bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024‒01‒28
forty-four papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico 
  1. Genetic variants affecting NQO1 protein levels impact the efficacy of idebenone treatment in Leber hereditary optic neuropathy.
  2. Mitochondrial CISD1/Cisd accumulation blocks mitophagy and genetic or pharmacological inhibition rescues neurodegenerative phenotypes in Pink1/parkin models.
  3. Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.
  4. Mitochondrial translocation of TFEB regulates complex I and inflammation.
  5. From Beach to the Bedside: Harnessing Mitochondrial Function in Human Diseases Using New Marine-Derived Strategies.
  6. AFG3L2 and ACO2-linked Dominant Optic Atrophy: genotype-phenotype characterization compared to OPA1 patients.
  7. Applications of near-infrared spectroscopy in epilepsy, with a focus on mitochondrial disorders.
  8. Omaveloxolone: a groundbreaking milestone as the first FDA-approved drug for Friedreich ataxia.
  9. Drosophila MIC10b can polymerize into cristae-shaping filaments.
  10. CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex.
  11. Editorial: Mitochondria at the nexus of metabolism, aging, and disease.
  12. Mitochondrial dynamics and mitochondrial autophagy: Molecular structure, orchestrating mechanism and related disorders.
  13. Decoding the nature and complexity of extracellular mtDNA: Types and implications for health and disease.
  14. The potential influence of melatonin on mitochondrial quality control: a review.
  15. Mitochondria in Multi-Directional Differentiation of Dental-Derived Mesenchymal Stem Cells.
  16. Direct neuronal reprogramming of NDUFS4 patient cells identifies the unfolded protein response as a novel general reprogramming hurdle.
  17. Mitochondria in Mesenchymal Stem Cells: Key to Fate Determination and Therapeutic Potential.
  18. Is mitochondrial DNA copy number from human blood associated with iron deposits in the brain?
  19. Protocol for measuring mitochondrial size in mouse and human liver tissues.
  20. Cardiomyocyte maturation alters molecular stress response capacities and determines cell survival upon mitochondrial dysfunction.
  21. Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implications.
  22. Mitochondrial-related microRNAs and their roles in cellular senescence.
  23. Challenges and opportunities to bridge translational to clinical research for personalized mitochondrial medicine.
  24. Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms.
  25. The Research Progress of Mitochondrial Transplantation in the Treatment of Mitochondrial Defective Diseases.
  26. Effect of paternal aging and vitrification on mitochondrial DNA copy number and telomere length of mouse blastocysts.
  27. Advances in crosstalk among innate immune pathways activated by mitochondrial DNA.
  28. Shared structural features of Miro binding control mitochondrial homeostasis.
  29. Early interventions improve child neurodevelopment.
  30. Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling.
  31. Functional interplay of lipid droplets and mitochondria.
  32. Endometrial organoids: a reservoir of functional mitochondria for uterine repair.
  33. Perspectives of the Friedreich ataxia community on gene therapy clinical trials.
  34. Deciphering cell states and genealogies of human hematopoiesis.
  35. Epigenetic regulation of the nuclear genome associated with mitochondrial dysfunction in Leber's hereditary optic neuropathy (LHON).
  36. Maintaining the Mitochondrial Quality Control System Was a Key Event of Tanshinone IIA against Deoxynivalenol-Induced Intestinal Toxicity.
  37. Omaveloxolone for the treatment of Friedreich Ataxia: clinical trial results and practical considerations.
  38. Caspase-dependent apoptosis in Ribloflavin transporter deficiency iPSCs and derived motor neurons.
  39. Mitochondrial and Cellular Function in Fibroblasts, Induced Neurons, and Astrocytes Derived from Case Study Patients: Insights into Major Depression as a Mitochondria-Associated Disease.
  40. Mitochondrial Dysfunction in Periodontitis and Associated Systemic Diseases: Implications for Pathomechanisms and Therapeutic Strategies.
  41. Peroxisome proliferator-activated receptor γ coactivator 1α regulates downstream of tyrosine kinase-7 (Dok-7) expression important for neuromuscular junction formation.
  42. Motion of VAPB molecules reveals ER-mitochondria contact site subdomains.
  43. Complement system response to adeno-associated virus (AAV) vector gene therapy.
  44. A comprehensive review on signaling attributes of serine and serine metabolism in health and disease.
  1. Cell Rep Med. 2024 Jan 17. pii: S2666-3791(23)00612-2. [Epub ahead of print] 101383
    Genetic variants affecting NQO1 protein levels impact the efficacy of idebenone treatment in Leber hereditary optic neuropathy.
