayama, Atsuko Imai-Okazaki, Yasushi Okazaki.
       BACKGROUND: Sengers syndrome is an autosomal recessive mitochondrial DNA depletion syndrome characterized by hypertrophic cardiomyopathy, congenital cataracts, skeletal myopathy, exercise intolerance, and lactic acidosis. Dysfunction of acylglycerol kinase (AGK) is responsible for the disease, and several AGK gene variants have been reported.
    METHODS: We employed a comprehensive genomic analysis approach, including whole-genome sequencing and RNA sequencing, combined with various bioinformatics tools.
    RESULTS: Our analysis successfully diagnosed Sengers syndrome in a patient by detecting a known pathogenic variant and a previously unreported large deletion involving the AGK gene in a segmental duplication.
    CONCLUSION: This study demonstrates the effectiveness of combining multiple genomic analysis approaches for the accurate diagnosis of Sengers syndrome, particularly in cases involving complex genetic variations such as large deletions in segmental duplications.
    Keywords:  Sengers syndrome; genetic analysis; mitochondrial DNA depletion syndrome; mitochondrial disease; mitochondrial respiratory chain complex deficiencies
    DOI:  https://doi.org/10.1002/mgg3.70048
  5. Biomolecules. 2024 Dec 31. pii: 38. [Epub ahead of print]15(1):
    NADH Reductive Stress and Its Correlation with Disease Severity in Leigh Syndrome: A Pilot Study Using Patient Fibroblasts and a Mouse Model.
    Tamaki Ishima, Natsuka Kimura, Mizuki Kobayashi, Chika Watanabe, Eriko F Jimbo, Ryosuke Kobayashi, Takuro Horii, Izuho Hatada, Kei Murayama, Akira Ohtake, Ryozo Nagai, Hitoshi Osaka, Kenichi Aizawa.
      Nicotinamide adenine dinucleotide (NAD) is a critical cofactor in mitochondrial energy production. The NADH/NAD+ ratio, reflecting the balance between NADH (reduced) and NAD+ (oxidized), is a key marker for the severity of mitochondrial diseases. We recently developed a streamlined LC-MS/MS method for the precise measurement of NADH and NAD+. Utilizing this technique, we quantified NADH and NAD+ levels in fibroblasts derived from pediatric patients and in a Leigh syndrome mouse model in which mitochondrial respiratory chain complex I subunit Ndufs4 is knocked out (KO). In patient-derived fibroblasts, NAD+ levels did not differ significantly from those of healthy controls (p = 0.79); however, NADH levels were significantly elevated (p = 0.04), indicating increased NADH reductive stress. This increase, observed despite comparable total NAD(H) levels between the groups, was attributed to elevated NADH levels. Similarly, in the mouse model, NADH levels were significantly increased in the KO group (p = 0.002), further suggesting that NADH elevation drives reductive stress. This precise method for NADH measurement is expected to outperform conventional assays, such as those for lactate, providing a simpler and more reliable means of assessing disease progression.
    Keywords:  LC-MS/MS; Leigh syndrome; NADH; Ndufs4-KO mice; mitochondrial diseases; reductive stress
    DOI:  https://doi.org/10.3390/biom15010038
  6. Phys Biol. 2025 Jan 31. 22(2):
    Electrical homeostasis of the inner mitochondrial membrane potential.
    Peyman Fahimi, Lázaro A M Castanedo, P Thomas Vernier, Chérif F Matta.
      The electric potential across the inner mitochondrial membrane must be maintained within certain bounds for the proper functioning of the cell. A feedback control mechanism for the homeostasis of this membrane potential is proposed whereby an increase in the electric field decreases the rate-limiting steps of the electron transport chain (ETC). An increase in trans-membrane electric field limits the rate of proton pumping to the inter-membrane gap by slowing the ETC reactions and by intrinsically induced electroporation that depolarizes the inner membrane. The proposed feedback mechanism is akin to a Le Chatelier's-type principle of trans-membrane potential feedback control.
    Keywords:  chemiosmotic theory; electrical feedback control in biological systems; mitochondrial biophysics; mitochondrial electric potential; mitochondrial homeostasis
    DOI:  https://doi.org/10.1088/1478-3975/adaa47
  7. J Cell Sci. 2025 Jan 30. pii: jcs.263637. [Epub ahead of print]
    Regulation of mitochondrial cristae organization by Myo19, Miro1/2 and Metaxin 3.
    Samruddhi S Shembekar, Petra Nikolaus, Ulrike Honnert, Marcus Höring, Aya Attia, Karin Topp, Birgit Lohmann, Gerhard Liebisch, Martin Bähler.
      The actin-based motor myosin-19 (Myo19) exerts force on mitochondrial membrane receptors Miro1/2, influencing endoplasmic reticulum (ER)-mitochondria contact sites and mitochondrial cristae structure. The Mitochondrial Intermembrane Bridging (MIB) complex connects the outer and inner mitochondrial membranes at the cristae junction through the MICOS system. However, the interaction between Myo19, Miro1/2, and the MIB/MICOS complex in cristae regulation remains unclear. This study investigates the roles of Miro1/2 and metaxin 3 (Mtx3), a MIB complex component, in linking Myo19 to MIB/MICOS. We show that Miro1/2 interact with Myo19 and the MIB complex, but not with Mtx3. Their mitochondrial membrane anchors are not essential for MIB interaction or cristae structure. However, Mtx3 is crucial for Myo19 and Miro1/2's connection to MIB/MICOS. Deleting Miro1/2 mimics Myo19 deficiency effects on ER-mitochondria contacts and cristae structure, while Mtx3 deletion does not. Notably, the loss of Myo19 and Miro1/2 alters mitochondrial lipid composition, reducing cardiolipin and its precursors, suggesting Myo19 and Miro1/2 influence cristae indirectly via lipid transfer at ER-mitochondria contact sites.
    Keywords:  Cristae organization; Lipid transfer; Mitochondria; Myosin; Rho GTPases
    DOI:  https://doi.org/10.1242/jcs.263637
  8. Cell Death Dis. 2025 Jan 25. 16(1): 40
    Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.
    Lohans Pedrera, Laura Prieto Clemente, Alina Dahlhaus, Sara Lotfipour Nasudivar, Sofya Tishina, Daniel Olmo González, Jenny Stroh, Fatma Isil Yapici, Randhwaj Pratap Singh, Nils Grotehans, Thomas Langer, Ana J García-Sáez, Silvia von Karstedt.
      Constitutive mitochondrial dynamics ensure quality control and metabolic fitness of cells, and their dysregulation has been implicated in various human diseases. The large GTPase Dynamin-related protein 1 (Drp1) is intimately involved in mediating constitutive mitochondrial fission and has been implicated in mitochondrial cell death pathways. During ferroptosis, a recently identified type of regulated necrosis driven by excessive lipid peroxidation, mitochondrial fragmentation has been observed. Yet, how this is regulated and whether it is involved in ferroptotic cell death has remained unexplored. Here, we provide evidence that Drp1 is activated upon experimental induction of ferroptosis and promotes cell death execution and mitochondrial fragmentation. Using time-lapse microscopy, we found that ferroptosis induced mitochondrial fragmentation and loss of mitochondrial membrane potential, but not mitochondrial outer membrane permeabilization. Importantly, Drp1 accelerated ferroptotic cell death kinetics. Notably, this function was mediated by the regulation of mitochondrial dynamics, as overexpression of Mitofusin 2 phenocopied the effect of Drp1 deficiency in delaying ferroptosis cell death kinetics. Mechanistically, we found that Drp1 is phosphorylated and activated after induction of ferroptosis and that it translocates to mitochondria. Further activation at mitochondria through the phosphatase PGAM5 promoted ferroptotic cell death. Remarkably, Drp1 depletion delayed mitochondrial and plasma membrane lipid peroxidation. These data provide evidence for a functional role of Drp1 activation and mitochondrial fragmentation in the acceleration of ferroptotic cell death, with important implications for targeting mitochondrial dynamics in diseases associated with ferroptosis.
    DOI:  https://doi.org/10.1038/s41419-024-07312-2
  9. Mol Biol Cell. 2025 Jan 29. mbcE25010035
    Mechanism of chaperone recruitment and retention on mitochondrial precursors.
    Szymon Juszkiewicz, Sew-Yeu Peak-Chew, Ramanujan S Hegde.
      Nearly all mitochondrial proteins are imported into mitochondria from the cytosol. How nascent mitochondrial precursors acquire and sustain import-competence in the cytosol under normal and stress conditions is incompletely understood. Here, we show that under normal conditions, the Hsc70 and Hsp90 systems interact with and redundantly minimize precursor degradation. During acute import stress, Hsp90 buffers precursor degradation, preserving proteins in an import-competent state until stress resolution. Unexpectedly, buffering by Hsp90 relies critically on a mitochondrial targeting signal (MTS), the absence of which greatly decreases precursor-Hsp90 interaction. Site-specific photo-crosslinking and biochemical reconstitution showed how the MTS directly engages co-chaperones of Hsc70 (St13 and Stip1) and Hsp90 (p23 and Cdc37) to facilitate chaperone retention on the mature domain. Thus, the MTS has a previously unappreciated role in regulating chaperone dynamics on mitochondrial precursors to buffer their degradation and maintain import competence, functions that may facilitate restoration of mitochondrial homeostasis after acute import stress.
    DOI:  https://doi.org/10.1091/mbc.E25-01-0035
  10. J Biol Chem. 2025 Jan 23. pii: S0021-9258(25)00064-X. [Epub ahead of print] 108217
    Characterization of the putative yeast mitochondrial triacylglycerol lipase Tgl2.
    Vitasta Tiku, Zacharias Fakih, Takashi Tatsuta, Martin Jung, Doron Rapaport, Kai Stefan Dimmer.
      Mitochondria derive the majority of their lipids from other organelles through contact sites. These lipids, primarily phosphoglycerolipids, are the main components of mitochondrial membranes. In the cell, neutral lipids like triacylglycerides (TAGs) are stored in lipid droplets, playing an important role in maintaining cellular health. Enzymes like lipases mobilize these TAGs according to cellular needs. Neutral lipids have not yet been reported to play an important role in mitochondria so the presence of a putative TAG lipase - Tgl2, in yeast mitochondria is surprising. Moreover, TGL2 and MCP2, a high-copy suppressor for ERMES deficient cells, display genetic interactions suggesting a potential link of both proteins to lipid metabolism. In this study, we characterize in detail Tgl2. We show that Tgl2 forms dimers through intermolecular disulfide bridges and a cysteine-dependent high molecular weight complex. Furthermore, we could identify the lipase motif and catalytic triad of Tgl2 through in silico comparison with other lipases. Mutating each of the three catalytically active residues resulted in variants that failed to rescue the growth phenotype of mcp2Δ tgl2Δ double deletion strain supporting the assumption that these residues are indeed essential for the protein's function. Additionally, we discovered that the catalytically active aspartate residue (D259) is important for protein stability. Steady state level analyses with unstable variants of Tgl2 led to the identification of Yme1 as the protease responsible for its quality control. Finally, we provide evidence that the overall increase in TAGs in cells lacking Mcp2 and Tgl2 originates from the mitochondria. Collectively, our study provides new insights into a key player in mitochondrial lipid homeostasis.
    Keywords:  intermembrane space; lipases; lipids; mitochondria
    DOI:  https://doi.org/10.1016/j.jbc.2025.108217
  11. Cell Mol Biol Lett. 2025 Jan 09. 30(1): 3
    Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells.
    Adhish S Walvekar, Marc Warmoes, Dean Cheung, Tim Sikora, Najmesadat Seyedkatouli, Gemma Gomez-Giro, Sebastian Perrone, Lisa Dengler, François Unger, Bruno F R Santos, Floriane Gavotto, Xiangyi Dong, Julia Becker-Kettern, Yong-Jun Kwon, Christian Jäger, Jens C Schwamborn, Nicole J Van Bergen, John Christodoulou, Carole L Linster.
       BACKGROUND: Metabolism is error prone. For instance, the reduced forms of the central metabolic cofactors nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH), can be converted into redox-inactive products, NADHX and NADPHX, through enzymatically catalyzed or spontaneous hydration. The metabolite repair enzymes NAXD and NAXE convert these damaged compounds back to the functional NAD(P)H cofactors. Pathogenic loss-of-function variants in NAXE and NAXD lead to development of the neurometabolic disorders progressive, early-onset encephalopathy with brain edema and/or leukoencephalopathy (PEBEL)1 and PEBEL2, respectively.
