bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–01–19
fifty-four papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial disorder diagnosis and management- what the pediatric neurologist wants to know.
  2. When the Expected Scenario Did Not Occur: A Novel NDUFA12 Mutation Resembling Neuromyelitis Optica Spectrum Disorder.
  3. Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria.
  4. Mitochondrial Complex I and ROS control synapse function through opposing pre- and postsynaptic mechanisms.
  5. Using HBmito Crimson to Observe Mitochondrial Cristae Through STED Microscopy.
  6. Reacting to reductive stress at the mitochondrial import gate.
  7. Interaction and regulation of the mitochondrial proteome - in health and disease.
  8. Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control.
  9. ATAD1 Regulates Neuronal Development and Synapse Formation Through Tuning Mitochondrial Function.
  10. Abnormal Redox Balance at Membrane Contact Sites Causes Axonopathy in Gdap1-related Charcot-marie-tooth Disease.
  11. The maize mTERF18 regulates transcriptional termination of the mitochondrial nad6 gene and is essential for kernel development.
  12. Mitochondrial Complex I Deficiency: Unraveling the Relevance of NDUFAF1 in Pediatric Hypertrophic Cardiomyopathy.
  13. Stress signaling caused by mitochondrial import malfunction can be terminated by SIFI: importance of stress response silencing.
  14. Imaging flow cytometry reveals divergent mitochondrial phenotypes in mitochondrial disease patients.
  15. Polyproline-Polyornithine Diblock Copolymers with Inherent Mitochondria Tropism.
  16. Mitochondrial DNA Mutations as a Factor in the Heritability of Atherosclerosis and Other Diseases.
  17. Mitochondrial HMG-CoA synthase deficiency.
  18. Protocol for mitochondrial variant enrichment from single-cell RNA sequencing using MAESTER.
  19. Novel Coenzyme Q2 (CoQ2) Mutation in a Pediatric Patient With Primary Steroid-Resistant Nephrotic Syndrome Due to Coenzyme Q10 (CoQ10) Deficiency.
  20. Targeting Endothelial Cell Mitochondrial Quality Control in PAH.
  21. HiFi long-read genomes for difficult-to-detect, clinically relevant variants.
  22. Chronic Low-Level IFN-γ Expression Disrupts Mitochondrial Complex I Activity in Renal Macrophages: An Early Mechanistic Driver of Lupus Nephritis Pathogenesis.
  23. NADH-bound AIF activates the mitochondrial CHCHD4/MIA40 chaperone by a substrate-mimicry mechanism.
  24. Mitochondrial segmentation and function prediction in live-cell images with deep learning.
  25. Complex I deficiency remains the most frequent cause of Leigh syndrome spectrum.
  26. Absence of MCJ/DnaJC15 promotes brown adipose tissue thermogenesis.
  27. Recommendations for mitochondria transfer and transplantation nomenclature and characterization.
  28. Continuity of Mitochondrial Budding: Insights from BS-C-1 Cells by In Situ Cryo-electron Tomography.
  29. Mitochondrial Electron Flow Dynamics Imaging for Assessing Mitochondrial Quality and Drug Screening.
  30. Transcriptome-wide outlier approach identifies individuals with minor spliceopathies.
  31. In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
  32. Somatic mutation as an explanation for epigenetic aging.
  33. From Text to Translation: Using Language Models to Prioritize Variants for Clinical Review.
  34. ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling.
  35. The role of mitochondrial remodeling in neurodegenerative diseases.
  36. Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions.
  37. Adenine nucleotide translocator and ATP synthase cooperate in mediating the mitochondrial permeability transition.
  38. Quantitative analyses of single mitochondrial components reveal an early role of small-mitochondrial-networks in priming neoplasticity.
  39. Safe and Orally Bioavailable Inhibitor of Serine Palmitoyltransferase Improves Age-Related Sarcopenia.
  40. FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production.
  41. Single-cell transcriptomics in a child with coenzyme Q10 nephropathy: potential of single-cell RNA sequencing in pediatric kidney disease.
  42. Cardiac-targeted delivery of a novel Drp1 inhibitor for acute cardioprotection.
  43. Recessive but damaging alleles of muscle-specific ribosomal protein gene RPL3L drive neonatal dilated cardiomyopathy.
  44. Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease.
  45. The Promise of Epigenetic Editing for Treating Brain Disorders.
  46. Current Advances and Challenges in Gene Therapies for Neurologic Disorders: A Review for the Clinician.
  47. Targeting mitophagy in neurodegenerative diseases.
  48. Early prediction of healthy ageing and age-related diseases using blood protein biomarkers.
  49. Dopamine degrades ferritin by chaperone-mediated autophagy to elevate mitochondrial iron level in astroglial cells.
  50. Applying artificial intelligence to uncover the genetic landscape of coagulation factors.
  51. Mitochondrial dysfunction is a major cause of thromboinflammation and inflammatory cell death in critical illnesses.
  52. Epigenetic ageing clocks: statistical methods and emerging computational challenges.
  53. Spatially resolved rewiring of mitochondria-lipid droplet interactions in hepatic lipid homeostasis.
  54. Intrinsic neuronal resilience as a tool for therapeutic discovery.
  1. Eur J Paediatr Neurol. 2024 Dec 15. pii: S1090-3798(24)00162-4. [Epub ahead of print]54 75-88
    Mitochondrial disorder diagnosis and management- what the pediatric neurologist wants to know.
    Oliver Heath, René G Feichtinger, Melanie T Achleitner, Peter Hofbauer, Doris Mayr, Kajus Merkevicius, Johannes Spenger, Katja Steinbrücker, Carina Steindl, Elke Tiefenthaler, Johannes A Mayr, Saskia B Wortmann.
      Childhood-onset mitochondrial disorders are rare genetic diseases that often manifest with neurological impairment due to altered mitochondrial structure or function. To date, pathogenic variants in 373 genes across the nuclear and mitochondrial genomes have been linked to mitochondrial disease, but the ensuing genetic and clinical complexity of these disorders poses considerable challenges to their diagnosis and management. Nevertheless, despite the current lack of curative treatment, recent advances in next generation sequencing and -omics technologies have laid the foundation for precision mitochondrial medicine through enhanced diagnostic accuracy and greater insight into pathomechanisms. This holds promise for the development of targeted treatments in this group of patients. Against a backdrop of inherent challenges and recent technological advances in mitochondrial medicine, this review discusses the current diagnostic approach to a child with suspected mitochondrial disease and outlines management considerations of particular relevance to paediatric neurologists. We highlight the importance of mitochondrial expertise centres in providing the laboratory infrastructure needed to supplement uninformative first line genomic testing with focused and/or further unbiased investigations where needed, as well as coordinating an integrated multidisciplinary model of care that is paramount to the management of patients affected by these conditions.
    Keywords:  Exome sequencing; Leigh syndrome; Multi-omics; Muscle biopsy; Treatment; Vitamin
    DOI:  https://doi.org/10.1016/j.ejpn.2024.10.009
  2. J Child Neurol. 2025 Jan 17. 8830738241313081
    When the Expected Scenario Did Not Occur: A Novel NDUFA12 Mutation Resembling Neuromyelitis Optica Spectrum Disorder.
    Ahmet Koçak, Emek Uyur Yalçin, Nilüfer Eldeş Hacifazlioğlu, İbrahim Taş, Rahşan Göçmen, Bahadır Konuşkan.
      Mitochondrial complex I transfers electrons from NADH (nicotinamide adenine dinucleotide) to ubiquinone, facilitating ATP synthesis via a proton gradient. Complex I defects are common among the mitochondrial diseases, especially in childhood. NDUFA12, located in complex I's transmembrane domain, is not directly involved in catalytic activity, but the NDUFA mutations are associated with Leigh syndrome and complex I defects. Complex I deficiency typically manifests as bilateral brainstem lesions and presents with dystonia, hypotonia, and optic nerve damage. This article discusses a patient with an NDUFA12 mutation resembling neuromyelitis optica spectrum disorder clinically and radiologically, highlighting the importance of considering NDUFA12 mutations in dystonia and optic neuritis diagnoses, particularly in neuromyelitis optica spectrum disorder cases that do not respond to standard treatments. Further research on NDUFA12 variants is needed for a better understanding of their phenotypic spectrum and to enhance diagnostic accuracy.
    Keywords:  Leigh syndrome; NDUFA12; mitochondrial complex I; mitochondrial disease; neuromyelitis optica; symmetric brainstem lesion
    DOI:  https://doi.org/10.1177/08830738241313081
  3. Acta Pharm Sin B. 2024 Dec;14(12): 5435-5450
    Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria.
    Yi Wang, Nahui Liu, Lifan Hu, Jingsong Yang, Mengmeng Han, Tianjiao Zhou, Lei Xing, Hulin Jiang.
      Leber's hereditary optic neuropathy (LHON) is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I, which is an important contributor to blindness among young adults across the globe. However, the disorder has no available cures, since the approved drug idebenone for LHON in Europe relies on bypassing complex I defects rather than fixing them. Herein, PARKIN mRNA-loaded nanoparticle (mNP)-engineered mitochondria (mNP-Mito) were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria, normalizing the function of complex I for treating LHON. The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex I via mitochondrial transfer, along with the elimination of dysfunctional mitochondria with impaired complex I via an enhanced PARKIN-mediated mitophagy process. In a mouse model induced with a complex I inhibitor (rotenone, Rot), mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex I activity (76.5%) compared to the group exposed to Rot damage (29.5%), which greatly promoted the restoration of ATP generation and mitigation of ocular mitochondrial disease-related phenotypes. This study highlights the significance of nanoengineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.
    Keywords:  Complex I defect; Engineered mitochondria; Idebenone; Leber's hereditary optic neuropathy; Mitochondrial disease; Mitochondrial function; Mitochondrial transfer; Nanoparticle
    DOI:  https://doi.org/10.1016/j.apsb.2024.08.007
  4. bioRxiv. 2024 Dec 31. pii: 2024.12.30.630694. [Epub ahead of print]
    Mitochondrial Complex I and ROS control synapse function through opposing pre- and postsynaptic mechanisms.
    Bhagaban Mallik, C Andrew Frank.
      Neurons require high amounts energy, and mitochondria help to fulfill this requirement. Dysfunctional mitochondria trigger problems in various neuronal tasks. Using the Drosophila neuromuscular junction (NMJ) as a model synapse, we previously reported that Mitochondrial Complex I (MCI) subunits were required for maintaining NMJ function and growth. Here we report tissue-specific adaptations at the NMJ when MCI is depleted. In Drosophila motor neurons, MCI depletion causes profound cytological defects and increased mitochondrial reactive oxygen species (ROS). But instead of diminishing synapse function, neuronal ROS triggers a homeostatic signaling process that maintains normal NMJ excitation. We identify molecules mediating this compensatory response. MCI depletion in muscles also enhances local ROS. But high levels of muscle ROS cause destructive responses: synapse degeneration, mitochondrial fragmentation, and impaired neurotransmission. In humans, mutations affecting MCI subunits cause severe neurological and neuromuscular diseases. The tissue-level effects that we describe in the Drosophila system are potentially relevant to forms of mitochondrial pathogenesis.