    Serena Jasmine Aleo, Valentina Del Dotto, Martina Romagnoli, Claudio Fiorini, Giada Capirossi, Camille Peron, Alessandra Maresca, Leonardo Caporali, Mariantonietta Capristo, Concetta Valentina Tropeano, Claudia Zanna, Fred N Ross-Cisneros, Alfredo A Sadun, Maria Gemma Pignataro, Carla Giordano, Chiara Fasano, Andrea Cavaliere, Anna Maria Porcelli, Gaia Tioli, Francesco Musiani, Alessia Catania, Costanza Lamperti, Stefania Bianchi Marzoli, Annamaria De Negri, Maria Lucia Cascavilla, Marco Battista, Piero Barboni, Michele Carbonelli, Giulia Amore, Chiara La Morgia, Dmitrii Smirnov, Catalina Vasilescu, Aiman Farzeen, Beryll Blickhaeuser, Holger Prokisch, Claudia Priglinger, Bettina Livonius, Claudia B Catarino, Thomas Klopstock, Valeria Tiranti, Valerio Carelli, Anna Maria Ghelli.
      Idebenone, the only approved treatment for Leber hereditary optic neuropathy (LHON), promotes recovery of visual function in up to 50% of patients, but we can neither predict nor understand the non-responders. Idebenone is reduced by the cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons to respiratory complex III, bypassing complex I affected in LHON. We show here that two polymorphic variants drastically reduce NQO1 protein levels when homozygous or compound heterozygous. This hampers idebenone reduction. In its oxidized form, idebenone inhibits complex I, decreasing respiratory function in cells. By retrospectively analyzing a large cohort of idebenone-treated LHON patients, classified by their response to therapy, we show that patients with homozygous or compound heterozygous NQO1 variants have the poorest therapy response, particularly if carrying the m.3460G>A/MT-ND1 LHON mutation. These results suggest consideration of patient NQO1 genotype and mitochondrial DNA mutation in the context of idebenone therapy.
    Keywords:  LHON; Leber hereditary optic neuropathy; NQO1; complex I; cybrids; fibroblasts; idebenone; mtDNA; retinal ganglion cells
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101383
  2. Mol Neurodegener. 2024 Jan 25. 19(1): 12
    Mitochondrial CISD1/Cisd accumulation blocks mitophagy and genetic or pharmacological inhibition rescues neurodegenerative phenotypes in Pink1/parkin models.
    Aitor Martinez, Alvaro Sanchez-Martinez, Jake T Pickering, Madeleine J Twyning, Ana Terriente-Felix, Po-Lin Chen, Chun-Hong Chen, Alexander J Whitworth.
      BACKGROUND: Mitochondrial dysfunction and toxic protein aggregates have been shown to be key features in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease (PD). Functional analysis of genes linked to PD have revealed that the E3 ligase Parkin and the mitochondrial kinase PINK1 are important factors for mitochondrial quality control. PINK1 phosphorylates and activates Parkin, which in turn ubiquitinates mitochondrial proteins priming them and the mitochondrion itself for degradation. However, it is unclear whether dysregulated mitochondrial degradation or the toxic build-up of certain Parkin ubiquitin substrates is the driving pathophysiological mechanism leading to PD. The iron-sulphur cluster containing proteins CISD1 and CISD2 have been identified as major targets of Parkin in various proteomic studies.METHODS: We employed in vivo Drosophila and human cell culture models to study the role of CISD proteins in cell and tissue viability as well as aged-related neurodegeneration, specifically analysing aspects of mitophagy and autophagy using orthogonal assays.
    RESULTS: We show that the Drosophila homolog Cisd accumulates in Pink1 and parkin mutant flies, as well as during ageing. We observed that build-up of Cisd is particularly toxic in neurons, resulting in mitochondrial defects and Ser65-phospho-Ubiquitin accumulation. Age-related increase of Cisd blocks mitophagy and impairs autophagy flux. Importantly, reduction of Cisd levels upregulates mitophagy in vitro and in vivo, and ameliorates pathological phenotypes in locomotion, lifespan and neurodegeneration in Pink1/parkin mutant flies. In addition, we show that pharmacological inhibition of CISD1/2 by rosiglitazone and NL-1 induces mitophagy in human cells and ameliorates the defective phenotypes of Pink1/parkin mutants.
    CONCLUSION: Altogether, our studies indicate that Cisd accumulation during ageing and in Pink1/parkin mutants is a key driver of pathology by blocking mitophagy, and genetically and pharmacologically inhibiting CISD proteins may offer a potential target for therapeutic intervention.
    Keywords:  Ageing; Autophagy; CISD1; CISD2; Cisd; Mitochondria; Mitophagy; Neurodegeneration; PINK1; Parkin; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s13024-024-00701-3
  3. Neurotherapeutics. 2024 Jan 19. pii: S1878-7479(24)00002-3. [Epub ahead of print]21(1): e00316
    Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.
    Daniel G Calame, Lisa T Emrick.