    METHODS: To gain insights into the molecular disease mechanisms, we investigated the metabolic impact of NAXD deficiency in human cell models. Control and NAXD-deficient cells were cultivated under different conditions, followed by cell viability and mitochondrial function assays as well as metabolomic analyses without or with stable isotope labeling. Enzymatic assays with purified recombinant proteins were performed to confirm molecular mechanisms suggested by the cell culture experiments.
    RESULTS: HAP1 NAXD knockout (NAXDko) cells showed growth impairment specifically in a basal medium containing galactose instead of glucose. Surprisingly, the galactose-grown NAXDko cells displayed only subtle signs of mitochondrial impairment, whereas metabolomic analyses revealed a strong inhibition of the cytosolic, de novo serine synthesis pathway in those cells as well as in NAXD patient-derived fibroblasts. We identified inhibition of 3-phosphoglycerate dehydrogenase as the root cause for this metabolic perturbation. The NAD precursor nicotinamide riboside (NR) and inosine exerted beneficial effects on HAP1 cell viability under galactose stress, with more pronounced effects in NAXDko cells. Metabolomic profiling in supplemented cells indicated that NR and inosine act via different mechanisms that at least partially involve the serine synthesis pathway.
    CONCLUSIONS: Taken together, our study identifies a metabolic vulnerability in NAXD-deficient cells that can be targeted by small molecules such as NR or inosine, opening perspectives in the search for mechanism-based therapeutic interventions in PEBEL disorders.
    Keywords:  3-Phosphoglycerate dehydrogenase; Inborn errors of metabolism; Inosine; Metabolite damage and repair; NAD(P)H hydration; NAXD; Nicotinamide riboside; Serine biosynthesis
    DOI:  https://doi.org/10.1186/s11658-024-00681-8
  12. Nat Commun. 2025 Jan 24. 16(1): 978
    SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation.
    Izabella A Pena, Jeffrey S Shi, Sarah M Chang, Jason Yang, Samuel Block, Charles H Adelmann, Heather R Keys, Preston Ge, Shveta Bathla, Isabella H Witham, Grzegorz Sienski, Angus C Nairn, David M Sabatini, Caroline A Lewis, Nora Kory, Matthew G Vander Heiden, Myriam Heiman.
      Many essential proteins require pyridoxal 5'-phosphate, the active form of vitamin B6, as a cofactor for their activity. These include enzymes important for amino acid metabolism, one-carbon metabolism, polyamine synthesis, erythropoiesis, and neurotransmitter metabolism. A third of all mammalian pyridoxal 5'-phosphate-dependent enzymes are localized in the mitochondria; however, the molecular machinery involved in the regulation of mitochondrial pyridoxal 5'-phosphate levels in mammals remains unknown. In this study, we used a genome-wide CRISPR interference screen in erythroleukemia cells and organellar metabolomics to identify the mitochondrial inner membrane protein SLC25A38 as a regulator of mitochondrial pyridoxal 5'-phosphate. Loss of SLC25A38 causes depletion of mitochondrial, but not cellular, pyridoxal 5'-phosphate, and impairs cellular proliferation under both physiological and low vitamin B6 conditions. Metabolic changes associated with SLC25A38 loss suggest impaired mitochondrial pyridoxal 5'-phosphate-dependent enzymatic reactions, including serine to glycine conversion catalyzed by serine hydroxymethyltransferase-2 as well as ornithine aminotransferase. The proliferation defect of SLC25A38-null K562 cells in physiological and low vitamin B6 media can be explained by the loss of serine hydroxymethyltransferase-2-dependent production of one-carbon units and downstream de novo nucleotide synthesis. Our work points to a role for SLC25A38 in mitochondrial pyridoxal 5'-phosphate accumulation and provides insights into the pathology of congenital sideroblastic anemia.
    DOI:  https://doi.org/10.1038/s41467-025-56130-3
  13. Elife. 2025 Jan 29. pii: RP102852. [Epub ahead of print]13
    PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response.
    Ling Cheng, Ian Meliala, Yidi Kong, Jingyuan Chen, Christopher G Proud, Mikael Björklund.
      Mitochondrial dysfunction is involved in numerous diseases and the aging process. The integrated stress response (ISR) serves as a critical adaptation mechanism to a variety of stresses, including those originating from mitochondria. By utilizing mass spectrometry-based cellular thermal shift assay (MS-CETSA), we uncovered that phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitory protein (RKIP), is thermally stabilized by stresses which induce mitochondrial ISR. Depletion of PEBP1 impaired mitochondrial ISR activation by reducing eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and subsequent ISR gene expression, which was independent of PEBP1's role in inhibiting the RAF/MEK/ERK pathway. Consistently, overexpression of PEBP1 potentiated ISR activation by heme-regulated inhibitor (HRI) kinase, the principal eIF2α kinase in the mitochondrial ISR pathway. Real-time interaction analysis using luminescence complementation in live cells revealed an interaction between PEBP1 and eIF2α, which was disrupted by eIF2α S51 phosphorylation. These findings suggest a role for PEBP1 in amplifying mitochondrial stress signals, thereby facilitating an effective cellular response to mitochondrial dysfunction. Therefore, PEBP1 may be a potential therapeutic target for diseases associated with mitochondrial dysfunction.
    Keywords:  PEBP1; cell biology; human; integrated stress response; mitochondrial dysfunction
    DOI:  https://doi.org/10.7554/eLife.102852
  14. Trends Endocrinol Metab. 2025 Jan 28. pii: S1043-2760(25)00003-7. [Epub ahead of print]
    Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
    Brandon Chen, Yatrik M Shah, Costas A Lyssiotis.
      Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox demands within the same cell. They demonstrate that subcellular mitochondrial heterogeneity enables metabolic compartmentalization to permit concurrent oxidative ATP production and reductive proline biosynthesis.
    Keywords:  metabolic compartmentalization; mitochondria dynamics; mitochondrial ultrastructure; organelle communication; proline metabolism
    DOI:  https://doi.org/10.1016/j.tem.2025.01.003
  15. J Cell Sci. 2025 Jan 29. pii: jcs.263685. [Epub ahead of print]
    Mitochondria-plasma membrane contact sites regulate the ER-mitochondria encounter structure.
    Jason C Casler, Clare S Harper, Laura L Lackner.
      Cells form multiple, molecularly distinct membrane contact sites (MCSs) between organelles. Despite knowing the molecular identity of several of these complexes, little is known about how MCSs are coordinately regulated in space and time to promote organelle function. Here, we examined two well-characterized mitochondria-ER MCSs - the ER-Mitochondria encounter structure (ERMES) and the mitochondria-ER-cortex anchor (MECA). We report that loss of MECA results in a substantial reduction in the number of ERMES contacts. Rather than reducing ERMES protein levels, loss of MECA results in an increase in the size of ERMES contacts. Using live cell microscopy, we demonstrate that ERMES contacts display several dynamic behaviors, such as de novo formation, fusion, and fission, that are altered in the absence of MECA or by changes in growth conditions. Unexpectedly, we find that the mitochondria-PM tethering, not the mitochondria-ER tethering, function of MECA regulates ERMES contacts. Remarkably, synthetic tethering of mitochondria to the PM in the absence of MECA is sufficient to rescue the distribution of ERMES foci. Overall, our work reveals how one MCS can influence the regulation and function of another.
    Keywords:  Membrane contact sites; Mitochondria; Mitochondrial positioning
    DOI:  https://doi.org/10.1242/jcs.263685
  16. Adv Sci (Weinh). 2025 Jan 31. e2415303
    Near Infrared-Mediated Intracellular NADH Delivery Strengthens Mitochondrial Function and Stability in Muscle Dysfunction Model.
    Hui Bang Cho, Hye-Ryoung Kim, Sujeong Lee, Chae Won Cho, Ji-In Park, Seulki Youn, Gyuwon So, Sumin Kang, Hye Jin Kim, Keun-Hong Park.
      Mitochondrial transfer emerges as a promising therapy for the restoration of mitochondrial function in damaged cells, mainly due to its limited immunogenicity. However, isolated mitochondria rapidly lose function because they produce little energy outside cells. Therefore, this study investigates whether near infrared (NIR)-mediated nicotinamide adenine dinucleotide (NADH) pre-treatment enhances mitochondrial function and stability in mitochondria-donor cells prior to transplantation. Clinical applications of NADH, an essential electron donor in the oxidative phosphorylation process, are restricted due to the limited cellular uptake of NADH. To address this, a photo-mediated method optimizes direct NADH delivery into cells and increases NADH absorption. L6 cells treated with NADH and irradiated with NIR enhanced NADH uptake, significantly improving mitochondrial energy production and function. Importantly, the improved functional characteristics of the mitochondria are maintained even after isolation from cells. Primed mitochondria, i.e., those enhanced by NIR-mediated NADH uptake (P-MT), are encapsulated in fusogenic liposomes and delivered into muscle cells with mitochondrial dysfunction. Compared to conventional mitochondria, P-MT mitochondria promote greater mitochondrial recovery and muscle regeneration. These findings suggest that NIR-mediated NADH delivery is an effective strategy for improving mitochondrial function, and has the potential to lead to novel treatments for mitochondrial disorders and muscle degeneration.
    Keywords:  NADH delivery; mitochondrial priming; mitotherapy; muscle regeneration; near‐infrared (NIR)
    DOI:  https://doi.org/10.1002/advs.202415303
  17. Proc Natl Acad Sci U S A. 2025 Feb 04. 122(5): e2422447122
    Serine phosphorylation facilitates protein degradation by the human mitochondrial ClpXP protease.
    Yue Feng, Monica M Goncalves, Yulia Jitkova, Alexander F A Keszei, Yongran Yan, Chaitra Sarathy, Jonathan St-Germain, Tristan M G Kenney, Matthew Tcheng, Vincent Trudel, Ross S Mancini, Rahul Upadhyay, Rose Hurren, Marcela Gronda, Matthew Schultz, Kaylen Soriano, Kaitlin Lees, Neil C Pomroy, S Quinn W Currie, Gilbert G Privé, Mark A Reed, Andrei K Yudin, Linda Z Penn, Cheryl H Arrowsmith, Brian Raught, Mohammad T Mazhab-Jafari, Siavash Vahidi, Aaron D Schimmer.
      ClpXP is a two-component mitochondrial matrix protease. The caseinolytic mitochondrial matrix peptidase chaperone subunit X (ClpX) recognizes and translocates protein substrates into the degradation chamber of the caseinolytic protease P (ClpP) for proteolysis. ClpXP degrades damaged respiratory chain proteins and is necessary for cancer cell survival. Despite the critical role of ClpXP in mitochondrial protein quality control, the specific degrons, or modifications that tag substrate proteins for degradation by human ClpXP, are still unknown. We demonstrated that phosphorylated serine (pSer) targets substrates to ClpX and facilitates their degradation by ClpXP in biochemical assays. In contrast, ClpP hyperactivated by the small-molecule drug ONC201 lost the preference for phosphorylated substrates. Hydrogen deuterium exchange mass spectrometry combined with biochemical assays showed that pSer binds the RKL loop of ClpX. ClpX variants with substitutions in the RKL loop failed to recognize phosphorylated substrates. In intact cells, ClpXP also preferentially degraded substrates with pSer. Moreover, ClpX substrates with the pSer were selectively found in aggregated mitochondrial proteins. Our work uncovers a mechanism for substrate recognition by ClpXP, with implications for targeting acute myeloid leukemia and other disorders involving ClpXP dysfunction.
    Keywords:  AAA+ proteases; degron; mitochondrial proteostasis; phosphorylation; protein degradation
    DOI:  https://doi.org/10.1073/pnas.2422447122
  18. Proc Natl Acad Sci U S A. 2025 Feb 04. 122(5): e2412029122
    Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain.
    Enrico Bagnoli, Yu-En Lin, Sophie Burel, Ebsy Jaimon, Odetta Antico, Christos Themistokleous, Jonas M Nikoloff, Samuel Squires, Ilaria Morella, Jens O Watzlawik, Fabienne C Fiesel, Wolfdieter Springer, Francesca Tonelli, Pawel Lis, Simon P Brooks, Stephen B Dunnett, Riccardo Brambilla, Dario R Alessi, Suzanne R Pfeffer, Miratul M K Muqit.
      Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1) are associated with familial Parkinson's disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock-in mice with PINK1 knock-out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2-mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1-mediated Rab and Ub phosphorylation. In addition, we observe that a pool of the Rab-specific, protein phosphatase family member 1H phosphatase, is transcriptionally up-regulated and recruited to damaged mitochondria, independent of PINK1 or LRRK2 activity. Parallel signaling of LRRK2 and PINK1 pathways is supported by assessment of motor behavioral studies that show no evidence of genetic interaction in crossed mouse lines. Previously we showed loss of cilia in LRRK2 R1441C mice and herein we show that PINK1 KO mice exhibit a ciliogenesis defect in striatal cholinergic interneurons and astrocytes that interferes with Hedgehog induction of glial derived-neurotrophic factor transcription. This is not exacerbated in double-mutant LRRK2 and PINK1 mice. Overall, our analysis indicates that LRRK2 activation and/or loss of PINK1 function along parallel pathways to impair ciliogenesis, suggesting a convergent mechanism toward PD. Our data suggest that reversal of defects downstream of ciliogenesis offers a common therapeutic strategy for LRRK2 or PINK1 PD patients, whereas LRRK2 inhibitors that are currently in clinical trials are unlikely to benefit PINK1 PD patients.
    Keywords:  LRRK2; PINK1; brain; ciliogenesis; phosphorylation
    DOI:  https://doi.org/10.1073/pnas.2412029122
  19. Cell Biosci. 2025 Jan 24. 15(1): 9
    Mitochondrial base editing: from principle, optimization to application.
    Jinling Tang, Kunzhao Du.
      In recent years, mitochondrial DNA (mtDNA) base editing systems have emerged as bioengineering tools. DddA-derived cytosine base editors (DdCBEs) have been developed to specifically induce C-to-T conversion in mtDNA by the fusion of sequence-programmable transcription activator-like effector nucleases (TALENs) or zinc-finger nucleases (ZFNs), and split deaminase derived from interbacterial toxins. Similar to DdCBEs, mtDNA adenine base editors have been developed with the ability to introduce targeted A-to-G conversions into human mtDNA. In this review, we summarize the principles of mtDNA base-editing systems and elaborate on the evolution of different platforms of mtDNA base editors, including their deaminase replacement, engineering of DddAtox variants, structure optimization and editing outcomes. Finally, we highlight their applications in animal models and human embroys and discuss the future developmental direction and challenges of mtDNA base editors.
    Keywords:  DdCBEs; Genetic engineering; Mitochondrial DNA; TALENs; mtDNA base editing
    DOI:  https://doi.org/10.1186/s13578-025-01351-8
  20. Neurology. 2025 Feb 25. 104(4): e209779
    Characterization of Factors Associated With Death in Deceased Patients With Mitochondrial Disorders: A Multicenter Cross-Sectional Survey.
    as the Hong Kong Mitochondrial Diseases Interest Group
       BACKGROUND AND OBJECTIVES: Mitochondrial disorders are multiorgan disorders resulting in significant morbidity and mortality. We aimed to characterize death-associated factors in an international cohort of deceased individuals with mitochondrial disorders.
    METHODS: This cross-sectional multicenter observational study used data provided by 26 mitochondrial disease centers from 8 countries from January 2022 to March 2023. Individuals with genetically confirmed mitochondrial disorders were included, along with patients with clinically or genetically diagnosed Leigh syndrome. Collected data included demographic and genetic diagnosis variables, clinical phenotype, involvement of organs and systems, conditions leading to death, and supportive care. We defined pediatric and adult groups based on age at death before or after 18 years, respectively. We used Kruskal-Wallis with post hoc Dunn test with Bonferroni correction and Fisher exact test for comparisons, Spearman rank test for correlations, and multiple linear regression for multivariable analysis.
    RESULTS: Data from 330 deceased individuals with mitochondrial disorders (191 [57.9%] pediatric) were analyzed. The shortest survival times were observed in hepatocerebral syndrome (median 0.3, interquartile range [IQR] 0.2-0.6 years) and mitochondrial cardiomyopathy (median 0.3, IQR 0.2-5.2 years) and the longest in chronic progressive external ophthalmoplegia plus (median 26.5, IQR 22.8-40.2 years) and sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (median 21.0, IQR 13.8-28.5 years). Respiratory failure and pulmonary infections were the most common conditions associated with death (52/330, 15.7% and 46/330, 13.9%, respectively). Noninvasive ventilation was required more often in children (57/191, 29.8%) than adults (12/139, 8.6%, p < 0.001), as was nasogastric or gastric tube (131/191, 68.6% in children and 39/139, 28.1% in adults, p < 0.001). On multivariate analysis, individuals with movement disorders and nuclear gene involvement had increased odds of any respiratory support use (OR 2.42 (95% CI 1.17-5.22) and OR 2.39 (95% CI 1.16-5.07), respectively).
    DISCUSSION: This international collaboration highlights the importance of respiratory care and infection management and provides a reference for prognostication across different mitochondrial disorders.
    DOI:  https://doi.org/10.1212/WNL.0000000000209779
  21. Nat Commun. 2025 Jan 30. 16(1): 1181
    SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters.
    Mingyang Chen, Luexiang Yuan, Binxin Chen, Hui Chang, Jun Luo, Hengbin Zhang, Zhongjian Chen, Jiao Kong, Yaodong Yi, Mengru Bai, Minlei Dong, Hui Zhou, Huidi Jiang.
      Nicotinamide (NAM), a main precursor of NAD+, is essential for cellular fuel respiration, energy production, and other cellular processes. Transporters for other precursors of NAD+ such as nicotinic acid and nicotinamide mononucleotide (NMN) have been identified, but the cellular transporter of nicotinamide has not been elucidated. Here, we demonstrate that equilibrative nucleoside transporter 1 and 2 (ENT1 and 2, encoded by SLC29A1 and 2) drive cellular nicotinamide uptake and establish nicotinamide metabolism homeostasis. In addition, ENT1/2 exhibits a strong capacity to change the cellular metabolite composition and the transcript, especially those related to nicotinamide. We further observe that ENT1/2 regulates cellular respiration and senescence, contributing by altering the NAD+ pool level and mitochondrial status. Changes to cellular respiration, mitochondrial status and senescence by ENT1/2 knockdown are reversed by NMN supplementation. Together, ENT1 and ENT2 act as both cellular nicotinamide-level keepers and nicotinamide biological regulators through their NAM transport functions.
    DOI:  https://doi.org/10.1038/s41467-025-56402-y
  22. Mol Genet Metab. 2025 Jan 20. pii: S1096-7192(25)00014-9. [Epub ahead of print]144(3): 109023
    Comprehensive analysis of GDF15 as a biomarker in primary mitochondrial myopathies.
    Paloma Martín-Jimenez, Laura Bermejo-Guerrero, María Navarro-Riquelme, Pablo Serrano-Lorenzo, Rocío Garrido-Moraga, Aurelio Hernández-Laín, Ana Hernández-Voth, David Lora, Montserrat Morales, Joaquín Arenas, Alberto Blázquez, Miguel Ángel Martín, Cristina Domínguez-González.
       BACKGROUND AND OBJECTIVES: Mitochondrial diseases are caused by defects in oxidative phosphorylation, with primary mitochondrial myopathies (PMM) being a subset where muscle involvement is predominant. PMM presents symptoms ranging from exercise intolerance to progressive muscle weakness, often involving ocular muscles, leading to ptosis and progressive external ophthalmoplegia (PEO). PMM can be due to variants in mitochondrial or nuclear DNA. Growth differentiation factor 15 (GDF15) has been identified as an accurate biomarker for mitochondrial dysfunction. This study evaluates the utility of GDF15 as a biomarker for monitoring PMM.
    METHODS: This observational study involved 50 adult PMM patients. Clinical data were collected alongside functional motor outcomes measured by the Motor Research Council scale, 6-min walk test, North Star Ambulatory Assessment, and 100-m run test (100MRT). Biomarkers including serum lactate, creatine kinase (CK), creatinine, and plasma GDF15 were assessed.
    RESULTS: Patients exhibited diverse phenotypes, including exercise intolerance (8 %), progressive myopathy (22 %), isolated PEO (24 %), and PEO plus (42 %). Significant correlations were found among motor function tests, with 100MRT being particularly sensitive. Biomarker analysis showed elevated lactate in 32 %, elevated CK in 54 %, reduced creatinine in 76 %, and elevated GDF15 in 86 % of cases. GDF15 levels correlated with motor performance, lactate levels, and mtDNA mutation load in muscle. Creatinine levels were strongly linked to disease severity.
    DISCUSSION: This study underscores the heterogeneity of PMM and the importance of reliable biomarkers. GDF15 was consistently elevated across all PMM phenotypes and genotypes, correlating well with disease severity. Reduced creatinine also emerged as a potential prognostic marker.
    Keywords:  Biomarker; GDF15; Mitochondrial disease; Natural history; Primary mitochondrial myopathy
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109023
  23. Stem Cell Res. 2025 Jan 20. pii: S1873-5061(25)00012-1. [Epub ahead of print]83 103662
    Generation of induced pluripotent stem cell line ISMMSi060-A from a patient with combined oxidative phosphorylation deficiency 25.
    Sophia E Salemi, Erdene Baljinnyam, Norman N Liu, Ruiqi Hu, Samuele G Marro, Bryn D Webb.
      We have described a novel mitochondrial disorder caused by biallelic pathogenic variants in the methionyl-tRNA synthetase 2 gene (MARS2), now termed Combined oxidative phosphorylation deficiency 25 (COXPD25). This study focuses on the generation and characterization of induced pluripotent stem cells (iPSCs) from fibroblasts of a patient with COXPD25. The resulting iPSC line ISMMSi060-A, carries the compound heterozygous variants c.550C > T; p.Gln184* and c.424C > T; p.Arg142Trp in MARS2. The iPSCs exhibited normal cell morphology, expression of pluripotency markers, genome integrity, and the ability to differentiate.
    Keywords:  Combined oxidative phosphorylation deficiency; MARS2; Mitochondrial aminoacyl-tRNA synthetase
    DOI:  https://doi.org/10.1016/j.scr.2025.103662
  24. Free Radic Biol Med. 2025 Jan 24. pii: S0891-5849(24)01165-1. [Epub ahead of print]
    Modelling the human Coenzyme Q deficiency in Drosophila melanogaster.
    Daniel J M Fernández-Ayala, Sandra Jiménez-Gancedo, Ignacio Guerra, Juan D Hernández-Camacho, Marta Neto, Filippo Scialo, Verónica Astillero-López, Ana Belén Cortés-Rodríguez, Carlos Santos-Ocaña, Juan Carlos Rodríguez-Aguilera, Fernando Casares, Alberto Sanz, Guillermo López-Lluch, Plácido Navas.
      The interference of the expression of each of the genes involved in the synthesis of coenzyme Q (CoQ) in Drosophila melanogaster can help to understand the pathophysiology of CoQ-dependent mitochondrial diseases in humans. We have knocked-down all genes involved in the CoQ biosynthesis pathway at different temperatures to induce depletion of CoQ at different levels throughout the body and in a tissue-specific manner. The efficiency of the knockdowns was quantified by Q-RTPCR and determination of CoQ levels by HPLC-UV+ECD. We performed mitochondria purification and quantified respiratory chain activity, both mitochondrial hydrogen peroxide and superoxide production, resistance to mechanical stress and determination of life expectancy. Finally, we evaluated the effect of CoQ10 supplementation as phenotype rescue therapy. D. melanogaster presents 3 isoforms of CoQ: CoQ8, CoQ9 and CoQ10. The level of depletion depended on the efficiency of the RNAi used and is specific for each gene. The interference of some genes interrupted fly development in embryogenesis (pdss2) or during metamorphosis (pdss1, coq3, coq5, coq8 and coq10), while in other cases viable adults can be obtained (coq2, coq6 and coq7). The knockdown of coq7 accumulated intermediates of the CoQ biosynthesis pathway at all stages of development, altered electron transfer with poor assembly of mitochondrial complexes, and deregulated mitochondrial hydrogen peroxide and superoxide production. Coq7 mutant flies showed partial lethality in metamorphosis, bang sensitivity and reduced life span of surviving animals. CoQ10 supplementation rescued the coq7-mutant phenotypes. Knock-down in the imaginal disc generated gene-specific eye deformities that can be mitigated by CoQ10 supplementation. Our results indicate that interference of the CoQ biosynthesis pathway in D. melanogaster shows a great diversity of phenotypes depending on the target gene, mirroring the heterogeneity of CoQ deficiency syndrome in humans and point to why mutations in certain genes are rarely found in patients.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.056
  25. Nat Commun. 2025 Jan 25. 16(1): 1021
    The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.
    Foozhan Tahmasebinia, Yinglu Tang, Rushi Tang, Yi Zhang, Will Bonderer, Maisa de Oliveira, Bretton Laboret, Songjie Chen, Ruiqi Jian, Lihua Jiang, Michael Snyder, Chun-Hong Chen, Yawei Shen, Qing Liu, Boxiang Liu, Zhihao Wu.