    Keywords:  Drosophila; Mito-GFP; Mitochondrial Complex I; NACA; ND-20L; ROS; homeostatic plasticity; mitochondria; rotenone; sod2
    DOI:  https://doi.org/10.1101/2024.12.30.630694
  5. Bio Protoc. 2025 Jan 05. 15(1): e5150
    Using HBmito Crimson to Observe Mitochondrial Cristae Through STED Microscopy.
    Xichuan Ge, Wei Ren, Chunyan Shan, Peng Xi, Baoxiang Gao.
      Mitochondrial cristae, formed by folding the mitochondrial inner membrane (IM), are essential for cellular energy supply. However, the observation of the IM is challenging due to the limitations in spatiotemporal resolution offered by conventional microscopy and the absence of suitable in vitro probes specifically targeting the IM. Here, we describe a detailed imaging protocol for the mitochondrial inner membrane using the Si-rhodamine dye HBmito Crimson, which has excellent photophysical properties, to label live cells for imaging via stimulated emission depletion (STED) microscopy. This allows for STED imaging over more than 500 frames (approximately one hour), with a spatial resolution of 40 nm, enabling the observation of cristae dynamics during various mitochondrial processes. The protocol includes detailed steps for cell staining, image acquisition, image processing, and resolution analysis. Utilizing the superior resolution of STED microscopy, the structure and complex dynamic changes of cristae can be visualized. Key features • The protocol is designed to visualize mitochondrial cristae in living cells using STED microscopy. • The protocol enables nanoscale observation of dynamic mitochondrial cristae. • Real-time observation of mitochondrial morphological changes, fusion, and fission events.
    Keywords:  Fluorescence labeling; Live cell imaging; Low-saturation power; Mitochondria cristae; Super-resolution imaging
    DOI:  https://doi.org/10.21769/BioProtoc.5150
  6. Trends Cell Biol. 2025 Jan 13. pii: S0962-8924(24)00281-2. [Epub ahead of print]
    Reacting to reductive stress at the mitochondrial import gate.
    Sylvie Callegari.
      A byproduct of mitochondrial energy production is the generation of reactive oxygen species (ROS). Too much ROS is toxic, but ROS deficiency is equally deleterious (reductive stress). In a recent study, McMinimy et al. uncovered a ubiquitin proteasome-mediated mechanism at the translocase of the outer membrane (TOM) complex, which senses ROS depletion and adjusts mitochondrial protein import accordingly.
    Keywords:  TOM complex; mitochondrial import; proteasome; reactive oxygen species; reductive stress; ubiquitin
    DOI:  https://doi.org/10.1016/j.tcb.2024.12.013
  7. Expert Rev Proteomics. 2025 Jan 15. 1-15
    Interaction and regulation of the mitochondrial proteome - in health and disease.
    Johan Palmfeldt.
       INTRODUCTION: Mitochondria contain multiple pathways including energy metabolism and several signaling and synthetic pathways. Mitochondrial proteomics is highly valuable for studying diseases including inherited metabolic disorders, complex and common disorders like neurodegeneration, diabetes, and cancer, since they all to some degree have mitochondrial underpinnings.
    AREAS COVERED: The main mitochondrial functions and pathways are outlined, and systematic protein lists are presented. The main energy metabolic pathways are as follows: iron-sulfur cluster synthesis, one carbon metabolism, catabolism of hydrogen sulfide, kynurenines and reactive oxygen species (ROS), and others, described with the aim of laying a foundation for systematic mitochondrial pathway analysis based on proteomics data. The links of the proteins and pathways to functional effects and diseases are discussed. The disease examples are focussed on inherited metabolic disorders, cancer, neurological, and cardiovascular disorders.
    EXPERT OPINION: To elucidate the role of mitochondria in health and disease, there is a need for comprehensive proteomics analyses with stringent, systematic data treatment for proper interpretation of mitochondrial pathway data. In that way, comprehensive hypothesis-based research can be performed based on proteomics data.
    Keywords:  Mitochondrion; NAD; biomarker panels; kynurenine; metabolic disorders; oxidative phosphorylation; proteomics; stress response
    DOI:  https://doi.org/10.1080/14789450.2025.2451704
  8. bioRxiv. 2024 Dec 30. pii: 2024.12.30.630791. [Epub ahead of print]
    Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control.
    María J Pérez, Rocío B Colombo, Sebastián M Real, María T Branham, Sergio R Laurito, Carlos T Moraes, Lía Mayorga.
      Mitochondrial diseases, caused by mutations in either nuclear or mitochondrial DNA (mtDNA), currently have limited treatment options. For mtDNA mutations, reducing mutant-to-wild-type mtDNA ratio (heteroplasmy shift) is a promising therapeutic option, though current approaches face significant challenges. Previous research has shown that severe mitochondrial dysfunction triggers an adaptive nuclear epigenetic response, characterized by changes in DNA methylation, which does not occur or is less important when mitochondrial impairment is subtle. Building on this, we hypothesized that targeting nuclear DNA methylation could selectively compromise cells with high levels of mutant mtDNA, favor ones with lower mutant load and thereby reduce overall heteroplasmy. Using cybrid models harboring two disease-causing mtDNA mutations-m.13513G>A and m.8344A>G-at varying heteroplasmy levels, we discovered that both the mutation type and load distinctly shape the nuclear DNA methylome. We found this methylation pattern to be critical for the survival of high-heteroplasmy cells but not for the low-heteroplasmy ones. Consequently, by disrupting this epigenetic programming with FDA approved DNA methylation inhibitors we managed to selectively impact high-heteroplasmy cybrids and reduce heteroplasmy. These findings were validated in both cultured cells and an in vivo xenograft model. Our study reveals a previously unrecognized role for nuclear DNA methylation in regulating cell survival in the context of mitochondrial heteroplasmy. This insight not only advances our understanding of mitochondrial-nuclear interactions but also introduces epigenetic modulation as a possible therapeutic avenue for mitochondrial diseases.
    DOI:  https://doi.org/10.1101/2024.12.30.630791
  9. Int J Mol Sci. 2024 Dec 24. pii: 44. [Epub ahead of print]26(1):
    ATAD1 Regulates Neuronal Development and Synapse Formation Through Tuning Mitochondrial Function.
    Hao-Hao Yan, Jia-Jia He, Chuanhai Fu, Jia-Hui Chen, Ai-Hui Tang.
      Mitochondrial function is essential for synaptic function. ATAD1, an AAA+ protease involved in mitochondrial quality control, governs fission-fusion dynamics within the organelle. However, the distribution and functional role of ATAD1 in neurons remain poorly understood. In this study, we demonstrate that ATAD1 is primarily localized to mitochondria in dendrites and, to a lesser extent, in spines in cultured hippocampal neurons. We found that ATAD1 deficiency disrupts the mitochondrial fission-fusion balance, resulting in mitochondrial fragmentation. This deficiency also impairs dendritic branching, hinders dendritic spine maturation, and reduces glutamatergic synaptic transmission in hippocampal neuron. To further investigate the underlying mechanism, we employed an ATP hydrolysis-deficient mutant of ATAD1 to rescue the neuronal deficits associated with ATAD1 loss. We discovered that the synaptic deficits are independent of the mitochondrial morphology changes but rely on its ATP hydrolysis. Furthermore, we show that ATAD1 loss leads to impaired mitochondrial function, including decreased ATP production, impaired membrane potential, and elevated oxidative stress. In conclusion, our results provide evidence that ATAD1 is crucial for maintaining mitochondrial function and regulating neurodevelopment and synaptic function.
    Keywords:  ATAD1; mitochondrial dysfunction; neuronal development; synapse formation
    DOI:  https://doi.org/10.3390/ijms26010044
  10. Res Sq. 2024 Dec 31. pii: rs.3.rs-5682984. [Epub ahead of print]
    Abnormal Redox Balance at Membrane Contact Sites Causes Axonopathy in Gdap1-related Charcot-marie-tooth Disease.
    Francesc Palau, Lara Cantarero, Mónica Roldán, María Rodríguez-Sanz, Angela Mathison, Yaiza Díaz-Osorio, Jordi Pijuan, Marcos Frías, Raul Urrutia, Janet Hoenicka.
      Pathogenic variants of GDAP1 cause Charcot-Marie-Tooth disease (CMT), an inherited neuropathy characterized by axonal degeneration. GDAP1, an atypical glutathione S-transferase, localizes to the outer mitochondrial membrane (OMM), regulating this organelle's dynamics, transport, and membrane contact sites (MCSs). It has been proposed that GDAP1 functions as a cellular redox sensor. However, its precise contribution to redox homeostasis remains poorly understood, as does the possible redox regulation at mitochondrial MCSs. Given the relationship between the peroxisomal redox state and overall cellular redox balance, we investigated the role of GDAP1 in peroxisomal function and mitochondrial MCSs maintenance by using high-resolution microscopy, live cell imaging with pH-sensitive fluorescent probes, and transcriptomic and lipidomic analyses in the Gdap1-/- mice and patient-derived fibroblasts. We demonstrate that GDAP1 deficiency disrupts mitochondria-peroxisome MCSs and leads to peroxisomal abnormalities, which are reversible upon pharmacological activation of PPARγ or glutathione supplementation. These results identify GDAP1 as a new tether of mitochondria-peroxisome MCSs that maintain peroxisomal number and integrity. The supply of glutathione (GSH-MEE) or GDAP1 overexpression suffices to rescue these MCSs. Furthermore, GDAP1 may regulate the redox state within the microdomain of mitochondrial MCSs, as suggested by decreased pH at mitochondria-lysosome contacts in patient-derived fibroblasts, highlighting the relationship between GDAP1 and redox-sensitive targets. Finally, in vivo analysis of sciatic nerve tissue in Gdap1-/- mice revealed significant axonal structural abnormalities, including nodes of Ranvier disruption and defects in the distribution and morphology of mitochondria, lysosomes, and peroxisomes, emphasizing the importance of GDAP1 in sustaining axon integrity in the peripheral nervous system. Taken together, this study positions GDAP1 as a multifunctional protein that mediates mitochondrial interaction with cellular organelles of diverse functions, contributes to redox state sensing, and helps maintain axonal homeostasis. In addition, we identify PPAR as a novel therapeutic target, based on knowledge of the underlying pathogenetic mechanisms.
    DOI:  https://doi.org/10.21203/rs.3.rs-5682984/v1
  11. J Genet Genomics. 2025 Jan 09. pii: S1673-8527(25)00003-7. [Epub ahead of print]
    The maize mTERF18 regulates transcriptional termination of the mitochondrial nad6 gene and is essential for kernel development.
    Zhengwei Guan, Yong Wang, Jun Yang.
      Mitochondria are semi-autonomous organelle present in eukaryotic cells, containing their own genome and transcriptional machinery. However, their functions are intricately linked to proteins encoded by the nuclear genome. Mitochondrial transcription termination factors (mTERFs) are nucleic acid-binding proteins involved in RNA splicing and transcription termination within plant mitochondria and chloroplasts. Despite their recognized importance, the specific roles of mTERF proteins in maize remain largely unexplored. Here, we clone and functionally characterize maize mTERF18 gene. Our findings reveal that mTERF18 mutations lead to severely undifferentiated embryos, resulting in abortive phenotypes. Early kernel exhibits abnormal basal endosperm transfer layer and a significant reduction in both starch and protein accumulation in mterf18. We identify the mTERF18 gene through mapping-based cloning and validate this gene through allelic tests. mTERF18 is widely expressed across various maize tissues and encodes a highly conserved mitochondrial protein. Transcriptome data reveal that mTERF18 mutations disrupt transcriptional termination of the nad6 gene, leading to undetectable levels of Nad6 protein and reduced complex I assembly and activity. Furthermore, transmission electron microscopy observation of mterf18 endosperm uncover severe mitochondrial defects. Collectively, these findings highlight the critical role of mTERF18 in mitochondrial gene transcription termination and its pivotal impact on maize kernel development.