      The 40S ribosomal subunit recycling pathway is an integral link in the cellular quality control network, occurring after translational errors have been corrected by the ribosome-associated quality control (RQC) machinery. Despite our understanding of its role, the impact of translation quality control on cellular metabolism remains poorly understood. Here, we reveal a conserved role of the 40S ribosomal subunit recycling (USP10-G3BP1) complex in regulating mitochondrial dynamics and function. The complex binds to fission-fusion proteins located at mitochondrial hotspots, regulating the functional assembly of endoplasmic reticulum-mitochondria contact sites (ERMCSs). Furthermore, it alters the activity of mTORC1/2 pathways, suggesting a link between quality control and energy fluctuations. Effective communication is essential for resolving proteostasis-related stresses. Our study illustrates that the USP10-G3BP1 complex acts as a hub that interacts with various pathways to adapt to environmental stimuli promptly. It advances our molecular understanding of RQC regulation and helps explain the pathogenesis of human proteostasis and mitochondrial dysfunction diseases.
    DOI:  https://doi.org/10.1038/s41467-025-56346-3
  26. Biomolecules. 2025 Jan 08. pii: 87. [Epub ahead of print]15(1):
    An Addendum to the Chemiosmotic Theory of Mitochondrial Activity: The Role of RNA as a Proton Sink.
    Ramin M Farahani.
      Mitochondrial ATP synthesis is driven by harnessing the electrochemical gradient of protons (proton motive force) across the mitochondrial inner membrane via the process of chemiosmosis. While there is consensus that the proton gradient is generated by components of the electron transport chain, the mechanism by which protons are supplied to ATP synthase remains controversial. As opposed to a global coupling model whereby protons diffuse into the intermembrane space, a localised coupling model predicts that protons remain closely associated with the lipid membrane prior to interaction with ATP synthase. Herein, a revised version of the chemiosmotic theory is proposed by introducing an RNA-based proton sink which aligns the release of sequestered protons to availability of ADP and Pi thereby maximising the efficiency of oxidative phosphorylation.
    Keywords:  RNA; chemiosmosis; proton motive force; proton sink
    DOI:  https://doi.org/10.3390/biom15010087
  27. Int J Mol Sci. 2025 Jan 20. pii: 846. [Epub ahead of print]26(2):
    De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy-Case Report and Literature Review.
    Martina Magistrati, Luisa Zupin, Eleonora Lamantea, Enrico Baruffini, Daniele Ghezzi, Andrea Legati, Fulvio Celsi, Flora Maria Murru, Valeria Capaci, Maurizio Pinamonti, Rossana Bussani, Marco Carrozzi, Cristina Dallabona, Massimo Zeviani, Maria Teresa Bonati.
      Pathogenic variants in DNM1L, encoding dynamin-like protein-1 (DRP1), cause a lethal encephalopathy. DRP1 defective function results in altered mitochondrial networks, characterized by elongated/spaghetti-like, highly interconnected mitochondria. We validated in yeast the pathogenicity of a de novo DNM1L variant identified by whole exome sequencing performed more than 10 years after the patient's death. Meanwhile, we reviewed the broadness and specificities of DNM1L-related phenotype. The patient, who exhibited developmental delay in her third year, developed a therapy-refractory myoclonic status epilepticus, followed by neurological deterioration with brain atrophy and refractory epilepsy. She died of heart failure due to hypertrophic cardiomyopathy. She was found to be heterozygous for the DNM1L variant (NM_ 012062.5):c.1201G>A, p.(Gly401Ser). We demonstrated its deleterious impact and dominant negative effect by assessing haploid and diploid mutant yeast strains, oxidative growth, oxygen consumption, frequency of petite, and architecture of the mitochondrial network. Structural modeling of p.(Gly401Ser) predicted the interference of the mutant protein in the self-oligomerization of the DRP1 active complex. DNM1L-related phenotypes include static or (early) lethal encephalopathy and neurodevelopmental disorders. In addition, there may be ophthalmological impairment, peripheral neuropathy, ataxia, dystonia, spasticity, myoclonus, and myopathy. The clinical presentations vary depending on mutations in different DRP1 domains. Few pathogenic variants, the p.(Gly401Ser) included, cause an encephalocardiomyopathy with refractory status epilepticus.
    Keywords:  DNM1L; burst suppression; global developmental regression; hypertrophic cardiomyopathy (HC); lethal encephalocardiomyopathy; refractory status epilepticus (RSE); retrospective post-mortem diagnosis
    DOI:  https://doi.org/10.3390/ijms26020846
  28. Heliyon. 2025 Jan 15. 11(1): e41592
    The landscape of rare mitochondrial DNA variants in sudden cardiac death: A potential role for ATP synthase.
    Elena Luppi, Monica De Luise, Carla Bini, Guido Pelletti, Gaia Tioli, Ivana Kurelac, Luisa Iommarini, Susi Pelotti, Giuseppe Gasparre.
      Sudden cardiac death (SCD) is a major health concern, which can be the sign of a latent mitochondrial disease. However, mitochondrial DNA (mtDNA) contribution is largely unexplored in SCD at population level. Recently, mtDNA variants have been associated with congenital cardiopathy and higher risk of ischemic heart disease, suggesting them as potential risk factors also in SCD. Therefore, we aimed to define the mtDNA mutational landscape in such phenotype, by sequencing the whole blood mtDNA genome in a pilot cohort of 28 unrelated subjects. Coding variants were prioritized according to their population and haplogroup frequency. Out of 28 patients, 36% were diagnosed with coronary artery disease, 39% with structural defects and 25% with unspecified cardiac disease. The overall frequency of macro-haplogroups followed the distribution in the European population. No known or novel mtDNA pathogenic variants were found. Two rRNA and 8 missense variants were rarer than polymorphisms as they had a frequency lower than 1% in population databases. 5/8 missense variants clustered in ATP synthase genes and 4/8 missense variants were previously detected in patients with suspected mitochondriopathy. We concluded that primary mitochondrial disease is not a major cause of SCD, but rare mtDNA variants may occur (35.7% in our cohort vs 0.65% in the population; p < 0.01), potentially modifying the risk.
    Keywords:  Heart disease; M chromosome; Mitochondrial genome; Mitochondrial haplogroups; SNVs; Sudden cardiac death
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e41592
  29. Genes (Basel). 2025 Jan 20. pii: 108. [Epub ahead of print]16(1):
    Atypical Leber Hereditary Optic Neuropathy (LHON) Associated with a Novel MT-CYB:m.15309T>C(Ile188Thr) Variant.
    Sanja Petrovic Pajic, Ana Fakin, Martina Jarc-Vidmar, Maja Sustar Habjan, Lucija Malinar, Kasja Pavlovic, Nina Krako Jakovljevic, Andjelka Isakovic, Sonja Misirlic-Dencic, Marija Volk, Ales Maver, Gregor Jezernik, Damjan Glavac, Borut Peterlin, Ivanka Markovic, Nebojsa Lalic, Marko Hawlina.
      Background: The study presents a detailed examination and follow-up of a Slovenian patient with an Leber Hereditary Optic Neuropathy (LHON)-like phenotype and bilateral optic neuropathy in whom genetic analysis identified a novel variant MT-CYB:m.15309T>C (Ile188Thr). Methods: We provide detailed analysis of the clinical examinations of a male patient with bilateral optic neuropathy from the acute stage to 8 years of follow-up. Complete ophthalmological exam, electrophysiology and optical coherence tomography (OCT) segmentation were performed. The genotype analysis was performed with a complete screening of the mitochondrial genome. Furthermore, proteomic analysis of the protein structure and function was performed to assess the pathogenicity of a novel variant of unknown significance. Mitochondrial function analysis of the patient's peripheral blood mononuclear cells (PBMCs) was performed with the objective of evaluating the mutation effect on mitochondrial function using flow cytometry and high-resolution respirometry. Results: The patient had a profound consecutive bilateral visual loss at 19 years of age due to optic neuropathy with characteristics of LHON; however, unlike patients with typical LHON, the patient experienced a fluctuation in visual function and significant late recovery. He had a total of three visual acuity deteriorations and improvements in the left eye, with concomitant visual loss in the right eye and a final visual acuity drop reaching nadir 9 months after onset. The visual loss was characterized by centrocecal scotoma, abnormal color vision and abnormal VEP, while deterioration of PERG N95 followed with a lag of several months. The OCT examination showed retinal nerve fiber layer thinning matching disease progression. Following a two-year period of legal blindness, the patient's visual function started to improve, and over the course of 5 years, it reached 0.5 and 0.7 Snellen (0.3 and 0.15 LogMAR) visual acuity (VA). Mitochondrial sequencing identified a presumably pathogenic variant m.15309T>C in the MT-CYB gene at 65% heteroplasmy, belonging to haplogroup K. Mitochondrial function assessment of the patient's PBMCs showed a lower respiration rate, an increase in reactive oxygen species production and the presence of mitochondrial depolarization, compared to an age- and sex-matched healthy control's PBMCs. Conclusions: A novel variant in the MT-CYB:m.15309T>C (Ile188Thr) gene was identified in a patient with optic nerve damage and the LHON phenotype without any additional systemic features and atypical presentation of the disease with late onset of visual function recovery. The pathogenicity of the variant is supported by proteomic analysis and the mitochondrial dysfunction observed in the patient's PBMCs.
    Keywords:  LHON; MT-CYB gene; MT-CYB:c.563T>C p.(Ile188Thr); VA improvement; chrM:15309T>C; electrophysiology; mitochondrial disfunction; proteomic analysis; retinal segmentation
    DOI:  https://doi.org/10.3390/genes16010108
  30. Nat Commun. 2025 Jan 26. 16(1): 1047
    Genome-wide profiling of tRNA modifications by Induro-tRNAseq reveals coordinated changes.
    Yuko Nakano, Howard Gamper, Henri McGuigan, Sunita Maharjan, Jiatong Li, Zhiyi Sun, Erbay Yigit, Sebastian Grünberg, Keerthana Krishnan, Nan-Sheng Li, Joseph A Piccirilli, Ralph Kleiner, Nicole Nichols, Brian D Gregory, Ya-Ming Hou.
      While all native tRNAs undergo extensive post-transcriptional modifications as a mechanism to regulate gene expression, mapping these modifications remains challenging. The critical barrier is the difficulty of readthrough of modifications by reverse transcriptases (RTs). Here we use Induro-a new group-II intron-encoded RT-to map and quantify genome-wide tRNA modifications in Induro-tRNAseq. We show that Induro progressively increases readthrough over time by selectively overcoming RT stops without altering the misincorporation frequency. In a parallel analysis of Induro vs. a related RT, we provide comparative datasets to facilitate the prediction of each modification. We assess tRNA modifications across five human cell lines and three mouse tissues and show that, while the landscape of modifications is highly variable throughout the tRNA sequence framework, it is stabilized for modifications that are required for reading of the genetic code. The coordinated changes have fundamental importance for development of tRNA modifications in protein homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-56348-1
  31. Nat Commun. 2025 Jan 30. 16(1): 1191
    Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth.
    Yanhan Jia, Sheng Wang, Sylvia Urban, Judith M Müller, Manuela Sum, Qing Wang, Helena Bauer, Uwe Schulte, Heike Rampelt, Nikolaus Pfanner, Katrin M Schüle, Axel Imhof, Ignasi Forné, Christopher Berlin, August Sigle, Christian Gratzke, Holger Greschik, Eric Metzger, Roland Schüle.
      Prostate cancer (PCa) growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). In this study, we identify lysine methyltransferase (KMT)9 as a regulator of PDC activity. KMT9 is localized in mitochondria of PCa cells, but not in mitochondria of other tumor cell types. Mitochondrial KMT9 regulates PDC activity by monomethylation of its subunit dihydrolipoamide transacetylase (DLAT) at lysine 596. Depletion of KMT9 compromises PDC activity, de novo lipogenesis, and PCa cell proliferation, both in vitro and in a PCa mouse model. Finally, in human patients, levels of mitochondrial KMT9 and DLAT K596me1 correlate with Gleason grade. Together, we present a mechanism of PDC regulation and an example of a histone methyltransferase with nuclear and mitochondrial functions. The dependency of PCa cells on mitochondrial KMT9 allows to develop therapeutic strategies to selectively fight PCa.
    DOI:  https://doi.org/10.1038/s41467-025-56492-8
  32. iScience. 2025 Jan 17. 28(1): 111656
    Nicotinamide mononucleotide restores impaired metabolism, endothelial cell proliferation and angiogenesis in old sedentary male mice.
    Kevin Kiesworo, Thomas Agius, Michael R Macarthur, Martine Lambelet, Arnaud Lyon, Jing Zhang, Guillermo Turiel, Zheng Fan, Sènan d'Almeida, Korkut Uygun, Heidi Yeh, Sébastien Déglise, Katrien de Bock, Sarah J Mitchell, Alejandro Ocampo, Florent Allagnat, Alban Longchamp.
      Aging is accompanied by a decline in neovascularization potential and increased susceptibility to ischemic injury. Here, we confirm the age-related impaired neovascularization following ischemic leg injury and impaired angiogenesis. The age-related deficits in angiogenesis arose primarily from diminished EC proliferation capacity, but not migration or VEGF sensitivity. Aged EC harvested from the mouse skeletal muscle displayed a pro-angiogenic gene expression phenotype, along with considerable changes in metabolic genes. Metabolomics analysis and 13C glucose tracing revealed impaired ATP production and blockade in glycolysis and TCA cycle in late passage HUVECs, which occurred at nicotinamide adenine dinucleotide (NAD⁺)-dependent steps, along with NAD+ depletion. Supplementation with nicotinamide mononucleotide (NMN), a precursor of NAD⁺, enhances late-passage EC proliferation and sprouting angiogenesis from aged mice aortas. Taken together, our study illustrates the importance of NAD+-dependent metabolism in the maintenance of EC proliferation capacity with age, and the therapeutic potential of NAD precursors.
    Keywords:  Cellular physiology; Metabolomics
    DOI:  https://doi.org/10.1016/j.isci.2024.111656
  33. Biomolecules. 2025 Jan 14. pii: 126. [Epub ahead of print]15(1):
    Remodeling of Mitochondria-Endoplasmic Reticulum Contact Sites Accompanies LUHMES Differentiation.
    Emad Norouzi Esfahani, Tomas Knedlik, Sang Hun Shin, Ana Paula Magalhães Rebelo, Agnese De Mario, Caterina Vianello, Luca Persano, Elena Rampazzo, Paolo Edomi, Camilla Bean, Dario Brunetti, Luca Scorrano, Samuele Greco, Marco Gerdol, Marta Giacomello.
      Neural progenitor cells (NPCs) are often used to study the subcellular mechanisms underlying differentiation into neurons in vitro. Works published to date have focused on the pathways that distinguish undifferentiated NPCs from mature neurons, neglecting the earlier and intermediate stages of this process. Current evidence suggests that mitochondria interaction with the ER is fundamental to a wide range of intracellular processes. However, it is not clear whether and how the mitochondria-ER interactions differ between NPCs and their differentiated counterparts. Here we take advantage of the widely used NPC line LUHMES to provide hints on the mitochondrial dynamic trait changes that occur during the first stage of their maturation into dopaminergic-like neurons. We observed that the morphology of mitochondria, their interaction with the ER, and the expression of several mitochondria-ER contact site resident proteins change, which suggests the potential contribution of mitochondria dynamics to NPC differentiation. Further studies will be needed to explore in depth these changes, and their functional outcomes, which may be relevant to the scientific community focusing on embryonic neurogenesis and developmental neurotoxicity.
    Keywords:  LUHMES; MERCs; Neural precursor cells; differentially expressed genes; mitochondria; mitochondria–ER contact sites
    DOI:  https://doi.org/10.3390/biom15010126
  34. Life Med. 2024 Apr;3(2): lnae017
    Mitochondrial transplantation for the treatment of cardiac and noncardiac diseases: mechanisms, prospective, and challenges.
    Xinyi Wang, Zhiyuan Liu, Ling Zhang, Guangyu Hu, Ling Tao, Fuyang Zhang.
      Mitochondrial transplantation (MT) is a promising therapeutic strategy that involves introducing healthy mitochondria into damaged tissues to restore cellular function. This approach has shown promise in treating cardiac diseases, such as ischemia-reperfusion injury, myocardial infarction, and heart failure, where mitochondrial dysfunction plays a crucial role. Transplanting healthy mitochondria into affected cardiac tissue has resulted in improved cardiac function, reduced infract size, and enhanced cell survival in preclinical studies. Beyond cardiac applications, MT is also being explored for its potential to address various noncardiac diseases, including stroke, infertility, and genetic mitochondrial disorders. Ongoing research focused on refining techniques for mitochondrial isolation, preservation, and targeted delivery is bolstering the prospects of MT as a clinical therapy. As the scientific community gains a deeper understanding of mitochondrial dynamics and pathology, the development of MT as a clinical therapy holds significant promise. This review provides an overview of recent research on MT and discusses the methodologies involved, including sources, isolation, delivery, internalization, and distribution of mitochondria. Additionally, it explores the effects of MT and potential mechanisms in cardiac diseases, as well as non-cardiac diseases. Future prospects for MT are also discussed.
    Keywords:  cardiac diseases; heart; mitochondria; mitochondrial transplantation; noncardiac diseases
    DOI:  https://doi.org/10.1093/lifemedi/lnae017
  35. Am J Hum Genet. 2025 Jan 22. pii: S0002-9297(25)00002-3. [Epub ahead of print]
    Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection.
    Shloka Negi, Sarah L Stenton, Seth I Berger, Paolo Canigiula, Brandy McNulty, Ivo Violich, Joshua Gardner, Todd Hillaker, Sara M O'Rourke, Melanie C O'Leary, Elizabeth Carbonell, Christina Austin-Tse, Gabrielle Lemire, Jillian Serrano, Brian Mangilog, Grace VanNoy, Mikhail Kolmogorov, Eric Vilain, Anne O'Donnell-Luria, Emmanuèle Délot, Karen H Miga, Jean Monlong, Benedict Paten.
      More than 50% of families with suspected rare monogenic diseases remain unsolved after whole-genome analysis by short-read sequencing (SRS). Long-read sequencing (LRS) could help bridge this diagnostic gap by capturing variants inaccessible to SRS, facilitating long-range mapping and phasing and providing haplotype-resolved methylation profiling. To evaluate LRS's additional diagnostic yield, we sequenced a rare-disease cohort of 98 samples from 41 families, using nanopore sequencing, achieving per sample ∼36× average coverage and 32-kb read N50 from a single flow cell. Our Napu pipeline generated assemblies, phased variants, and methylation calls. LRS covered, on average, coding exons in ∼280 genes and ∼5 known Mendelian disease-associated genes that were not covered by SRS. In comparison to SRS, LRS detected additional rare, functionally annotated variants, including structural variants (SVs) and tandem repeats, and completely phased 87% of protein-coding genes. LRS detected additional de novo variants and could be used to distinguish postzygotic mosaic variants from prezygotic de novos. Diagnostic variants were established by LRS in 11 probands, with diverse underlying genetic causes including de novo and compound heterozygous variants, large-scale SVs, and epigenetic modifications. Our study demonstrates LRS's potential to enhance diagnostic yield for rare monogenic diseases, implying utility in future clinical genomics workflows.
    Keywords:  clinical testing; gene conversion; haplotype phasing; long-read sequencing; methylation; rare-disease diagnosis; structural variants; variant annotation
    DOI:  https://doi.org/10.1016/j.ajhg.2025.01.002
  36. NPJ Digit Med. 2025 Jan 30. 8(1): 72
    A machine learning decision support tool optimizes WGS utilization in a neonatal intensive care unit.
    Edwin F Juarez, Bennet Peterson, Erica Sanford Kobayashi, Sheldon Gilmer, Laura E Tobin, Brandan Schultz, Jerica Lenberg, Jeanne Carroll, Shiyu Bai-Tong, Nathaly M Sweeney, Curtis Beebe, Lawrence Stewart, Lauren Olsen, Julie Reinke, Elizabeth A Kiernan, Rebecca Reimers, Kristen Wigby, Chris Tackaberry, Mark Yandell, Charlotte Hobbs, Matthew N Bainbridge.
      The Mendelian Phenotype Search Engine (MPSE), a clinical decision support tool using Natural Language Processing and Machine Learning, helped neonatologists expedite decisions to whole genome sequencing (WGS) to diagnose patients in the neonatal intensive care unit. After the MPSE was introduced, utilization of WGS increased, time to ordering WGS decreased, and WGS diagnostic yield increased.
    DOI:  https://doi.org/10.1038/s41746-025-01458-9
  37. Biol Cell. 2025 Jan;117(1): e2400082
    Revealing mitochondrial architecture and functions with single molecule localization microscopy.
    Nicolas Jolivet, Giulia Bertolin.
      Understanding the spatiotemporal organization of components within living systems requires the highest resolution possible. Microscopy approaches that allow for a resolution below 250 nm include electron and super-resolution microscopy (SRM). The latter combines advanced imaging techniques and the optimization of image processing methods. Over the last two decades, various SRM-related approaches have been introduced, especially those relying on single molecule localization microscopy (SMLM). To develop and apply SMLM approaches, mitochondria are an ideal cellular compartment due to their size, which is below the standard diffraction limit. Furthermore, mitochondria are a dynamic yet narrow compartment, and a resolution below 250 nm is required to study their composition and multifaceted functions. To this end, several SMLM technologies have been used to reveal mitochondrial composition. However, there is still room for improvement in existing techniques to study protein-protein interactions and protein dynamics within this compartment. This review aims to offer an updated overview of the existing SMLM techniques and probes associated with mitochondria to enhance their resolution at the nanoscale. Last, it paves the way for future SMLM improvements to better resolve mitochondrial dynamics and functions.
    Keywords:  mitochondria; single‐molecule localization microscopy; super‐resolution microscopy
    DOI:  https://doi.org/10.1111/boc.202400082
  38. Life Metab. 2024 Aug;3(4): loae020
    Genome-wide CRISPR screens identify PTPN21 and WDR26 as modulators of the mitochondrial stress-induced ISR.
    Wen Li, Mingyue Dong, Kaiyu Gao, Jialiang Guan, Ying Liu.
      
    DOI:  https://doi.org/10.1093/lifemeta/loae020
  39. Proc Natl Acad Sci U S A. 2025 Jan 14. 122(2): e2407909122
    Nonapoptotic role of EGL-1 in exopher production and neuronal health in Caenorhabditis elegans.
    Zheng Wu, Eric A Cardona, Jesse A Cohn, Jonathan T Pierce.
      While traditionally studied for their proapoptotic functions in activating the caspase, research suggests BH3-only proteins also have other roles such as mitochondrial dynamics regulation. Here, we find that EGL-1, the BH3-only protein in Caenorhabditis elegans, promotes the cell-autonomous production of exophers in adult neurons. Exophers are large, micron-scale vesicles that are ejected from the cell and contain cellular components such as mitochondria. EGL-1 facilitates exopher production potentially through regulation of mitochondrial dynamics. Moreover, an endogenous, low level of EGL-1 expression appears to benefit dendritic health. Our findings provide insights into the role of neuronal BH3-only protein in mitochondrial dynamics, downstream exopher production, and ultimately neuronal health.
    Keywords:  BH3-only protein; exopher; mitochondria; neuroprotection
    DOI:  https://doi.org/10.1073/pnas.2407909122
  40. Nucleic Acids Res. 2025 Jan 24. pii: gkaf021. [Epub ahead of print]53(3):
    Selection of initiator tRNA and start codon by mammalian mitochondrial initiation factor 3 in leaderless mRNA translation.
    Muhoon Lee, Taisei Wakigawa, Qimin Jia, Chang Liu, Ruiyuan Huang, Shuai Huang, Asuteka Nagao, Tsutomu Suzuki, Kozo Tomita, Shintaro Iwasaki, Nono Takeuchi-Tomita.
      The mammalian mitochondrial protein synthesis system produces 13 essential subunits of oxidative phosphorylation (OXPHOS) complexes. Translation initiation in mammalian mitochondria is characterized by the use of leaderless messenger RNAs (mRNAs) and non-AUG start codons, where the proofreading function of IF-3mt still remains elusive. Here, we developed a reconstituted mammalian mitochondrial translation system using in vitro transcribed and native mitochondrial transfer RNAs (tRNAs) to investigate IF-3mt's proofreading function. Similar to bacterial IF-3, IF-3mt permits an initiator tRNA to participate in initiation by discriminating the three G-C pairs in its anticodon stem, and by the cognate interactions of its anticodon with the AUG start codon. As a result, IF-3mt promotes the accurate initiation of leaderless mRNAs. Nevertheless, IF-3mt can also facilitate initiation from the non-AUG(AUA) start codon through its unique N- and C-terminal extensions, in concert with the 5-methylcytidine (m5C) or 5-formylcytidine (f5C) modification at the anticodon wobble position of mt-tRNAMet. This is partly because the IF-3mt-specific N- and C-terminal extensions and the KKGK-motif favor leaderless mRNA initiation and relax non-AUG start codon discrimination. Analyses of IF-3mt-depleted human cells revealed that IF-3mt indeed participates in translating the open reading frames (ORFs) of leaderless mRNAs, as well as the internal ORFs of dicistronic mRNAs.