    Keywords:  Kernel development; Mitochondria; Nad6; Transcriptional termination; Zea mays; mTERF18
    DOI:  https://doi.org/10.1016/j.jgg.2025.01.001
  12. Am J Med Genet A. 2025 Jan 16. e63994
    Mitochondrial Complex I Deficiency: Unraveling the Relevance of NDUFAF1 in Pediatric Hypertrophic Cardiomyopathy.
    Silvia Kalantari, Daniele Veraldi, Davide Politano, Antonia Apicella, Riccardo Castagnoli, Thomas Foiadelli, Fulvio D'Abrusco, Elisa Giorgio, Angela Berardinelli, Alessia Claudia Codazzi, Gianluigi Marseglia, Enza Maria Valente, Fabio Sirchia.
      Hypertrophic cardiomyopathy (HCM) is rare in childhood, but it is associated with significant morbidity and mortality. Genetic causes of HCM are mostly related to sarcomeric genes abnormalities; however, syndromic, metabolic, and mitochondrial disorders play an important role in its etiopathogenesis in pediatric patients. We here describe a new case of apparently isolated HCM due to mitochondrial assembly factor gene NDUFAF1 biallelic variants (c.631C > T and an intragenic deletion encompassing exon 3, NM_016013.4). Alterations of this nuclear gene have been associated to Mitochondrial complex I deficiency, nuclear type 11 (OMIM *618234). We here report the fourth case of a child affected by complex I deficiency due to alterations in NDUFAF1 gene. His clinical features appear simpler when compared to the other cases described in the medical literature, increasing our knowledge regarding the highly heterogeneous clinical presentation associated with this disorder.
    Keywords:  NDUFAF1; hypertrophic cardiomiopathy; mitochondrial complex I deficiency
    DOI:  https://doi.org/10.1002/ajmg.a.63994
  13. Neural Regen Res. 2025 Jan 13.
    Stress signaling caused by mitochondrial import malfunction can be terminated by SIFI: importance of stress response silencing.
    Grace Hohman, Michael Shahid, Mohamed A Eldeeb.
      
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01169
  14. iScience. 2025 Jan 17. 28(1): 111496
    Imaging flow cytometry reveals divergent mitochondrial phenotypes in mitochondrial disease patients.
    Irena J J Muffels, Richard Rodenburg, Hanneke L D Willemen, Désirée van Haaften-Visser, Hans Waterham, Niels Eijkelkamp, Sabine A Fuchs, Peter M van Hasselt.
      Traditional classification by clinical phenotype or oxidative phosphorylation (OXPHOS) complex deficiencies often fails to clarify complex genotype-phenotype correlations in mitochondrial disease. A multimodal functional assessment may better reveal underlying disease patterns. Using imaging flow cytometry (IFC), we evaluated mitochondrial fragmentation, swelling, membrane potential, reactive oxygen species (ROS) production, and mitochondrial mass in fibroblasts from 31 mitochondrial disease patients. Significant changes were observed in 97% of patients, forming two overarching groups with distinct responses to mitochondrial pathology. One group displayed low-to-normal membrane potential, indicating a hypometabolic state, while the other showed elevated membrane potential and swelling, suggesting a hypermetabolic state. Literature analysis linked these clusters to complex I stability defects (hypometabolic) and proton pumping activity (hypermetabolic). Thus, our IFC-based platform offers a novel approach to identify disease-specific patterns through functional responses, supporting improved diagnostic and therapeutic strategies.
    Keywords:  Biological sciences; Genetics; Health sciences; Human genetics; Medicine; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2024.111496
  15. Adv Mater. 2025 Jan 10. e2411595
    Polyproline-Polyornithine Diblock Copolymers with Inherent Mitochondria Tropism.
    Camilla Pegoraro, Ekaterina Karpova, Yusuf Qutbuddin, Esther Masiá Sanchis, Pavels Dimitrijevs, Cristián Huck-Iriart, Svetozar Gavrilović, Pavel Arsenyan, Petra Schwille, Carles Felip-León, Aroa Duro-Castano, Inmaculada Conejos-Sanchez, María J Vicent.
      Mitochondria play critical roles in regulating cell fate, with dysfunction correlating with the development of multiple diseases, emphasizing the need for engineered nanomedicines that cross biological barriers. Said nanomedicines often target fluctuating mitochondrial properties and/or present inefficient/insufficient cytosolic delivery (resulting in poor overall activity), while many require complex synthetic procedures involving targeting residues (hindering clinical translation). The synthesis/characterization of polypeptide-based cell penetrating diblock copolymers of poly-L-ornithine (PLO) and polyproline (PLP) (PLOn-PLPm, n:m ratio 1:3) are described as mitochondria-targeting nanocarriers. Synthesis involves a simple two-step methodology based on N-carboxyanhydride ring-opening polymerization, with the scale-up optimization using a "design of experiments" approach. The molecular mechanisms behind targetability and therapeutic activity are investigated through physical/biological processes for diblock copolymers themselves or as targeting moieties in a poly-L-glutamic (PGA)-based conjugate. Diblock copolymers prompt rapid cell entry via energy-independent mechanisms and recognize mitochondria through the mitochondria-specific phospholipid cardiolipin (CL). Stimuli-driven conditions and mitochondria polarization dynamics, which decrease efficacy depending on disease type/stage, do not compromise diblock copolymer uptake/targetability. Diblock copolymers exhibit inherent concentration-dependent anti-tumorigenic activity at the mitochondrial level. The diblock copolymer conjugate possesses improved safety, significant cell penetration, and mitochondrial accumulation via cardiolipin recognition. These findings may support the development of efficient and safe mitochondrial-targeting nanomedicines.
    Keywords:  cardiolipin‐specific mitochondrial targeting; design of experiments (doe); membrane remodeling; mitochondrial tropism; polypeptide‐based nanoconjugates; polyproline, subcellular organelle targeting
    DOI:  https://doi.org/10.1002/adma.202411595
  16. Curr Med Chem. 2025 Jan 14.
    Mitochondrial DNA Mutations as a Factor in the Heritability of Atherosclerosis and Other Diseases.
    Alexander N Orekhov, Nikolay A Orekhov, Vasily N Sukhorukov, Victoria A Khotina, Tatiana I Kovianova, Igor A Sobenin.
      This review discusses the possibility of inheritance of some diseases through mutations in mitochondrial DNA. These are examples of many mitochondrial diseases that can be caused by mutations in mitochondrial DNA. Symptoms and severity can vary widely depending on the specific mutation and affected tissues. An association between certain mutations in the mitochondrial genome and cancer was reported. In other studies of 2-4 generations in each family, we found that mitochondrial mutations associated with atherosclerosis are inherited. This may at least partially explain the inheritance of predisposition to atherosclerotic disease by maternal line. Furthermore, to prove the important role of mitochondrial mutations in the development of atherosclerotic manifestations at the cellular level, we developed a technique for editing the mitochondrial genome. A recent article described how one of the pro-atherogenic mutations, namely m.15059G>A, was eliminated from such monocyte-derived cells using the technique we developed. Elimination of this mutation resulted in the restoration to normal levels of initially defective mitophagy and impaired inflammatory response. These data strongly suggest that mitochondrial mutations are closely associated with the development of atherosclerotic lesions. Considering that they are inherited, it can be assumed that, at least partly, the genetic predisposition to atherosclerotic diseases is transmitted from mother to offspring. Thus, despite the small size of mitochondrial DNA, its mutations may play a role in the pathogenesis of diseases. Further study of their role will make it possible to consider mitochondrial mutations as promising diagnostic markers and disorders caused by mutations as pharmacological targets.
    Keywords:  Atherosclerosis; chronification of inflammation; cybrid; genome editing; inflammatory reaction; innate immune system; intolerant immune response; low-density lipoprotein; mitochondrial DNA mutations.; mitochondrial dysfunctions
    DOI:  https://doi.org/10.2174/0109298673291199241129044139
  17. Mol Genet Metab. 2025 Jan;pii: S1096-7192(24)00891-6. [Epub ahead of print]144(1): 109007
    Mitochondrial HMG-CoA synthase deficiency.
    Bram Decru, Marine Lys, Kobe Truijens, Nathalie Mercier, Jean Papadopoulos, Daisy Rymen, Dominique Roland, Joseph P Dewulf, Pieter Vermeersch.
      Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) deficiency is a rare, potentially life-threatening autosomal recessive disorder resulting from mutations in the HMGCS2 gene, leading to impaired ketogenesis. We systematically reviewed the clinical presentations, biochemical and genetic abnormalities in 93 reported cases and 2 new patients diagnosed based on biochemical findings. Reported onset ages ranged from 3 months to 6 years, mostly before the age of 3. Children younger than one year old are more prone to a severe clinical course. In most patients, the initial metabolic decompensation occurs after an episode of gastroenteritis or gastroenteritis-like symptoms. Other commonly observed symptoms during the first clinical episode included poor intake, altered consciousness, dyspnea, seizures and hepatomegaly. Severity was correlated with the number of truncating mutations. Most patients presented with acute metabolic decompensation with hypoglycemia, dicarboxyluria and inadequate ketonuria. Dicarboxylic acid levels were elevated in 54/56 cases. The organic acid 4-hydroxy-6-methyl-2-pyrone (4HMP) was detected in 33/35 urine samples taken during the acute episodes, but typically only retrospectively. The plasma C2/C0 acylcarnitine ratio was abnormal in 16/18 (88.9 %) of acute plasma samples, but only in 2/6 (33 %) of DBS samples. Other metabolites that have been reported are hydroxyhexenoic acid, 3,5-dihydroxyhexanoic (1,5 lactone), glutaric acidand 3-OH-isovaleric acid. Laboratories should look for 4HMP in urinary organic acid analysis and an increased plasma C2/C0 acylcarnitine ratio to facilitate the diagnosis of HMGCS2 deficiency, especially in cases of metabolic decompensation with dicarboxyluria without adequate ketonuria.
    Keywords:  4-hydroxy-6-methyl-2-pyrone; HMGCS2; Hypoketotic hypoglycemia; Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase
    DOI:  https://doi.org/10.1016/j.ymgme.2024.109007
  18. STAR Protoc. 2025 Jan 15. pii: S2666-1667(24)00729-9. [Epub ahead of print]6(1): 103564
    Protocol for mitochondrial variant enrichment from single-cell RNA sequencing using MAESTER.
    Jonathan D Good, Ksenia R Safina, Tyler E Miller, Peter van Galen.
      Single-cell RNA sequencing (scRNA-seq) enables detailed characterization of cell states but often lacks insights into tissue clonal structures. Here, we present a protocol to probe cell states and clonal information simultaneously by enriching mitochondrial DNA (mtDNA) variants from 3'-barcoded full-length cDNA. We describe steps for input library preparation, mtDNA enrichment, PCR product cleanup, and paired-end sequencing. We then detail computational steps for running maegatk, variant calling, and data integration to illuminate cell states and clonal dynamics in primary human tissues. For complete details on the use and execution of this protocol, please refer to Miller et al.1.