    DOI:  https://doi.org/10.1093/nar/gkaf021
  41. Sci Adv. 2025 Jan 31. 11(5): eadr8837
    Epstein-Barr virus-driven cardiolipin synthesis sustains metabolic remodeling during B cell transformation.
    Haixi You, Larissa Havey, Zhixuan Li, Yin Wang, John M Asara, Rui Guo.
      The Epstein-Barr virus (EBV) infects nearly 90% of adults globally and is linked to over 200,000 annual cancer cases. Immunocompromised individuals from conditions such as primary immune disorders, HIV, or posttransplant immunosuppressive therapies are particularly vulnerable because of EBV's transformative capability. EBV remodels B cell metabolism to support energy, biosynthetic precursors, and redox equivalents necessary for transformation. Most EBV-driven metabolic pathways center on mitochondria. However, how EBV regulates B cell mitochondrial function and metabolic fluxes remains unclear. Here, we show that EBV boosts cardiolipin (CL) biosynthesis, essential for mitochondrial cristae biogenesis, via EBV nuclear antigen 2/MYC-induced CL enzyme transactivation. Pharmacological and CRISPR genetic analyses underscore the essentiality of CL biosynthesis in EBV-transformed B cells. Metabolomic and isotopic tracing highlight CL's role in sustaining respiration, one-carbon metabolism, and aspartate synthesis. Disrupting CL biosynthesis destabilizes mitochondrial matrix enzymes pivotal to these pathways. We demonstrate EBV-induced CL metabolism as a therapeutic target, offering synthetic lethal strategies against EBV-associated B cell malignancies.
    DOI:  https://doi.org/10.1126/sciadv.adr8837
  42. Alzheimers Dement. 2025 Jan;21(1): e14560
    APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes.
    Srishruthi Thirumalai, Frederick J Livesey, Rickie Patani, Christy Hung.
       INTRODUCTION: Antisense oligonucleotides (ASOs) have shown promise in reducing amyloid precursor protein (APP) levels in neurons, but their effects in astrocytes, key contributors to neurodegenerative diseases, remain unclear. This study evaluates the efficacy of APP ASOs in astrocytes derived from an individual with Down syndrome (DS), a population at high risk for Alzheimer's disease (AD).
    METHODS: Human induced pluripotent stem cells (hiPSCs) from a healthy individual and an individual with DS were differentiated into astrocytes. Astrocytes were treated with APP ASOs for 10 days, and APP levels were quantified. Mitochondrial morphology and superoxide production in DS astrocytes were analyzed using super-resolution and confocal microscopy.
    RESULTS: APP ASOs significantly reduced APP levels in astrocytes from both control and DS individuals. In DS astrocytes, treatment restored mitochondrial health, increasing mitochondrial number and size while reducing superoxide production.
    DISCUSSION: APP ASOs effectively reduce APP levels and improve mitochondrial health in astrocytes, suggesting their potential as a therapeutic approach for DS and DS-related AD. Further in vivo studies are required to confirm these findings.
    HIGHLIGHTS: APP ASOs reduce APP levels in human iPSC-derived astrocytes. APP ASO treatment rescues mitochondrial phenotypes in trisomy 21 astrocytes. This study supports ASOs as a potential therapy for Down syndrome-related Alzheimer's disease.
    Keywords:  APP; Alzheimer's disease; Down syndrome; antisense oligonucleotides; astrocytes; mitochondrial function
    DOI:  https://doi.org/10.1002/alz.14560
  43. Nat Rev Genet. 2025 Jan 28.
    Spatial metabolomics to unravel cellular metabolism.
    Arafath K Najumudeen, Johan Vande Voorde.
      
    DOI:  https://doi.org/10.1038/s41576-025-00817-2
  44. Nat Genet. 2025 Jan 29.
    Synchronized long-read genome, methylome, epigenome and transcriptome profiling resolve a Mendelian condition.
    University of Washington Center for Rare Disease Research
      Resolving the molecular basis of a Mendelian condition remains challenging owing to the diverse mechanisms by which genetic variants cause disease. To address this, we developed a synchronized long-read genome, methylome, epigenome and transcriptome sequencing approach, which enables accurate single-nucleotide, insertion-deletion and structural variant calling and diploid de novo genome assembly. This permits the simultaneous elucidation of haplotype-resolved CpG methylation, chromatin accessibility and full-length transcript information in a single long-read sequencing run. Application of this approach to an Undiagnosed Diseases Network participant with a chromosome X;13-balanced translocation of uncertain significance revealed that this translocation disrupted the functioning of four separate genes (NBEA, PDK3, MAB21L1 and RB1) previously associated with single-gene Mendelian conditions. Notably, the function of each gene was disrupted via a distinct mechanism that required integration of the four 'omes' to resolve. These included fusion transcript formation, enhancer adoption, transcriptional readthrough silencing and inappropriate X-chromosome inactivation of autosomal genes. Overall, this highlights the utility of synchronized long-read multi-omic profiling for mechanistically resolving complex phenotypes.
    DOI:  https://doi.org/10.1038/s41588-024-02067-0
  45. Mol Cell Neurosci. 2025 Jan 23. pii: S1044-7431(25)00002-8. [Epub ahead of print]132 103992
    Mitochondrial fission and fusion in neurodegenerative diseases:Ca2+ signalling.
    Xuan Liu, Tianjiao Li, Xinya Tu, Mengying Xu, Jianwu Wang.
      Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive loss of neuronal structure and function. The pathogenesis is intricate and involves a network of interactions among multiple causes and systems. Mitochondria and Ca2+ signaling have long been considered to play important roles in the development of various NDs. Mitochondrial fission and fusion dynamics are important processes of mitochondrial quality control, ensuring the stability of mitochondrial structure and function. Mitochondrial fission and fusion imbalance and Ca2+ signaling disorders can aggravate the disease progression of NDs. In this review, we explore the relationship between mitochondrial dynamics and Ca2+ signaling in AD, PD, ALS, and HD, focusing on the roles of key regulatory proteins (Drp1, Fis1, Mfn1/2, and Opa1) and the association structures between mitochondria and the endoplasmic reticulum (MERCs/MAMs). We provide a detailed analysis of their involvement in the pathogenesis of these four NDs. By integrating these mechanisms, we aim to clarify their contributions to disease progression and offer insights into the development of therapeutic strategies that target mitochondrial dynamics and Ca2+ signaling. We also examine the progress in drug research targeting these pathways, highlighting their potential as therapeutic targets in the treatment of NDs.
    Keywords:  Ca(2+) signaling; Mitochondrial fusion and fission; Mitochondrial-associated membranes (MAMs); Mitochondrial–ER contact sites (MERCs); Neurodegenerative diseases; Potential drugs
    DOI:  https://doi.org/10.1016/j.mcn.2025.103992
  46. Life Metab. 2025 Feb;4(1): loae040
    Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability.
    Yik-Lam Cho, Hayden Weng Siong Tan, Jicheng Yang, Basil Zheng Mian Kuah, Nicole Si Ying Lim, Naiyang Fu, Boon-Huat Bay, Shuo-Chien Ling, Han-Ming Shen.
      Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the pentose phosphate pathway (PPP) in glycolysis. Glucose metabolism is closely implicated in the regulation of mitophagy, a selective form of autophagy for the degradation of damaged mitochondria. The PPP and its key enzymes such as G6PD possess important metabolic functions, including biosynthesis and maintenance of intracellular redox balance, while their implication in mitophagy is largely unknown. Here, via a whole-genome CRISPR-Cas9 screening, we identified that G6PD regulates PINK1 (phosphatase and tensin homolog [PTEN]-induced kinase 1)-Parkin-mediated mitophagy. The function of G6PD in mitophagy was verified via multiple approaches. G6PD deletion significantly inhibited mitophagy, which can be rescued by G6PD reconstitution. Intriguingly, while the catalytic activity of G6PD is required, the known PPP functions per se are not involved in mitophagy regulation. Importantly, we found a portion of G6PD localized at mitochondria where it interacts with PINK1. G6PD deletion resulted in an impairment in PINK1 stabilization and subsequent inhibition of ubiquitin phosphorylation, a key starting point of mitophagy. Finally, we found that G6PD deletion resulted in lower cell viability upon mitochondrial depolarization, indicating the physiological function of G6PD-mediated mitophagy in response to mitochondrial stress. In summary, our study reveals a novel role of G6PD as a key positive regulator in mitophagy, which bridges several important cellular processes, namely glucose metabolism, redox homeostasis, and mitochondrial quality control.
    Keywords:  G6PD; NADPH; PINK1; PPP; ROS; mitophagy
    DOI:  https://doi.org/10.1093/lifemeta/loae040
  47. Front Mol Neurosci. 2024 ;17 1527013
    Novel strategies targeting mitochondria-lysosome contact sites for the treatment of neurological diseases.
    Yinyin Xie, Wenlin Sun, Aoya Han, Xinru Zhou, Shijie Zhang, Changchang Shen, Yi Xie, Cui Wang, Nanchang Xie.
      Mitochondria and lysosomes are critical for neuronal homeostasis, as highlighted by their dysfunction in various neurological diseases. Recent studies have identified dynamic membrane contact sites between mitochondria and lysosomes, independent of mitophagy and the lysosomal degradation of mitochondrial-derived vesicles (MDVs), allowing bidirectional crosstalk between these cell compartments, the dynamic regulation of organelle networks, and substance exchanges. Emerging evidence suggests that abnormalities in mitochondria-lysosome contact sites (MLCSs) contribute to neurological diseases, including Parkinson's disease, Charcot-Marie-Tooth (CMT) disease, lysosomal storage diseases, and epilepsy. This article reviews recent research advances regarding the tethering processes, regulation, and function of MLCSs and their role in neurological diseases.
    Keywords:  lysosomal dynamics; mitochondria-lysosome contact sites; mitochondrial network; mitophagy; neurological diseases; substance exchanges
    DOI:  https://doi.org/10.3389/fnmol.2024.1527013
  48. Nat Rev Mol Cell Biol. 2025 Jan 27.
    The roles of mitochondria in global and local intracellular calcium signalling.
    Benjamín Cartes-Saavedra, Arijita Ghosh, György Hajnóczky.
      Activation of Ca2+ channels in Ca2+ stores in organelles and the plasma membrane generates cytoplasmic calcium ([Ca2+]c) signals that control almost every aspect of cell function, including metabolism, vesicle fusion and contraction. Mitochondria have a high capacity for Ca2+ uptake and chelation, alongside efficient Ca2+ release mechanisms. Still, mitochondria do not store Ca2+ in a prolonged manner under physiological conditions and lack the capacity to generate global [Ca2+]c signals. However, mitochondria take up Ca2+ at high local [Ca2+]c signals that originate from neighbouring organelles, and also during sustained global elevations of [Ca2+]c. Accumulated Ca2+ in the mitochondria stimulates oxidative metabolism and upon return to the cytoplasm, can produce spatially confined rises in [Ca2+]c to exert control over processes that are sensitive to Ca2+. Thus, the mitochondrial handling of [Ca2+]c is of physiological relevance. Furthermore, dysregulation of mitochondrial Ca2+ handling can contribute to debilitating diseases. We discuss the mechanisms and relevance of mitochondria in local and global calcium signals.
    DOI:  https://doi.org/10.1038/s41580-024-00820-1
  49. Int J Mol Sci. 2025 Jan 13. pii: 626. [Epub ahead of print]26(2):
    Mitochondrial microRNAs: Key Drivers in Unraveling Neurodegenerative Diseases.
    Raya Kh Yashooa, Elisa Duranti, Donatella Conconi, Marialuisa Lavitrano, Suhad A Mustafa, Chiara Villa.
      MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) crucial for regulating gene expression at the post-transcriptional level. Recent evidence has shown that miRNAs are also found in mitochondria, organelles that produce energy in the cell. These mitochondrial miRNAs, also known as mitomiRs, are essential for regulating mitochondrial function and metabolism. MitomiRs can originate from the nucleus, following traditional miRNA biogenesis pathways, or potentially from mitochondrial DNA, allowing them to directly affect gene expression and cellular energy dynamics within the mitochondrion. While miRNAs have been extensively investigated, the function and involvement of mitomiRs in the development of neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis remain to be elucidated. This review aims to discuss findings on the role of mitomiRs in such diseases and their potential as therapeutic targets, as well as to highlight future research directions.
    Keywords:  microRNAs; mitochondria; neurodegenerative disorders
    DOI:  https://doi.org/10.3390/ijms26020626
  50. bioRxiv. 2025 Jan 17. pii: 2025.01.15.633240. [Epub ahead of print]
    GenVarLoader: An accelerated dataloader for applying deep learning to personalized genomics.
    David Laub, Aaron Ho, Jeff Jaureguy, Adam Klie, Rany M Salem, Graham McVicker, Hannah Carter.
      Deep learning sequence models trained on personalized genomics can improve variant effect prediction, however, applications of these models are limited by computational requirements for storing and reading large datasets. We address this with GenVarLoader, which stores personalized genomic data in new memory-mapped formats with optimal data locality to achieve ~1,000x faster throughput and ~2,000x better compression compared to existing alternatives.
    DOI:  https://doi.org/10.1101/2025.01.15.633240
  51. Nat Metab. 2025 Jan 27.
    Epigenetic modification increases skeletal muscle resilience to metabolic stress.
      
    DOI:  https://doi.org/10.1038/s42255-024-01211-8
  52. Redox Biol. 2025 Jan 20. pii: S2213-2317(25)00015-1. [Epub ahead of print]80 103502
    Sub-organellar mitochondrial hydrogen peroxide observed using a SNAP tag targeted coumarin-based fluorescent reporter.
    Ross Eaglesfield, Erika Fernandez-Vizarra, Erik Lacko, Stuart T Caldwell, Nikki L Sloan, Daniel Siciarz, Richard C Hartley, Kostas Tokatlidis.
      Mitochondria are major sites of reactive oxygen species (ROS) production within cells. ROS are important signalling molecules, but excessive production can cause cellular damage and dysfunction. It is therefore crucial to accurately determine when, how and where ROS are produced within mitochondria. Previously, ROS detection involved various chemical probes and fluorescent proteins. These have limitations due to accumulation of the molecules only in the mitochondrial matrix, or the need for a new protein to be expressed for every different species. We report dynamic H2O2 flux changes within all mitochondrial sub-compartments with striking spatial resolution. We combined specific targeting of self-labeling proteins with novel H2O2-reactive probes. The approach is broad-ranging and flexible, with the same expressed proteins loadable with different dyes and sensors. It provides a framework for concomitant analysis of other chemical species, beyond ROS, whose dynamics within mitochondria are yet unknown, without needing to engineer new proteins.
    Keywords:  Mitochondria; Oxidative stress; ROS; Redox signalling; Self-labeling proteins; Sub-cellular compartments
    DOI:  https://doi.org/10.1016/j.redox.2025.103502
  53. Nucleic Acids Res. 2025 Jan 24. pii: gkae1325. [Epub ahead of print]53(3):
    WBSCR16 is essential for mitochondrial 16S rRNA processing in mammals.
    Shengjie Zhang, Zi Dong, Yang Feng, Wei Guo, Chen Zhang, Yifan Shi, Zhiyun Zhao, Jiqiu Wang, Guang Ning, Guorui Huang.
      Mitochondrial rRNAs play important roles in regulating mtDNA-encoded gene expression and energy metabolism subsequently. However, the proteins that regulate mitochondrial 16S rRNA processing remain poorly understood. Herein, we generated adipose-specific Wbscr16-/-mice and cells, both of which exhibited dramatic mitochondrial changes. Subsequently, WBSCR16 was identified as a 16S rRNA-binding protein essential for the cleavage of 16S rRNA-mt-tRNALeu, facilitating 16S rRNA processing and mitochondrial ribosome assembly. Additionally, WBSCR16 recruited RNase P subunit MRPP3 to nascent 16S rRNA and assisted in this specific cleavage. Furthermore, evidence showed that adipose-specific Wbscr16 ablation promotes energy wasting via lipid preference in brown adipose tissue, leading to excess energy expenditure and resistance to obesity. In contrast, overexpression of WBSCR16 upregulated 16S rRNA processing and induced a preference for glucose utilization in both transgenic mouse models and cultured cells. These findings suggest that WBSCR16 plays essential roles in mitochondrial 16S rRNA processing in mammals, and is the key mitochondrial protein to balance glucose and lipid metabolism.
    DOI:  https://doi.org/10.1093/nar/gkae1325
  54. Pediatr Dermatol. 2025 Jan 31.
    Cutaneous Manifestations of NAXD or NAXE Deficiency: A Literature Review for the Dermatologist.
    Boraan Abdulkarim, Setu Mittal, Hassan Vahidnezhad, Dawn Marie Davis, Michael J Camilleri, Nessa Aghazadeh Mohandesi.
      Nicotinamide adenine dinucleotide phosphate hydrate dehydratase (NAXD) and nicotinamide adenine dinucleotide phosphate hydrate epimerase (NAXE) deficiencies are rare autosomal recessive metabolic disorders characterized by severe neurological manifestations during infancy. In affected individuals, febrile illnesses can trigger progressive encephalopathy often accompanied by distinctive skin eruptions, resulting in high mortality rates. This study reviews the literature on NAXD/NAXE deficiencies, focusing on dermatological manifestations and their correlation with genotypic variations and treatment responses. A comprehensive literature search identified 45 patients with 31 pathogenic/likely pathogenic mutations, and a median age of onset at 1.16 years. Patients with NAXE deficiency exhibited a broader range of age of symptom onset compared to those affected with NAXD deficiency. Fever or infections were identified as the most common triggers for decompensation episodes. Skin manifestations were observed in 31% of patients with whole cell NAXD and NAXE deficiencies. The characteristic skin eruption comprises well-demarcated erythematous and erosive plaques progressing to blistering and necrosis, predominantly affecting flexural surfaces. The mortality rate was 78%, with survivors experiencing varying degrees of neurological sequelae. Niacin/nicotinamide supplementation resulted in improvements in skin lesions and survival rates. The review underscores the critical role of dermatologists in early diagnosis and intervention of NAXE and NAXD deficiencies. Recognizing characteristic skin manifestations is essential, particularly in patients with acute neurological decline following infections or vaccinations. Early intervention with specific supplements shows promise; however, further research is needed to establish standardized treatment protocols and enhance patient outcomes.
    Keywords:  NADHX; NADPHX; NAXD; NAXE; cutaneous manifestations; metabolite repair defect; niacin
    DOI:  https://doi.org/10.1111/pde.15868
  55. Life Metab. 2023 Dec;2(6): load040
    Manganese therapy for dyslipidemia and plaque reversal in murine models.
    Yawei Wang, Xin Feng, Wenjing Zhou, Runze Huang, Yating Hu, Hui Hui, Jie Tian, Xiao Wang, Xiao-Wei Chen.
      Precise control of circulating lipid levels is vital in both health and disease. We recently uncovered that bulk lipids, transported by lipoproteins, enter the circulation initially via the coat protein complex II (COPII) in a condensation-dependent manner. Divalent manganese, acting as a signaling messenger, selectively controls COPII condensation to regulate lipid homeostasis in vivo. Here, we present evidence for a manganese-based therapy in murine models of hypolipidemia and hyperlipidemia, aided by advanced in vivo multimodal imaging of atherosclerosis. Dietary titration of manganese supply enables tailored control of circulating lipid levels in whole animals, with no apparent toxicity. Strikingly, elevating the manganese signal through diets could not only effectively treat pathological hyperlipidemia but also further achieve significant reversal of atherosclerotic plaques. Hence, the study provides critical proof-of-principle for a novel therapy for deadly cardiovascular diseases with a potentially broad impact.
    DOI:  https://doi.org/10.1093/lifemeta/load040
  56. Clin Genet. 2025 Jan 24.
    Revealing Molecular Diagnosis With Whole Exome Sequencing in Patients With Inherited Retinal Disorders.
    Cuneyd Yavas, Yunus Emre Arvas, Mustafa Dogan, Alper Gezdirici, Elif Sibel Aslan, Murat Karapapak, Savas Barıs, Recep Eroz.
      Inherited retinal diseases (IRDs) constitute a heterogeneous group of clinically and genetically diverse conditions, standing as a primary cause of visual impairment among individuals aged 15-45, with an estimated incidence of 1:2000. Our study aimed to comprehensively evaluate the genetic variants underlying IRDs in the Turkish population. This study included 50 unrelated Turkish IRD patients and their families. Genomic DNA was extracted from each participant, and candidate variants were identified via next-generation sequencing to determine their pathogenicity. We detected variants in 58% of the patients, of which six novel variants were identified. Among these, 16 cases exhibited variants associated with retinitis pigmentosa and Stargardt disease, while 13 presented variants linked to other retinal diseases. The spectrum of identified variants included 21 homozygous cases and five compound heterozygous variants, both indicative of autosomal recessive inheritance. Three cases revealed heterozygous variants suggestive of autosomal dominant inheritance, and two cases featured hemizygous variants suggestive of X-linked inheritance. Importantly, no matches with copy number variants were detected in our analysis. This study comprehensively portrays clinical and genetic profiles within the Turkish population affected by IRDs. Identifying novel variants and delineating inheritance patterns contribute to a deeper understanding of the genetic diagnosis of IRDs, paving the way for more precise diagnostic and therapeutic interventions.
    Keywords:  eye diseases; inherited retinal diseases; variant; whole exome sequence
    DOI:  https://doi.org/10.1111/cge.14708
  57. Anal Chem. 2025 Jan 26.
    Super-Resolution Mitochondrial Fluorescent Probe for Accurate Monitoring of Drug-Induced Liver Injury.
    Hongyong Zheng, Weikang Peng, Miaomiao Liu, Mei Li, Wenwen Li, Jiayi Xing, Pengfei Shi, Qing Wang, Shusheng Zhang, Lei Yang.
      Drug-induced liver injury (DILI) has emerged as an urgent clinical challenge. It is characterized by mitochondrial dysfunction in liver cells, which leads to abnormal changes in H2O2 levels within the mitochondria. Super-resolution imaging allows for the observation of the fine structure of mitochondria at the nanometer scale, potentially enabling the detection of mitochondrial H2O2 levels during DILI at the subcellular organelle level. Here, we report the design and synthesis of a novel H2O2-activated probe for the detection of mitochondrial H2O2 levels. SML is a near-infrared (NIR) fluorescent probe with a large Stokes shift (260 nm) and a sensing mechanism based on intramolecular charge transfer (ICT) switching. Super-resolution imaging of mitochondrial H2O2 was conducted using structured illumination microscopy (SIM). The improved accuracy in observing periods of mitochondrial dysfunction allows the SML probe to be effectively utilized for the rapid monitoring nanoscale upregulation of H2O2 during DILI and hepatic fibrosis, thus providing SML with the capability to screen for effective therapeutic candidates.
    DOI:  https://doi.org/10.1021/acs.analchem.4c06168
  58. Redox Biol. 2025 Jan 27. pii: S2213-2317(25)00025-4. [Epub ahead of print]80 103512
    Norharmane prevents muscle aging via activation of SKN-1/NRF2 stress response pathways.
    Farida S Nirmala, Hyunjung Lee, Yejin Cho, Min Young Um, Hyo Deok Seo, Chang Hwa Jung, Jeong-Hoon Hahm, Jiyun Ahn.
      Sarcopenia, the age-related decline in muscle mass and function, is a significant contributor to increased frailty and mortality in the elderly. Currently, no FDA-approved treatment exists for sarcopenia. Here, we identified norharmane (NR), a β-carboline alkaloid, as a potential therapeutic agent for mitigating muscle aging. We aimed to determine the ability of NR to delay muscle aging in Caenorhabditis elegans (C. elegans), mouse, and muscle cells in mice and humans. NR treatment improved swimming ability and increased the maximum velocity in aged C. elegans. Transcriptomic analysis revealed that NR upregulated detoxification genes in C. elegans, including cytochrome P450, UGT, and GST enzymes. NR-induced benefits were dependent on the SKN-1/Nrf2 stress response pathway. In mammalian models, NR delayed cellular senescence in human skeletal muscle myoblasts and enhanced myogenesis in C2C12 cells and primary aged myoblasts. NR supplementation in aged mice prevented muscle loss, improved muscle function, and reduced markers of cellular senescence. We found that the p38 MAPK pathway mediated NR activation of Nrf2 by disrupting the Nrf2-Keap1 interaction. NR also improved oxygen consumption rates and promoted mitochondrial biogenesis. These findings suggest that NR is a promising candidate for preventing sarcopenia and improving muscle health.