    Keywords:  Genetics; RNA-seq; Sequence analysis; Single Cell
    DOI:  https://doi.org/10.1016/j.xpro.2024.103564
  19. Cureus. 2024 Dec;16(12): e75669
    Novel Coenzyme Q2 (CoQ2) Mutation in a Pediatric Patient With Primary Steroid-Resistant Nephrotic Syndrome Due to Coenzyme Q10 (CoQ10) Deficiency.
    Shahad Alwazzan, Osama Alnwaihi, Neetha John, Lova Satyanarayana Matsa, Hammad O Alshaya.
      Coenzyme Q2 (CoQ2) mutations are a group of autosomal recessive mitochondria-linked diseases that result in coenzyme Q10 (CoQ10) deficiency (CoQ10: a cofactor in mitochondrial energy production). Its deficiency leads to multiple systemic clinical presentations; however, isolated steroid-resistant nephrotic syndrome (SRNS) is considerably rare. Multiple genetic mutations have been reported with different ranges of severity and prognosis, with variable responses to CoQ10 supplementation. This case report describes a boy with CoQ10 deficiency due to a novel homozygous variation in the CoQ2 gene, c.1112T>A, p.(Leu371Gln). The patient presented with isolated SRNS, and oral supplementation of CoQ10 resulted in remission.
    Keywords:  coq10 deficiency; coq10 supplementation; coq2 mutations; nephrotic syndrome; steroid-resistant nephrotic syndrome
    DOI:  https://doi.org/10.7759/cureus.75669
  20. Circ Res. 2025 Jan 17. 136(2): 209-210
    Targeting Endothelial Cell Mitochondrial Quality Control in PAH.
    Mahin Gadkari, Karthik Suresh.
      
    Keywords:  Editorials; endothelial cells; mitochondrial diseases; pulmonary arterial hypertension; vascular diseases
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325940
  21. Am J Hum Genet. 2025 Jan 04. pii: S0002-9297(24)00455-5. [Epub ahead of print]
    HiFi long-read genomes for difficult-to-detect, clinically relevant variants.
    Wolfram Höps, Marjan M Weiss, Ronny Derks, Jordi Corominas Galbany, Amber den Ouden, Simone van den Heuvel, Raoul Timmermans, Jos Smits, Tom Mokveld, Egor Dolzhenko, Xiao Chen, Arthur van den Wijngaard, Michael A Eberle, Helger G Yntema, Alexander Hoischen, Christian Gilissen, Lisenka E L M Vissers.
      Clinical short-read exome and genome sequencing approaches have positively impacted diagnostic testing for rare diseases. Yet, technical limitations associated with short reads challenge their use for the detection of disease-associated variation in complex regions of the genome. Long-read sequencing (LRS) technologies may overcome these challenges, potentially qualifying as a first-tier test for all rare diseases. To test this hypothesis, we performed LRS (30× high-fidelity [HiFi] genomes) for 100 samples with 145 known clinically relevant germline variants that are challenging to detect using short-read sequencing and necessitate a broad range of complementary test modalities in diagnostic laboratories. We show that relevant variant callers readily re-identified the majority of variants (120/145, 83%), including ∼90% of structural variants, SNVs/insertions or deletions (indels) in homologous sequences, and expansions of short tandem repeats. Another 10% (n = 14) was visually apparent in the data but not automatically detected. Our analyses also identified systematic challenges for the remaining 7% (n = 11) of variants, such as the detection of AG-rich repeat expansions. Titration analysis showed that 90% of all automatically called variants could also be identified using 15-fold coverage. Long-read genomes thus identified 93% of challenging pathogenic variants from our dataset. Even with reduced coverage, the vast majority of variants remained detectable, possibly enhancing cost-effective diagnostic implementation. Most importantly, we show the potential to use a single technology to accurately identify all types of clinically relevant variants.
    Keywords:  challenging variants; clinical utility; diagnostics; genomics; long-read sequencing; omics; rare disease; short-read sequencing
    DOI:  https://doi.org/10.1016/j.ajhg.2024.12.013
  22. Int J Mol Sci. 2024 Dec 25. pii: 63. [Epub ahead of print]26(1):
    Chronic Low-Level IFN-γ Expression Disrupts Mitochondrial Complex I Activity in Renal Macrophages: An Early Mechanistic Driver of Lupus Nephritis Pathogenesis.
    Heekyong R Bae, Su-Kyung Shin, Ji-Yoon Lee, Yeo Jin Ko, Suntae Kim, Howard A Young, Eun-Young Kwon.
      Mitochondrial dysfunction and macrophage dysregulation are well recognized as significant contributors to the pathogenesis of autoimmune diseases. However, the detailed mechanisms connecting these two factors remain poorly understood. This study hypothesizes that low but chronic interferon-gamma (IFN-γ) plays a critical role in these processes. To explore this, we utilized ARE-Del mice, a model characterized by sustained low-level IFN-γ expression and lupus nephritis (LN)-like symptoms. Age- and tissue-dependent gene expression analyses in ARE-Del mice revealed significant suppression of mitochondrial complex I components and activities, particularly in the kidneys. The genotype-dependent suppression of mitochondrial complex I indicates early disruption, which leads to macrophage dysfunction. Notably, remission restored gene expression of mitochondrial complex I and macrophage dysfunction in isolated renal macrophages from NZB/W lupus-prone mice. These findings suggest that chronic low-level IFN-γ disrupts mitochondrial complex I activity in macrophages, highlighting its role in the early pathogenesis of autoimmune diseases like lupus nephritis. This provides new insights into the molecular interactions underlying autoimmune pathogenesis and suggests potential targets for therapeutic intervention.
    Keywords:  autoimmune diseases; interferon gamma; lupus nephritis; macrophage dysfunction; mitochondrial complex I
    DOI:  https://doi.org/10.3390/ijms26010063
  23. EMBO J. 2025 Jan 13.
    NADH-bound AIF activates the mitochondrial CHCHD4/MIA40 chaperone by a substrate-mimicry mechanism.
    Chris A Brosey, Runze Shen, John A Tainer.
      Mitochondrial metabolism requires the chaperoned import of disulfide-stabilized proteins via CHCHD4/MIA40 and its enigmatic interaction with oxidoreductase Apoptosis-inducing factor (AIF). By crystallizing human CHCHD4's AIF-interaction domain with an activated AIF dimer, we uncover how NADH allosterically configures AIF to anchor CHCHD4's β-hairpin and histidine-helix motifs to the inner mitochondrial membrane. The structure further reveals a similarity between the AIF-interaction domain and recognition sequences of CHCHD4 substrates. NMR and X-ray scattering (SAXS) solution measurements, mutational analyses, and biochemistry show that the substrate-mimicking AIF-interaction domain shields CHCHD4's redox-sensitive active site. Disrupting this shield critically activates CHCHD4 substrate affinity and chaperone activity. Regulatory-domain sequestration by NADH-activated AIF directly stimulates chaperone binding and folding, revealing how AIF mediates CHCHD4 mitochondrial import. These results establish AIF as an integral component of the metazoan disulfide relay and point to NADH-activated dimeric AIF as an organizational import center for CHCHD4 and its substrates. Importantly, AIF regulation of CHCHD4 directly links AIF's cellular NAD(H) sensing to CHCHD4 chaperone function, suggesting a mechanism to balance tissue-specific oxidative phosphorylation (OXPHOS) capacity with NADH availability.
    Keywords:  Apoptosis-inducing Factor (AIF); CHCHD4/MIA40; OXPHOS; Small-angle X-ray Scattering (SAXS); X-ray Crystallography
    DOI:  https://doi.org/10.1038/s44318-024-00360-6
  24. Nat Commun. 2025 Jan 16. 16(1): 743
    Mitochondrial segmentation and function prediction in live-cell images with deep learning.
    Yang Ding, Jintao Li, Jiaxin Zhang, Panpan Li, Hua Bai, Bin Fang, Haixiao Fang, Kai Huang, Guangyu Wang, Cameron J Nowell, Nicolas H Voelcker, Bo Peng, Lin Li, Wei Huang.
      Mitochondrial morphology and function are intrinsically linked, indicating the opportunity to predict functions by analyzing morphological features in live-cell imaging. Herein, we introduce MoDL, a deep learning algorithm for mitochondrial image segmentation and function prediction. Trained on a dataset of 20,000 manually labeled mitochondria from super-resolution (SR) images, MoDL achieves superior segmentation accuracy, enabling comprehensive morphological analysis. Furthermore, MoDL predicts mitochondrial functions by employing an ensemble learning strategy, powered by an extended training dataset of over 100,000 SR images, each annotated with functional data from biochemical assays. By leveraging this large dataset alongside data fine-tuning and retraining, MoDL demonstrates the ability to precisely predict functions of heterogeneous mitochondria from unseen cell types through small sample size training. Our results highlight the MoDL's potential to significantly impact mitochondrial research and drug discovery, illustrating its utility in exploring the complex relationship between mitochondrial form and function within a wide range of biological contexts.
    DOI:  https://doi.org/10.1038/s41467-025-55825-x
  25. Brain Commun. 2025 ;7(1): fcae470
    Complex I deficiency remains the most frequent cause of Leigh syndrome spectrum.
    Shamima Rahman.
      This scientific commentary refers to 'Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment', by Kaiyrzhanov et al. (https://doi.org/10.1093/braincomms/fcae453).
    DOI:  https://doi.org/10.1093/braincomms/fcae470
  26. Nat Commun. 2025 Jan 13. 16(1): 229
    Absence of MCJ/DnaJC15 promotes brown adipose tissue thermogenesis.
    Beatriz Cicuéndez, Alfonso Mora, Juan Antonio López, Andrea Curtabbi, Javier Pérez-García, Begoña Porteiro, Daniel Jimenez-Blasco, Pedro Latorre-Muro, Paula Vo, Madison Jerome, Beatriz Gómez-Santos, Rafael Romero-Becerra, Magdalena Leiva, Elena Rodríguez, Marta León, Luis Leiva-Vega, Noemi Gómez-Lado, Jorge L Torres, Lourdes Hernández-Cosido, Pablo Aguiar, Miguel Marcos, Martin Jastroch, Andreas Daiber, Patricia Aspichueta, Juan Pedro Bolaños, Jessica B Spinelli, Pere Puigserver, José Antonio Enriquez, Jesús Vázquez, Cintia Folgueira, Guadalupe Sabio.
      Obesity poses a global health challenge, demanding a deeper understanding of adipose tissue (AT) and its mitochondria. This study describes the role of the mitochondrial protein Methylation-controlled J protein (MCJ/DnaJC15) in orchestrating brown adipose tissue (BAT) thermogenesis. Here we show how MCJ expression decreases during obesity, as evident in human and mouse adipose tissue samples. MCJKO mice, even without UCP1, a fundamental thermogenic protein, exhibit elevated BAT thermogenesis. Electron microscopy unveils changes in mitochondrial morphology resembling BAT activation. Proteomic analysis confirms these findings and suggests involvement of the eIF2α mediated stress response. The pivotal role of eIF2α is scrutinized by in vivo CRISPR deletion of eIF2α in MCJKO mice, abrogating thermogenesis. These findings uncover the importance of MCJ as a regulator of BAT thermogenesis, presenting it as a promising target for obesity therapy.