    Keywords:  Mitochondrial function; Myogenesis; Norharmane; Nrf2; SKN-1; Sarcopenia
    DOI:  https://doi.org/10.1016/j.redox.2025.103512
  59. Comput Struct Biotechnol J. 2025 ;27 265-277
    AI-driven multi-omics integration for multi-scale predictive modeling of genotype-environment-phenotype relationships.
    You Wu, Lei Xie.
      Despite the wealth of single-cell multi-omics data, it remains challenging to predict the consequences of novel genetic and chemical perturbations in the human body. It requires knowledge of molecular interactions at all biological levels, encompassing disease models and humans. Current machine learning methods primarily establish statistical correlations between genotypes and phenotypes but struggle to identify physiologically significant causal factors, limiting their predictive power. Key challenges in predictive modeling include scarcity of labeled data, generalization across different domains, and disentangling causation from correlation. In light of recent advances in multi-omics data integration, we propose a new artificial intelligence (AI)-powered biology-inspired multi-scale modeling framework to tackle these issues. This framework will integrate multi-omics data across biological levels, organism hierarchies, and species to predict genotype-environment-phenotype relationships under various conditions. AI models inspired by biology may identify novel molecular targets, biomarkers, pharmaceutical agents, and personalized medicines for presently unmet medical needs.
    Keywords:  Complex disease; Deep learning; Drug discovery; Machine learning; Omics data; Precision medicine; Single cell
    DOI:  https://doi.org/10.1016/j.csbj.2024.12.030
  60. Sci Signal. 2025 Jan 21. 18(870): eadn9868
    Biotin mitigates the development of manganese-induced, Parkinson's disease-related neurotoxicity in Drosophila and human neurons.
    Yunjia Lai, Pablo Reina-Gonzalez, Gali Maor, Gary W Miller, Souvarish Sarkar.
      Chronic exposure to manganese (Mn) induces manganism and has been widely implicated as a contributing environmental factor to Parkinson's disease (PD), featuring notable overlaps between the two in motor symptoms and clinical hallmarks. Here, we developed an adult Drosophila model of Mn toxicity that recapitulated key parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosomes and mitochondria. Metabolomics analysis of the brain and body tissues of these flies at an early stage of toxicity identified systemic changes in the metabolism of biotin (also known as vitamin B7) in Mn-treated groups. Biotinidase-deficient flies showed exacerbated Mn-induced neurotoxicity, parkinsonism, and mitochondrial dysfunction. Supplementing the diet of wild-type flies with biotin ameliorated the pathological phenotypes of concurrent exposure to Mn. Biotin supplementation also ameliorated the pathological phenotypes of three standard fly models of PD. Furthermore, supplementing the culture media of human induced stem cells (iPSCs) differentiated midbrain dopaminergic neurons with biotin protected against Mn-induced mitochondrial dysregulation, cytotoxicity, and neuronal loss. Last, analysis of the expression of genes encoding biotin-related proteins in patients with PD revealed increased amounts of biotin transporters in the substantia nigra compared with healthy controls, suggesting a potential role of altered biotin metabolism in PD. Together, our findings identified changes in biotin metabolism as underlying Mn neurotoxicity and parkinsonian pathology in flies, for which dietary biotin supplementation was preventative.
    DOI:  https://doi.org/10.1126/scisignal.adn9868
  61. Acta Naturae. 2024 Oct-Dec;16(4):16(4): 27-37
    The Characteristics of the Metabolomic Profile in Patients with Parkinson's Disease and Vascular Parkinsonism.
    E V Predtechenskaya, A D Rogachev, P M Melnikova.
      The gradually increasing age of the world population implies that the prevalence of neurodegenerative diseases also continues to rise. These diseases are characterized by a progressive loss of cognitive and motor functions. Parkinson's disease, which involves the gradual death of specialized neural tissue, is a striking example of a neurodegenerative process. The pathomorphological analysis shows that chronic cerebral ischemia is accompanied by extensive complex neurodegeneration; parkinsonism is its clinical manifestation in 20-30% of cases. Although Parkinson's disease and vascular parkinsonism are similar, these two pathologies have fundamentally different etiopathogeneses. But their set of differential diagnosis traits is confined to some features of the neurological status. There currently exist no diagnostic markers for individual neurodegenerative pathologies or the neurodegeneration phenomenon in general. Metabolomic profiling can be a promising means for finding a unique "fingerprint" of the disease. Identifying the biomarkers of various neurodegenerative diseases will help shorten the time to the diagnosis, forecast the course of the disease, and personalize the therapeutic approach. This review summarizes and compares the current concepts of metabolomics research into Parkinson's disease and vascular parkinsonism, as well as the respective animal models.
    Keywords:  Parkinson’s disease; biomarker; mass spectrometry; metabolomics; vascular parkinsonism
    DOI:  https://doi.org/10.32607/actanaturae.27511
  62. Brain Res Bull. 2025 Jan 22. pii: S0361-9230(25)00034-6. [Epub ahead of print]221 111222
    Genetic and neurochemical profiles underlying cortical morphometric vulnerability to Parkinson's disease.
    Su Yan, Jun Lu, Bingfang Duan, Hongquan Zhu, Tian Tian, Yuanyuan Qin, Yuanhao Li, Wenzhen Zhu.
       BACKGROUND: Increasing evidence has documented cortical involvement at all stages of PD. The local vulnerabilities within certain brain regions in PD have been previously demonstrated, whereas its underlying genetic and neurochemical factors remain unclear. This study aims to investigate the spatial spectrum of cortical atrophy in Parkinson's disease (PD) and link these variances in gray matter properties and curvature respectively to putative molecular pathways and neurotransmitter factors.
    METHODS: We recruited 141 clinically diagnosed PD patients and 70 healthy controls. Cortical morphological abnormalities of PD were obtained by intergroup comparisons in gray matter properties metrics and curvature measurements. Then we performed gene-category enrichment and spatial correlation analyses to evaluate the specific correspondence between cortical alteration in PD and genetic expression from the Allen Human Brain Atlas and normative neurotransmitter atlases from Neuromaps.
    RESULTS: We found decreased gray matter properties in temporal, somatomotor, cingulate and occipital cortices, decreased curvature measures in occipital, temporal and orbitofrontal cortices, and increased curvature measures in somatomotor, prefrontal and posterior parietal cortices for PD patients. The related genes were enriched for the glucose metabolism, mitochondrial function, and post-translational histone modifications processes. In addition, the serotonin and norepinephrine transporter devoted more to gray matter properties alterations while the dopamine, gamma-aminobutyric acid receptors, and norepinephrine transporter were strong contributors of curvature abnormalities in PD.
    CONCLUSIONS: Collectively, the present study offered interpretation of cortical morphological alterations and the cortical pathogenic theory in PD from genetic and neurochemical perspectives, which inspire further research on new pharmacotherapeutic approaches.
    Keywords:  Cortical morphology; Gene expression; Neurotransmitter system; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111222
  63. Mol Inform. 2025 Jan;44(1): e202400002
    Structural and Dynamic Assessment of Disease-Causing Mutations for the Carnitine Transporter OCTN2.
    Johannes Jokiel, Marcel Bermudez.
      Primary carnitine deficiency (PCD) is a rare autosomal recessive genetic disorder caused by missense mutations in the SLC22A5 gene encoding the organic carnitine transporter novel type 2 (OCTN2). This study investigates the structural consequences of PCD-causing mutations, focusing on the N32S variant. Using an alpha-fold model, molecular dynamics simulations reveal altered interactions and dynamics suggesting potential mechanistic changes in carnitine transport. In addition, we identify mutation hotspots (R169, E452) across the SLC family with the major facilitator superfamily (MFS) fold. Our data demonstrates the applicability of structural modeling for linking genetic information and clinical observations and providing a rationale for the influence of disease-causing mutations on protein dynamics.
    Keywords:  carnitine; genetic variant; molecular dynamics; molecular modeling; solute carrier protein; transporter
    DOI:  https://doi.org/10.1002/minf.202400002
  64. NPJ Aging. 2025 Jan 27. 11(1): 4
    NAD World 3.0: the importance of the NMN transporter and eNAMPT in mammalian aging and longevity control.
    Shin-Ichiro Imai.
      Over the past five years, systemic NAD+ (nicotinamide adenine dinucleotide) decline has been accepted to be a key driving force of aging in the field of aging research. The original version of the NAD World concept was proposed in 2009, providing an integrated view of the NAD+-centric, systemic regulatory network for mammalian aging and longevity control. The reformulated version of the concept, the NAD World 2.0, was then proposed in 2016, emphasizing the importance of the inter-tissue communications between the hypothalamus and peripheral tissues including adipose tissue and skeletal muscle. There has been significant progress in our understanding of the importance of nicotinamide mononucleotide (NMN), a key NAD+ intermediate, and nicotinamide phosphoribosyltransferase (NAMPT), particularly extracellular NAMPT (eNAMPT). With these exciting developments, the further reformulated version of the concept, the NAD World 3.0, is now proposed, featuring multi-layered feedback loops mediated by NMN and eNAMPT for mammalian aging and longevity control.
    DOI:  https://doi.org/10.1038/s41514-025-00192-6
  65. Hum Genet. 2025 Jan 27.
    An augmented transformer model trained on protein family specific variant data leads to improved prediction of variants of uncertain significance.
    Dinesh Joshi, Swatantra Pradhan, Rakshanda Sajeed, Rajgopal Srinivasan, Sadhna Rana.
      Variants of uncertain significance (VUS) represent variants that lack sufficient evidence to be confidently associated with a disease, thus posing a challenge in the interpretation of genetic testing results. Here we report an improved method for predicting the VUS of Arylsulfatase A (ARSA) gene as part of the Critical Assessment of Genome Interpretation challenge (CAGI6). Our method uses a transfer learning approach that leverages a pre-trained protein language model to predict the impact of mutations on the activity of the ARSA enzyme, whose deficiency is known to cause a rare genetic disorder, metachromatic leukodystrophy. Our innovative framework combines zero-shot log odds scores and embeddings from the ESM, an evolutionary scale model as features for training a supervised model on gene variants functionally related to the ARSA gene. The zero-shot log odds score feature captures the generic properties of the proteins learned due to its pre-training on millions of sequences in the UniProt data, while the ESM embeddings for the proteins in the ARSA family capture features specific to the family. We also tested our approach on another enzyme, N-acetyl-glucosaminidase (NAGLU), that belongs to the same superfamily as ARSA. Our results demonstrate that the performance of our family models (augmented ESM models) is either comparable or better than the ESM models. The ARSA model compares favorably with the majority of state-of-the-art predictors on area under precision and recall curve (AUPRC) performance metric. However, the NAGLU model outperforms all pathogenicity predictors evaluated in this study on AUPRC metric. The improved AUPRC has relevance in a diagnostic setting where variant prioritization generally entails identifying a small number of pathogenic variants from a larger number of benign variants. Our results also indicate that genes that have sparse or no experimental variant impact data, the family variant data can serve as a proxy training data for making accurate predictions. Attention analysis of active sites and binding sites in ARSA and NAGLU proteins shed light on probable mechanisms of pathogenicity for positions that are highly attended.
    DOI:  https://doi.org/10.1007/s00439-025-02727-z
  66. Cell Chem Biol. 2025 Jan 21. pii: S2451-9456(25)00002-9. [Epub ahead of print]
    A genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells.
    Joseph J Smith, Taylor R Valentino, Austin H Ablicki, Riddhidev Banerjee, Adam R Colligan, Debra M Eckert, Gabrielle A Desjardins, Katharine L Diehl.
      Acetyl-coenzyme A is a central metabolite that participates in many cellular pathways. Evidence suggests that acetyl-CoA metabolism is highly compartmentalized in mammalian cells. Yet methods to measure acetyl-CoA in living cells are lacking. Herein, we engineered an acetyl-CoA biosensor from the bacterial protein PanZ and circularly permuted green fluorescent protein (cpGFP). The sensor, "PancACe," has a maximum change of ∼2-fold and a response range of ∼10 μM-2 mM acetyl-CoA. We demonstrated that the sensor has a greater than 7-fold selectivity over coenzyme A, butyryl-CoA, malonyl-CoA, and succinyl-CoA, and a 2.3-fold selectivity over propionyl-CoA. We expressed the sensor in E. coli and showed that it enables detection of rapid changes in acetyl-CoA levels. By localizing the sensor to either the cytoplasm, nucleus, or mitochondria in human cells, we showed that it enables subcellular detection of changes in acetyl-CoA levels, the magnitudes of which agreed with an orthogonal PicoProbe assay.
    Keywords:  acetyl-CoA; biosensor; coenzyme A; metabolism; metabolite; protein engineering
    DOI:  https://doi.org/10.1016/j.chembiol.2025.01.002
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