    DOI:  https://doi.org/10.1038/s41467-024-54353-4
  27. Nat Metab. 2025 Jan 16.
    Recommendations for mitochondria transfer and transplantation nomenclature and characterization.
    Jonathan R Brestoff, Keshav K Singh, Katia Aquilano, Lance B Becker, Michael V Berridge, Eric Boilard, Andrés Caicedo, Clair Crewe, José Antonio Enríquez, Jianqing Gao, Åsa B Gustafsson, Kazuhide Hayakawa, Maroun Khoury, Yun-Sil Lee, Daniele Lettieri-Barbato, Patricia Luz-Crawford, Heidi M McBride, James D McCully, Ritsuko Nakai, Jiri Neuzil, Martin Picard, Alexander G Rabchevsky, Anne-Marie Rodriguez, Shiladitya Sengupta, Alexander J Sercel, Toshio Suda, Michael A Teitell, Alain R Thierry, Rong Tian, Melanie Walker, Minghao Zheng.
      Intercellular mitochondria transfer is an evolutionarily conserved process in which one cell delivers some of their mitochondria to another cell in the absence of cell division. This process has diverse functions depending on the cell types involved and physiological or disease context. Although mitochondria transfer was first shown to provide metabolic support to acceptor cells, recent studies have revealed diverse functions of mitochondria transfer, including, but not limited to, the maintenance of mitochondria quality of the donor cell and the regulation of tissue homeostasis and remodelling. Many mitochondria-transfer mechanisms have been described using a variety of names, generating confusion about mitochondria transfer biology. Furthermore, several therapeutic approaches involving mitochondria-transfer biology have emerged, including mitochondria transplantation and cellular engineering using isolated mitochondria. In this Consensus Statement, we define relevant terminology and propose a nomenclature framework to describe mitochondria transfer and transplantation as a foundation for further development by the community as this dynamic field of research continues to evolve.
    DOI:  https://doi.org/10.1038/s42255-024-01200-x
  28. Microsc Microanal. 2025 Jan 13. pii: ozae122. [Epub ahead of print]
    Continuity of Mitochondrial Budding: Insights from BS-C-1 Cells by In Situ Cryo-electron Tomography.
    Judy Z Hu, Lijun Qiao, Xianhai Zhao, Chang-Jun Liu, Guo-Bin Hu.
      Mitochondrial division is a fundamental biological process essensial for cellular functionality and vitality. The prevailing hypothesis that dynamin related protein 1 (Drp1) provides principal control in mitochondrial division, in which it also involves the endoplasmic reticulum (ER) and the cytoskeleton, does not account for all the observations. Therefore. the hypothesis may be incomplete. Our previous study in HeLa cells led to a new hypothesis of mitochondrial division by budding. To follow-up our previous study, we employed in situ cryo-electron tomography to visualize mitochondrial budding in the intact healthy monkey kidney cells (BS-C-1 cells). Our findings reaffirm single and multiple mitochondrial budding, consistent with our observations in HeLa cells. Notably, the budding regions vary significantly in diameter and length, which may represent different stages of budding. More interestingly, neither rings nor ring-like structures, nor the wrapping of ER tubes was observed in the budding regions, suggesting mitochondrial budding is independent from Drp1 and ER. Meanwhile, we uncovered direct interactions between mitochondria and large vesicles that are distinct from small mitochondrial-derived vesicles and extracellular mitovesicles. We propose that these interacting vesicles may have mitochondrial origins.
    Keywords:   in situ cryo-electron tomography; cryo-electron microscopy (Cryo-EM); cryo-electron tomography (Cryo-ET); mitochondrial budding; mitochondrial division; mitochondrial dynamics
    DOI:  https://doi.org/10.1093/mam/ozae122
  29. Adv Sci (Weinh). 2025 Jan 13. e2410561
    Mitochondrial Electron Flow Dynamics Imaging for Assessing Mitochondrial Quality and Drug Screening.
    Youxiao Ren, Ling-Ling Wu, Wenjing Song, Yanan Gao, Litao Shao, Zhiyuan Lu, Songsong Wang, Xintian Shao, Zhenjie Yu, Mengrui Zhang, Jing Wu, Liwen Han, Kewu Zeng, Qixin Chen.
      Mitochondrial quality control is paramount for cellular development, with mitochondrial electron flow (Mito-EF) playing a central role in maintaining mitochondrial homeostasis. However, unlike visible protein entities, which can be monitored through chemical biotechnology, regulating mitochondrial quality control by invisible entities such as Mito-EF has remained elusive. Here, a Mito-EF tracker (Mito-EFT) with a four-pronged probe design is presented to elucidate the dynamic mechanisms of Mito-EF's involvement in mitochondrial quality control. Heightened aggregation of Mito-EF in fiber-like healthy mitochondria compared to round-like damaged mitochondria is demonstrated, revealed Mito-EF aggregation correlated with mitochondrial morphological remodeling, particularly in regions undergoing mitochondrial fission and fusion, and show the Mito-EF signal associated with mitochondrial cristae maintained by Dynamin-Related Protein 1 (DRP1). This underscores the importance of considering Mito-EF in assessing mitochondrial quality control parameters. A novel drug screening evaluation parameter, Mito-EF is also introduced to screen and discover mitochondrial-targeted therapeutic modulators. This tracker provides new avenues for investigating the role of Mito-EF in maintaining mitochondrial homeostasis and quality control, offering a potent tool for assessing mitochondrial quality and drug screening.
    Keywords:  drug screening; imaging; mitochondria; mitochondrial electron flow; morphology
    DOI:  https://doi.org/10.1002/advs.202410561
  30. medRxiv. 2025 Jan 03. pii: 2025.01.02.24318941. [Epub ahead of print]
    Transcriptome-wide outlier approach identifies individuals with minor spliceopathies.
    Undiagnosed Disease Network
      RNA-sequencing has improved the diagnostic yield of individuals with rare diseases. Current analyses predominantly focus on identifying outliers in single genes that can be attributed to cis-acting variants within or near that gene. This approach overlooks causal variants with trans-acting effects on splicing transcriptome-wide, such as variants impacting spliceosome function. We present a transcriptomics-first method to diagnose individuals with rare diseases by examining transcriptome-wide patterns of splicing outliers. Using splicing outlier detection methods - FRASER and FRASER2 - we identified splicing outliers from whole blood for 390 individuals from the Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) and Undiagnosed Diseases Network (UDN) consortia. We examined all samples for excess intron retention events in minor intron containing genes. Minor introns, which make up about 0.5% of all introns in the human genome, are removed by small nuclear RNAs (snRNAs) in the minor spliceosome. This approach identified five cases with excess intron retention events in minor intron containing genes, all of which were found to harbor rare, biallelic variants in the minor spliceosome snRNAs. Four had rare, compound heterozygous variants in RNU4ATAC. These results led to the reclassification of four variants. Additionally, one case had rare, highly conserved, compound heterozygous variants in RNU6ATAC that may disrupt the formation of the catalytic spliceosome, suggesting a novel disease-gene candidate. These results demonstrate that examining RNA-sequencing data for known transcriptome-wide signatures can increase the diagnostic yield of individuals with rare diseases, provide variant-to-functional interpretation of spliceopathies, and potentially uncover novel disease genes.
    DOI:  https://doi.org/10.1101/2025.01.02.24318941
  31. bioRxiv. 2025 Jan 02. pii: 2025.01.02.629617. [Epub ahead of print]
    In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
    Hanna F Willenbockel, Alexander T Williams, Alfredo Lucas, Birte Dowerg, Pedro Cabrales, Christian M Metallo, Thekla Cordes.
      Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized via tricarboxylic acid (TCA) metabolism downstream of TLR signaling. Itaconate-based treatment strategies are being explored to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation, and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13 C itaconate tracing, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine, and fuels TCA cycle metabolism specifically in the liver and kidneys. These studies further revealed that itaconate is converted into acetyl-CoA, mesaconate, and citramalate in mitochondria. Itaconate administration also influenced branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase (SDH) and methylmalonyl-CoA mutase (MUT) activity. Our findings uncovered a previously unknown aspect of the itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.
    DOI:  https://doi.org/10.1101/2025.01.02.629617
  32. Nat Aging. 2025 Jan 13.
    Somatic mutation as an explanation for epigenetic aging.
    Zane Koch, Adam Li, Daniel S Evans, Steven Cummings, Trey Ideker.
      DNA methylation marks have recently been used to build models known as epigenetic clocks, which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In an analysis of multimodal data from 9,331 human individuals, we found that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but with pervasive remodeling of the methylome out to ±10 kilobases. This one-to-many mapping allows mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging more rapidly or slowly than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life.
    DOI:  https://doi.org/10.1038/s43587-024-00794-x
  33. medRxiv. 2024 Dec 31. pii: 2024.12.31.24319792. [Epub ahead of print]
    From Text to Translation: Using Language Models to Prioritize Variants for Clinical Review.
    Weijiang Li, Xiaomin Li, Ethan Lavallee, Alice Saparov, Marinka Zitnik, Christopher Cassa.
      Despite rapid advances in genomic sequencing, most rare genetic variants remain insufficiently characterized for clinical use, limiting the potential of personalized medicine. When classifying whether a variant is pathogenic, clinical labs adhere to diagnostic guidelines that comprehensively evaluate many forms of evidence including case data, computational predictions, and functional screening. While a substantial amount of clinical evidence has been developed for these variants, the majority cannot be definitively classified as 'pathogenic' or 'benign', and thus persist as 'Variants of Uncertain Significance' (VUS). We processed over 2.4 million plaintext variant summaries from ClinVar, employing sentence-level classification to remove content that does not contain evidence and removing uninformative summaries. We developed ClinVar-BERT to discern clinical evidence within these summaries by fine-tuning a BioBERT-based model with labeled records. When validated classifications from this model against orthogonal functional screening data, ClinVar-BERT significantly separated estimates of functional impact in clinically actionable genes, including BRCA1 (p = 1.90 × 10 - 20 ), TP53 (p = 1.14 × 10 - 47 ), and PTEN (p = 3.82 × 10 - 7 ). Additionally, ClinVar-BERT achieved an AUROC of 0.927 in classifying ClinVar VUS against this functional screening data. This suggests that ClinVar-BERT is capable of discerning evidence from diagnostic reports and can be used to prioritize variants for re-assessment by diagnostic labs and expert curation panels.
    DOI:  https://doi.org/10.1101/2024.12.31.24319792
  34. iScience. 2025 Jan 17. 28(1): 111544
    ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling.
    Kashif Shaikh, Melissa Bowman, Sarah M McCormick, Linlin Gao, Jiawen Zhang, Jesse White, John Tawil, Arun Kapoor, Ravit Arav-Boger, Christopher C Norbury, Edward W Harhaj.
      ZFAND6 is a zinc finger protein that interacts with TNF receptor-associated factor 2 (TRAF2) and polyubiquitin chains and has been linked to tumor necrosis factor (TNF) signaling. Here, we report a previously undescribed function of ZFAND6 in maintaining mitochondrial homeostasis by promoting mitophagy. Deletion of ZFAND6 in bone marrow-derived macrophages (BMDMs) upregulates reactive oxygen species (ROS) and the accumulation of damaged mitochondria due to impaired mitophagy. Consequently, mitochondrial DNA (mtDNA) is released into the cytoplasm, triggering the spontaneous expression of interferon-stimulated genes (ISGs) in a stimulator of interferon genes (STING) dependent manner, which leads to enhanced viral resistance. Mechanistically, ZFAND6 bridges a TRAF2-cIAP1 interaction and mediates the recruitment of TRAF2 to damaged mitochondria, which is required for the initiation of ubiquitin-dependent mitophagy. Our results suggest that ZFAND6 promotes the interactions of TRAF2 and cIAP1 and the clearance of damaged mitochondria by mitophagy to maintain mitochondrial homeostasis.
    Keywords:  Cell biology; Omics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.111544
  35. Neurochem Int. 2025 Jan 09. pii: S0197-0186(24)00254-7. [Epub ahead of print]183 105927
    The role of mitochondrial remodeling in neurodegenerative diseases.
    Duanqin Guan, Congmin Liang, Dongyan Zheng, Shizhen Liu, Jiankun Luo, Ziwei Cai, He Zhang, Jialong Chen.
      Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.
    Keywords:  Biosynthesis; Mitochondrial quality control; Mitochondrial remodeling; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.neuint.2024.105927
  36. Curr Neurol Neurosci Rep. 2025 Jan 16. 25(1): 16
    Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions.
    David Pellerin, Pablo Iruzubieta, Isaac R L Xu, Matt C Danzi, Andrea Cortese, Matthis Synofzik, Henry Houlden, Stephan Zuchner, Bernard Brais.
       PURPOSE OF REVIEW: Autosomal dominant cerebellar ataxias, also known as spinocerebellar ataxias (SCAs), are genetically and clinically diverse neurodegenerative disorders characterized by progressive cerebellar dysfunction. Despite advances in sequencing technologies, a large proportion of patients with SCA still lack a definitive genetic diagnosis. The advent of advanced bioinformatic tools and emerging genomics technologies, such as long-read sequencing, offers an unparalleled opportunity to close the diagnostic gap for hereditary ataxias. This article reviews the recently identified repeat expansion SCAs and describes their molecular basis, epidemiology, and clinical features.
    RECENT FINDINGS: Leveraging advanced bioinformatic tools and long-read sequencing, recent studies have identified novel pathogenic short tandem repeat expansions in FGF14, ZFHX3, and THAP11, associated with SCA27B, SCA4, and SCA51, respectively. SCA27B, caused by an intronic (GAA)•(TTC) repeat expansion, has emerged as one of the most common forms of adult-onset hereditary ataxias, especially in European populations. The coding GGC repeat expansion in ZFHX3 causing SCA4 was identified more than 25 years after the disorder's initial clinical description and appears to be a rare cause of ataxia outside northern Europe. SCA51, caused by a coding CAG repeat expansion, is overall rare and has been described in a small number of patients. The recent identification of three novel pathogenic repeat expansions underscores the importance of this class of genomic variation in the pathogenesis of SCAs. Progress in sequencing technologies holds promise for closing the diagnostic gap in SCAs and guiding the development of therapeutic strategies for ataxia.
    Keywords:  Autosomal dominant cerebellar ataxia; FGF14; Genome sequencing; Spinocerebellar ataxia; Spinocerebellar ataxia 27B (SCA27B); Spinocerebellar ataxia 4 (SCA4); Spinocerebellar ataxia 51 (SCA51); THAP11; ZFHX3
    DOI:  https://doi.org/10.1007/s11910-024-01400-8
  37. J Physiol. 2025 Jan 14.
    Adenine nucleotide translocator and ATP synthase cooperate in mediating the mitochondrial permeability transition.
    Ludovica Tommasin, Andrea Carrer, Federica Boscolo Nata, Elena Frigo, Federico Fogolari, Giovanna Lippe, Michela Carraro, Paolo Bernardi.
      The permeability transition (PT) is a permeability increase of the mitochondrial inner membrane causing mitochondrial swelling in response to matrix Ca2+. The PT is mediated by regulated channel(s), the PT pore(s) (PTP), which can be generated by at least two components, adenine nucleotide translocator (ANT) and ATP synthase. Whether these provide independent permeation pathways remains to be established. Here, we assessed the contribution of ANT to the PT based on the effects of the selective ANT inhibitors atractylate (ATR) and bongkrekate (BKA), which trigger and inhibit channel formation by ANT, respectively. BKA partially inhibited Ca2+-dependent PT and did not prevent the inducing effect of phenylarsine oxide, which was still present in mouse embryonic fibroblasts deleted for all ANT isoforms. The contribution of ANT to the PT emerged at pH 6.5 (a condition that inhibits ATP synthase channel opening) in the presence of ATR, which triggered mitochondrial swelling and elicited currents in patch-clamped mitoplasts. Unexpectedly, ANT-dependent PT at pH 6.5 could also be stimulated by benzodiazepine-423 [a selective ligand of the oligomycin sensitivity conferral protein (OSCP) subunit of ATP synthase], suggesting that the ANT channel is regulated by the peripheral stalk of ATP synthase. In keeping with docking simulations, ANT could be co-immunoprecipitated with ATP synthase subunits c and g, and oligomycin (which binds adjacent c subunits) decreased the association of ANT with subunit c. These results reveal a close cooperation between ANT and ATP synthase in the PT and open new perspectives in the study of this process. KEY POINTS: We have assessed the relative role of adenine nucleotide translocator (ANT) and ATP synthase in generating the mitochondrial permeability transition (PT). At pH 7.4, bongkrekate had little effect on Ca2+-dependent PT, and did not prevent the inducing effect of phenylarsine oxide, which was still present in mouse embryonic fibroblasts deleted for all ANT isoforms. The contribution of ANT emerged at pH 6.5 (which inhibits ATP synthase channel opening) in the presence of atractylate, which triggered mitochondrial swelling and elicited currents in patch-clamped mitoplasts. Benzodiazepine-423, a selective ligand of the oligomycin sensitivity conferral protein subunit of ATP synthase, stimulated ANT-dependent PT at pH 6.5, suggesting that the ANT channel is regulated by the peripheral stalk of ATP synthase. ANT could be co-immunoprecipitated with ATP synthase subunits c and g; oligomycin, which binds adjacent c subunits, decreased the association with subunit c, in keeping with docking simulations.
    Keywords:  ATP synthase; adenine nucleotide translocator; calcium; mitochondria; permeability transition
    DOI:  https://doi.org/10.1113/JP287147
  38. bioRxiv. 2025 Jan 02. pii: 2024.12.26.630414. [Epub ahead of print]
    Quantitative analyses of single mitochondrial components reveal an early role of small-mitochondrial-networks in priming neoplasticity.
    Mayank Saini, Swati Agarwala, Biratal Wagle, Brian Spurlock, Bharti Golchha, Danitra Parker, Kasturi Mitra.
      Quantitative understanding of mitochondrial heterogeneity is necessary for elucidating the precise role of these multifaceted organelles in tumor cell development. We demonstrate an early mechanistic role of mitochondria in initiating neoplasticity by performing quantitative analyses of structure-function of single mitochondrial components coupled with single cell transcriptomics. We demonstrate that the large Hyperfused-Mitochondrial-Networks (HMNs) of keratinocytes promptly get converted to the heterogenous Small-Mitochondrial-Networks (SMNs) as the stem cell enriching dose of the model carcinogen, TCDD, depolarizes mitochondria. This happens by physical reorganization of the HMN nodes and edges, which enriches redox tuned SMNs with distinct network complexity. This leads to establishment of transcriptomic interaction between the upregulated redox relevant mtDNA genes and the lineage specific stemness gene, KRT15, prior to cell cycle exit. The SMN enrichment and related transcriptomic connections are sustained in the neoplastic cell population. Consistently, carcinogenic dose incapable of causing pronounced neoplastic stem cell enrichment fails to establish specific enrichment of SMNs and its linked mtDNA-KRT15(stemness) transcriptomic interaction prior to cell cycle exit. The mtDNA-KRT15 modulation is confirmed in cSCC tumors, while highlighting patient heterogeneity. Therefore, we propose that early enrichment of redox-tuned SMNs primes neoplastic transformation by establishing mtDNA-stemness transcriptomic interaction prior to cell cycle exit towards specifying quiescent neoplastic stem cells. Our data implies that redox-tuned SMNs, created by mitochondrial fission, would be sustained by tuning the balance of mitochondrial fission-fusion during neoplastic transformation. The proposed early role of mitochondria in cancer etiology is potentially relevant for designing precision strategies for cancer prevention and therapy.
    Significance Statement: The challenges of understanding the complex role of the multifaceted and heterogenous cellular organelles, mitochondria, can be potentially overcome with their quantitative analyses. We use a combinatorial approach of quantitative analyses of single-mitochondrial-components and scRNA-seq to elucidate a mechanism of mitochondrial priming of cancer initiation by a model carcinogen. We propose that conversion of large Hyperfused-Mitochondrial-Networks (HMNs) to Small-Mitochondrial-Networks (SMNs) primes non-transformed keratinocytes towards their neoplastic transformation. Mechanistically, the SMNs, enriched by modulation of the physical nodes and edges of mitochondrial networks, tunes mitochondrial redox balance to establish transcriptomic interactions towards specifying a state of stemness. Further probing of our fundamental findings in the light of cancer heterogeneity may facilitate refinement of the various proposed mitochondria based targeted cancer therapies.
    DOI:  https://doi.org/10.1101/2024.12.26.630414
  39. ACS Pharmacol Transl Sci. 2025 Jan 10. 8(1): 203-215
    Safe and Orally Bioavailable Inhibitor of Serine Palmitoyltransferase Improves Age-Related Sarcopenia.
    Johanne Poisson, Ioanna Daskalaki, Vijay Potluri, Jean-David Morel, Sandra Rodriguez-Lopez, Alessia De Masi, Giorgia Benegiamo, Suresh Jain, Tanes Lima, Johan Auwerx.
      The accumulation of ceramides and related metabolites has emerged as a pivotal mechanism contributing to the onset of age-related diseases. However, small molecule inhibitors targeting the ceramide de novo synthesis pathway for clinical use are currently unavailable. We synthesized a safe and orally bioavailable inhibitor, termed ALT-007, targeting the rate-limiting enzyme of ceramide de novo synthesis, serine palmitoyltransferase (SPT). In a mouse model of age-related sarcopenia, ALT-007, administered through the diet, effectively restored muscle mass and function compromised by aging. Mechanistic studies revealed that ALT-007 enhances protein homeostasis in Caenorhabditis elegans and mouse models of aging and age-related diseases, such as sarcopenia and inclusion body myositis (IBM); this effect is mediated by a specific reduction in very-long chain 1-deoxy-sphingolipid species, which accumulate in both muscle and brain tissues of aged mice and in muscle cells from IBM patients. These findings unveil a promising therapeutic avenue for developing safe ceramide inhibitors to address age-related neuromuscular diseases.
    DOI:  https://doi.org/10.1021/acsptsci.4c00587
  40. FEBS Open Bio. 2025 Jan 16.
    FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production.
    Yushi Otsuka, Masato Yano.
      FAM136A deficiency has been associated with Ménière's disease. However, the underlying mechanism of action of this protein remains unclear. We hypothesized that FAM136A functions in maintaining mitochondria, even in HepG2 cells. To better characterize FAM136A function, we analyzed the cellular response caused by its depletion. FAM136A depletion induced reactive oxygen species (ROS) and reduced both mitochondrial membrane potential and ATP production. However, cleaved caspase-9 levels did not increase significantly. We next investigated why the depletion of FAM136A reduced the mitochondrial membrane potential and ATP production but did not lead to apoptosis. Depletion of FAM136A induced the mitochondrial unfolded protein response (UPRmt) and the expression levels of gluconeogenic phosphoenolpyruvate carboxykinases (PCK1 and PCK2) and ketogenic 3-hydroxy-3-methylglutaryl-CoA synthases (HMGCS1 and HMGCS2) were upregulated. Furthermore, depletion of FAM136A reduced accumulation of holocytochrome c synthase (HCCS), a FAM136A interacting enzyme that combines heme to apocytochrome c to produce holocytochrome c. Notably, the amount of heme in cytochrome c did not change significantly with FAM136A depletion, although the amount of total cytochrome c protein increased significantly. This observation suggests that greater amounts of cytochrome c remain unbound to heme in FAM136A-depleted cells.
    Keywords:  ATP; FAM136A; holocytochrome c synthetase; mitochondrial membrane potential; mitochondrial stress
    DOI:  https://doi.org/10.1002/2211-5463.13967
  41. Pediatr Nephrol. 2025 Jan 14.
    Single-cell transcriptomics in a child with coenzyme Q10 nephropathy: potential of single-cell RNA sequencing in pediatric kidney disease.
    Peong Gang Park, Sowon Choi, Yo Han Ahn, Seong Heon Kim, Chaeyoon Kim, Hyun Je Kim, Hee Gyung Kang.
       BACKGROUND: Coenzyme Q10 (CoQ10) nephropathy is a well-known cause of hereditary steroid-resistant nephrotic syndrome, primarily impacting podocytes. This study aimed to elucidate variations in individual cell-level gene expression in CoQ10 nephropathy using single-cell transcriptomics.
    METHODS: We conducted single-cell sequencing of a kidney biopsy specimen from a 5-year-old boy diagnosed with a CoQ10 nephropathy caused by a compound heterozygous COQ2 mutation complicated with immune complex-mediated glomerulonephritis. The analysis focused on the proportion of cell types, differentially expressed genes in each cell type, and changes in gene expression related to mitochondrial function and oxidative phosphorylation (OXPHOS).
    RESULTS: Our findings revealed a uniform downregulation of mitochondrial gene expression across various cell types in the context of these mutations. Notably, there was a specific decrease in mitochondrial gene expression across all cell types. The study also highlighted an altered immune cell population proportion attributed to the COQ2 gene mutation. Pathway analysis indicated a downregulation in OXPHOS and an upregulation of various synthesis pathways, particularly in podocytes.
    CONCLUSIONS: This study improves our understanding of CoQ10 nephropathy's pathogenesis and highlights the potential applications of single-cell sequencing in pediatric hereditary kidney diseases.
    Keywords:   COQ2 mutation; Coenzyme Q10 nephropathy; Hereditary nephropathy; Single-cell RNA sequencing; Single-cell transcriptomics
    DOI:  https://doi.org/10.1007/s00467-024-06611-2
  42. J Mol Cell Cardiol Plus. 2024 Sep;9 100085
    Cardiac-targeted delivery of a novel Drp1 inhibitor for acute cardioprotection.
    Jarmon G Lees, David W Greening, David A Rudd, Jonathon Cross, Ayeshah A Rosdah, Xiangfeng Lai, Tsung Wu Lin, Ren Jie Phang, Anne M Kong, Yali Deng, Simon Crawford, Jessica K Holien, Derek J Hausenloy, Hsin-Hui Shen, Shiang Y Lim.
      Dynamin-related protein 1 (Drp1) is a mitochondrial fission protein and a viable target for cardioprotection against myocardial ischaemia-reperfusion injury. Here, we reported a novel Drp1 inhibitor (DRP1i1), delivered using a cardiac-targeted nanoparticle drug delivery system, as a more effective approach for achieving acute cardioprotection. DRP1i1 was encapsulated in cubosome nanoparticles with conjugated cardiac-homing peptides (NanoDRP1i1) and the encapsulation efficiency was 99.3 ± 0.1 %. In vivo, following acute myocardial ischaemia-reperfusion injury in mice, NanoDRP1i1 significantly reduced infarct size and serine-616 phosphorylation of Drp1, and restored cardiomyocyte mitochondrial size to that of sham group. Imaging by mass spectrometry revealed higher accumulation of DRP1i1 in the heart tissue when delivered as NanoDRP1i1. In human cardiac organoids subjected to simulated ischaemia-reperfusion injury, treatment with NanoDRP1i1 at reperfusion significantly reduced cardiac cell death, contractile dysfunction, and mitochondrial superoxide levels. Following NanoDRP1i1 treatment, cardiac organoid proteomics further confirmed reprogramming of contractile dysfunction markers and enrichment of the mitochondrial protein network, cytoskeletal and metabolic regulation networks when compared to the simulated injury group. These proteins included known cardioprotective regulators identified in human organoids and in vivo murine studies following ischaemia-reperfusion injury. DRP1i1 is a promising tool compound to study Drp1-mediated mitochondrial fission and exhibits promising therapeutic potential for acute cardioprotection, especially when delivered using the cardiac-targeted cubosome nanoparticles.
    Keywords:  Cardiac organoids; Cubosome; Dynamin-related protein 1; Mitochondria; Myocardial ischaemia-reperfusion injury
    DOI:  https://doi.org/10.1016/j.jmccpl.2024.100085
  43. bioRxiv. 2025 Jan 03. pii: 2025.01.02.630345. [Epub ahead of print]
    Recessive but damaging alleles of muscle-specific ribosomal protein gene RPL3L drive neonatal dilated cardiomyopathy.
    Michael R Murphy, Mythily Ganapathi, Teresa M Lee, Joshua M Fisher, Megha V Patel, Parul Jayakar, Amanda Buchanan, Rajesh K Soni, Yue Yin, Feiyue Yang, Muredach P Reilly, Wendy K Chung, Xuebing Wu.
      The heart employs a specialized ribosome in its muscle cells to translate genetic information into proteins, a fundamental adaptation with an elusive physiological role. Its significance is underscored by the discovery of neonatal patients suffering from often fatal heart failure caused by rare compound heterozygous variants in RPL3L, a muscle-specific ribosomal protein that replaces the ubiquitous RPL3 in cardiac ribosomes. RPL3L -linked heart failure represents the only known human disease arising from mutations in tissue-specific ribosomes, yet the underlying pathogenetic mechanisms remain poorly understood despite an increasing number of reported cases. While the autosomal recessive inheritance pattern suggests a loss-of-function mechanism, Rpl3l -knockout mice display only mild phenotypes, attributed to up-regulation of the ubiquitous Rpl3. Interestingly, living human knockouts of RPL3L have been identified. Here, we report two new cases of RPL3L -linked severe neonatal heart failure and uncover an unusual pathogenetic mechanism through integrated analyses of population genetic data, patient cardiac tissue, and isogenic cells expressing RPL3L variants. Our findings demonstrate that patient hearts lack sufficient RPL3 compensation. Moreover, contrary to a simple loss-of-function mechanism often associated with autosomal recessive diseases, RPL3L -linked disease is driven by a combination of gain-of-toxicity and loss-of-function. Most patients carry a recurrent toxic missense variant alongside a non-recurrent loss-of-function variant. The non-recurrent variants trigger partial compensation of RPL3 similar to Rpl3l -knockout mice. In contrast, the recurrent missense variants exhibit increased affinity for the RPL3/RPL3L chaperone GRWD1 and 60S biogenesis factors, sequester 28S rRNA in the nucleus, disrupt ribosome biogenesis, and trigger severe cellular toxicity that extends beyond the loss of ribosomes. These findings elucidate the pathogenetic mechanisms underlying muscle-specific ribosome dysfunction in neonatal heart failure, providing critical insights for genetic screening and therapeutic development. Our findings also suggest that gain-of-toxicity mechanisms may be more widespread in autosomal recessive diseases, especially for those involving genes with paralogs.
    DOI:  https://doi.org/10.1101/2025.01.02.630345
  44. Sci Transl Med. 2025 Jan 15. 17(781): eadn8699
    Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease.
    TRR241 IBDome Consortium
      Dysregulation at the intestinal epithelial barrier is a driver of inflammatory bowel disease (IBD). However, the molecular mechanisms of barrier failure are not well understood. Here, we demonstrate dysregulated mitochondrial fusion in intestinal epithelial cells (IECs) of patients with IBD and show that impaired fusion is sufficient to drive chronic intestinal inflammation. We found reduced expression of mitochondrial fusion-related genes, such as the dynamin-related guanosine triphosphatase (GTPase) optic atrophy 1 (OPA1), and fragmented mitochondrial networks in crypt IECs of patients with IBD. Mice with Opa1 deficiency in the gut epithelium (Opa1i∆IEC) spontaneously developed chronic intestinal inflammation with mucosal ulcerations and immune cell infiltration. Intestinal inflammation in Opa1i∆IEC mice was driven by microbial translocation and associated with epithelial progenitor cell death and gut barrier dysfunction. Opa1-deficient epithelial cells and human organoids exposed to a pharmacological OPA1 inhibitor showed disruption of the mitochondrial network with mitochondrial fragmentation and changes in mitochondrial size, ultrastructure, and function, resembling changes observed in patient samples. Pharmacological inhibition of the GTPase dynamin-1-like protein in organoids derived from Opa1i∆IEC mice partially reverted this phenotype. Together, our data demonstrate a role for epithelial OPA1 in regulating intestinal immune homeostasis and epithelial barrier function. Our data provide a mechanistic explanation for the observed mitochondrial dysfunction in IBD and identify mitochondrial fusion as a potential therapeutic target in this disease.
    DOI:  https://doi.org/10.1126/scitranslmed.adn8699
  45. Subcell Biochem. 2025 ;108 111-190
    The Promise of Epigenetic Editing for Treating Brain Disorders.
    Luis A González Molina, Amalia M Dolga, Marianne G Rots, Federica Sarno.
      Brain disorders, especially neurodegenerative diseases, affect millions of people worldwide. There is no causal treatment available; therefore, there is an unmet clinical need for finding therapeutic options for these diseases. Epigenetic research has resulted in identification of various genomic loci with differential disease-specific epigenetic modifications, mainly DNA methylation. These biomarkers, although not yet translated into clinically approved options, offer therapeutic targets as epigenetic modifications are reversible. Indeed, clinical trials are designed to inhibit epigenetic writers, erasers, or readers using epigenetic drugs to interfere with epigenetic dysregulation in brain disorders. However, since such drugs elicit genome-wide effects and potentially cause toxicity, the recent developments in the field of epigenetic editing are gaining widespread attention. In this review, we provide examples of epigenetic biomarkers and epi-drugs, while describing efforts in the field of epigenetic editing, to eventually make a difference for the currently incurable brain disorders.
    Keywords:  DNA methylation biomarkers, histone modifications, Epi-drugs; Epigenetic editing; Epigenetics; Neurodegenerative diseases; Neuropsychiatric disorders
    DOI:  https://doi.org/10.1007/978-3-031-75980-2_4
  46. Neurol Genet. 2025 Feb;11(1): e200229
    Current Advances and Challenges in Gene Therapies for Neurologic Disorders: A Review for the Clinician.
    Giulia Stefania Porcari, John Warren Collyer, Laura Ann Adang, Deepa Soundara Rajan.
      Over 300 million people globally are affected by rare diseases, many of which present predominantly with neurologic symptoms. Rare neurologic disorders pose significant diagnostic and therapeutic challenges including delayed diagnoses, limited treatment options, and a shortage of specialists. However, advancements in diagnostics, particularly next-generation sequencing and expansion of newborn screening, have significantly shortened the time to diagnosis for many of these disorders. Concurrently, the past decade has witnessed exponential development of new treatments for rare neurologic diseases, with several approved gene therapies and more trials under way. A range of targeted therapies now offers hope for not only symptomatic management but also for disease modification. As treatments transition from clinical trials to clinical practice, the responsibility of identifying and monitoring patients may increasingly fall on the general neurologists. This evolving therapeutic landscape highlights the urgent need to enhance our understanding of this new class of medications and the details on clinical eligibility and monitoring of patients with diseases that have approved gene therapies. This article provides a comprehensive overview of gene-targeted therapies currently available for neurologic disorders, with a focus on their mechanisms, challenges, and post-treatment considerations.
    DOI:  https://doi.org/10.1212/NXG.0000000000200229
  47. Nat Rev Drug Discov. 2025 Jan 14.
    Targeting mitophagy in neurodegenerative diseases.
    Odetta Antico, Paul W Thompson, Nicholas T Hertz, Miratul M K Muqit, Laura E Parton.
      Mitochondrial dysfunction is a hallmark of idiopathic neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease and Huntington disease. Familial forms of Parkinson disease and amyotrophic lateral sclerosis are often characterized by mutations in genes associated with mitophagy deficits. Therefore, enhancing the mitophagy pathway may represent a novel therapeutic approach to targeting an underlying pathogenic cause of neurodegenerative diseases, with the potential to deliver neuroprotection and disease modification, which is an important unmet need. Accumulating genetic, molecular and preclinical model-based evidence now supports targeting mitophagy in neurodegenerative diseases. Despite clinical development challenges, small-molecule-based approaches for selective mitophagy enhancement - namely, USP30 inhibitors and PINK1 activators - are entering phase I clinical trials for the first time.
    DOI:  https://doi.org/10.1038/s41573-024-01105-0
  48. Nat Metab. 2025 Jan 13.
    Early prediction of healthy ageing and age-related diseases using blood protein biomarkers.
      
    DOI:  https://doi.org/10.1038/s42255-024-01199-1
  49. Free Radic Biol Med. 2025 Jan 14. pii: S0891-5849(25)00021-8. [Epub ahead of print]
    Dopamine degrades ferritin by chaperone-mediated autophagy to elevate mitochondrial iron level in astroglial cells.
    Som Dev, Somya Asthana, Pratibha Singh, Pankaj Seth, Chayanika Banerjee, Chinmay K Mukhopadhyay.
      Iron accumulation and mitochondrial dysfunction in astroglia are reported in Parkinson's disease (PD). Astroglia control iron availability in neurons in which dopamine (DA) synthesis is affected in PD. Despite their intimate relationship the role of DA in astroglial iron homeostasis is limited. Here we show that DA degrades iron storage protein ferritin in astroglial cells involving lysosomal proteolysis. Lysosomal ferritinophagy is mainly associated with macroautophagy; however, we revealed the involvement of chaperone-mediated autophagy (CMA) in DA-induced ferritin degradation. In CMA, cytosolic proteins containing a specific pentapeptide motif bind with HSC70 to be transported to lysosome mediated by LAMP2A. We identified the conserved pentapeptide motif in ferritin-H (Ft-H), mutations of which resulted loss of its interaction with HSC70. Pharmacological inhibitors of HSC70 or LAMP2/2A knockdown blocks DA-induced Ft-H degradation. DA also induces cytosolic cargo NCOA4 for ferritinophagy. We further reveal that DA promotes cathepsin B to lysis ferritin within the lysosome. Inhibitor of cathepsin B, knocking down of LAMP2, or HSC70 inhibitor attenuate DA-induced elevated mitochondrial iron level. Our results establish a direct role of DA on astroglial iron homeostasis and novel involvement of CMA in ferritin degradation in response to a biological stimulus. These results also may help in better understanding iron dyshomeostasis and mitochondrial dysfunction reported in PD.
    Keywords:  Dopamine; NCOA4; astroglia; cathepsin B; chaperone-mediated autophagy; ferritin; mitochondrial iron
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.021
  50. J Thromb Haemost. 2025 Jan 09. pii: S1538-7836(24)00779-7. [Epub ahead of print]
    Applying artificial intelligence to uncover the genetic landscape of coagulation factors.
    Giulia Soldà, Rosanna Asselta.
      Artificial intelligence (AI) is rapidly advancing our ability to identify and interpret genetic variants associated with coagulation factor deficiencies. This review introduces AI, with a specific focus on machine learning (ML) methods, and examines its applications in the field of coagulation genetics over the past decade. We observed a significant increase in AI-related publications, with a focus on hemophilia A and B. ML approaches have shown promise in predicting the functional impact of genetic variants and establishing genotype-phenotype correlations, exemplified by tools like "Hema-Class" for FVIII variants. However, some challenges remain, including the need to expand variant selection beyond missense mutations (which is now the standard of most studies). For the future, the integration of AI in calling, detecting, and interpreting genetic variants can significantly improve our ability to process large-scale genomic data. In this frame, we discuss various AI/ML-based tools for genetic variant detection and interpretation, highlighting their strengths and limitations. As the field evolves, the synergistic application of multiple AI models, coupled with rigorous validation strategies, will be crucial in advancing our understanding of coagulation disorders and for personalizing treatment approaches.
    Keywords:  Artificial intelligence; coagulation factor; genetics; mutation; polymorphism
    DOI:  https://doi.org/10.1016/j.jtha.2024.12.030
  51. Inflamm Res. 2025 Jan 13. 74(1): 17
    Mitochondrial dysfunction is a major cause of thromboinflammation and inflammatory cell death in critical illnesses.
    Toshiaki Iba, Julie Helms, Cheryl L Maier, Ricard Ferrer, Jerrold H Levy.
       BACKGROUND: Mitochondria generate the adenosine triphosphate (ATP) necessary for eukaryotic cells, serving as their primary energy suppliers, and contribute to host defense by producing reactive oxygen species. In many critical illnesses, including sepsis, major trauma, and heatstroke, the vicious cycle between activated coagulation and inflammation results in tissue hypoxia-induced mitochondrial dysfunction, and impaired mitochondrial function contributes to thromboinflammation and cell death.
    METHODS: A computer-based online search was performed using the PubMed and Web of Science databases for published articles concerning sepsis, trauma, critical illnesses, cell death, mitochondria, inflammation, coagulopathy, and organ dysfunction.
    RESULTS: Mitochondrial outer membrane permeabilization triggers apoptosis by releasing cytochrome c and activating caspases. Apoptosis is a non-inflammatory programmed cell death but requires sufficient ATP supply. Therefore, conversion to inflammatory necrosis may occur due to a lack of ATP in critical illness. Severely damaged mitochondria release excess reactive oxygen species and injurious mitochondrial DNA, inducing cell death. Besides non-programmed necrosis, mitochondrial damage can trigger programmed inflammatory cell death, including necroptosis, pyroptosis, and ferroptosis. Additionally, a unique form of DNA-ejecting cell death, known as etosis, occurs in monocytes and granulocytes following external stimuli and mitochondrial damage. The type of cell death chosen remains uncertain but is known to depend on the cell type, the nature of the injury, and the degree of damage.
    CONCLUSIONS: Mitochondria damage is the major contributor to the cell death mechanism that leads to organ damage in critical illnesses. Regulating and restoring mitochondrial function holds promise for developing new therapeutic approaches for mitigating critical diseases.
    Keywords:  Apoptosis; Ferroptosis; Mitochondria; Neutrophil extracellular trap; Pyroptosis
    DOI:  https://doi.org/10.1007/s00011-025-01994-w
  52. Nat Rev Genet. 2025 Jan 13.
    Epigenetic ageing clocks: statistical methods and emerging computational challenges.
    Andrew E Teschendorff, Steve Horvath.
      Over the past decade, epigenetic clocks have emerged as powerful machine learning tools, not only to estimate chronological and biological age but also to assess the efficacy of anti-ageing, cellular rejuvenation and disease-preventive interventions. However, many computational and statistical challenges remain that limit our understanding, interpretation and application of epigenetic clocks. Here, we review these computational challenges, focusing on interpretation, cell-type heterogeneity and emerging single-cell methods, aiming to provide guidelines for the rigorous construction of interpretable epigenetic clocks at cell-type and single-cell resolution.
    DOI:  https://doi.org/10.1038/s41576-024-00807-w
  53. bioRxiv. 2024 Dec 12. pii: 2024.12.10.627730. [Epub ahead of print]
    Spatially resolved rewiring of mitochondria-lipid droplet interactions in hepatic lipid homeostasis.
    Sun Woo Sophie Kang, Lauryn A Brown, Colin B Miller, Katherine M Barrows, Jihye L Golino, Constance M Cultraro, Daniel Feliciano, Mercedes B Cornelius-Muwanuzi, Andy D Tran, Michael Kruhlak, Alexei Lobanov, Maggie Cam, Natalie Porat-Shliom.
      Hepatic lipid accumulation, or Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), is a significant risk factor for liver cancer. Despite the rising incidence of MASLD, the underlying mechanisms of steatosis and lipotoxicity remain poorly understood. Interestingly, lipid accumulation also occurs during fasting, driven by the mobilization of adipose tissue-derived fatty acids into the liver. However, how hepatocytes adapt to increased lipid flux during nutrient deprivation and what occurs differently in MASLD is not known. To investigate the differences in lipid handling in response to nutrient deficiency and excess, we developed a novel single-cell tissue imaging (scPhenomics) technique coupled with spatial proteomics. Our investigation revealed extensive remodeling of lipid droplet (LD) and mitochondrial topology in response to dietary conditions. Notably, fasted mice exhibited extensive mitochondria-LD interactions, which were rarely observed in Western Diet (WD)-fed mice. Spatial proteomics showed an increase in PLIN5 expression, a known mediator of LD-mitochondria interaction, in response to fasting. To examine the functional role of mitochondria-LD interaction on lipid handling, we overexpressed PLIN5 variants. We found that the phosphorylation state of PLIN5 impacts its capacity to form mitochondria-LD contact sites. PLIN5 S155A promoted extensive organelle interactions, triglyceride (TG) synthesis, and LD expansion in mice fed a control diet. Conversely, PLIN5 S155E expressing cells had fewer LDs and contact sites and contained less TG. Wild-type (WT) PLIN5 overexpression in WD-fed mice reduced steatosis and improved redox state despite continued WD consumption. These findings highlight the importance of organelle interactions in lipid metabolism, revealing a critical mechanism by which hepatocytes maintain homeostasis during metabolic stress. Our study underscores the potential utility of targeting mitochondria-LD interactions for therapeutic intervention.
    DOI:  https://doi.org/10.1101/2024.12.10.627730
  54. Brain. 2025 Jan 15. pii: awaf010. [Epub ahead of print]
    Intrinsic neuronal resilience as a tool for therapeutic discovery.
    Stefania Corti, Eva Hedlund.
      
    DOI:  https://doi.org/10.1093/brain/awaf010
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