      Mitochondria are critical for brain development and homeostasis. Therefore, pathogenic variation in the mitochondrial or nuclear genome which disrupts mitochondrial function frequently results in developmental disorders and neurodegeneration at the organismal level. Large-scale application of genome-wide technologies to individuals with mitochondrial diseases has dramatically accelerated identification of mitochondrial disease-gene associations in humans. Multi-omic and high-throughput studies involving transcriptomics, proteomics, metabolomics, and saturation genome editing are providing deeper insights into the functional consequence of mitochondrial genomic variation. Integration of deep phenotypic and genomic data through allelic series continues to uncover novel mitochondrial functions and permit mitochondrial gene function dissection on an unprecedented scale. Finally, mitochondrial disease-gene associations illuminate disease mechanisms and thereby direct therapeutic strategies involving small molecules and RNA-DNA therapeutics. This review summarizes progress in functional genomics and small molecule therapeutics in mitochondrial neurodevelopmental disorders.
    Keywords:  Functional genomics; Mitochondrial disease; Neurodevelopmental disorders; Small molecules; Therapeutics
    DOI:  https://doi.org/10.1016/j.neurot.2024.e00316
  4. EMBO Rep. 2024 Jan 23.
    Mitochondrial translocation of TFEB regulates complex I and inflammation.
    Chiara Calabrese, Hendrik Nolte, Melissa R Pitman, Raja Ganesan, Philipp Lampe, Raymond Laboy, Roberto Ripa, Julia Fischer, Ruhi Polara, Sameer Kumar Panda, Sandhya Chipurupalli, Saray Gutierrez, Daniel Thomas, Stuart M Pitson, Adam Antebi, Nirmal Robinson.
      TFEB is a master regulator of autophagy, lysosome biogenesis, mitochondrial metabolism, and immunity that works primarily through transcription controlled by cytosol-to-nuclear translocation. Emerging data indicate additional regulatory interactions at the surface of organelles such as lysosomes. Here we show that TFEB has a non-transcriptional role in mitochondria, regulating the electron transport chain complex I to down-modulate inflammation. Proteomics analysis reveals extensive TFEB co-immunoprecipitation with several mitochondrial proteins, whose interactions are disrupted upon infection with S. Typhimurium. High resolution confocal microscopy and biochemistry confirms TFEB localization in the mitochondrial matrix. TFEB translocation depends on a conserved N-terminal TOMM20-binding motif and is enhanced by mTOR inhibition. Within the mitochondria, TFEB and protease LONP1 antagonistically co-regulate complex I, reactive oxygen species and the inflammatory response. Consequently, during infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines, contributing to innate immune pathogenesis.
    Keywords:  LONP1; Metabolism; Mitochondria; Salmonella; TFEB
    DOI:  https://doi.org/10.1038/s44319-024-00058-0
  5. Int J Mol Sci. 2024 Jan 09. pii: 834. [Epub ahead of print]25(2):
    From Beach to the Bedside: Harnessing Mitochondrial Function in Human Diseases Using New Marine-Derived Strategies.
    Serena Mirra, Gemma Marfany.
      Mitochondria are double-membrane organelles within eukaryotic cells that act as cellular power houses owing to their ability to efficiently generate the ATP required to sustain normal cell function. Also, they represent a "hub" for the regulation of a plethora of processes, including cellular homeostasis, metabolism, the defense against oxidative stress, and cell death. Mitochondrial dysfunctions are associated with a wide range of human diseases with complex pathologies, including metabolic diseases, neurodegenerative disorders, and cancer. Therefore, regulating dysfunctional mitochondria represents a pivotal therapeutic opportunity in biomedicine. Marine ecosystems are biologically very diversified and harbor a broad range of organisms, providing both novel bioactive substances and molecules with meaningful biomedical and pharmacological applications. Recently, many mitochondria-targeting marine-derived molecules have been described to regulate mitochondrial biology, thus exerting therapeutic effects by inhibiting mitochondrial abnormalities, both in vitro and in vivo, through different mechanisms of action. Here, we review different strategies that are derived from marine organisms which modulate specific mitochondrial processes or mitochondrial molecular pathways and ultimately aim to find key molecules to treat a wide range of human diseases characterized by impaired mitochondrial function.
    Keywords:  disease; marine natural products; marine organisms; mitochondria; therapy
    DOI:  https://doi.org/10.3390/ijms25020834
  6. Am J Ophthalmol. 2024 Jan 24. pii: S0002-9394(24)00014-X. [Epub ahead of print]
    AFG3L2 and ACO2-linked Dominant Optic Atrophy: genotype-phenotype characterization compared to OPA1 patients.
    Giulia Amore, Martina Romagnoli, Michele Carbonelli, Maria Lucia Cascavilla, Anna Maria De Negri, Arturo Carta, Vincenzo Parisi, Antonio Di Renzo, Costantino Schiavi, Chiara Lenzetti, Corrado Zenesini, Danara Ormanbekova, Flavia Palombo, Claudio Fiorini, Leonardo Caporali, Valerio Carelli, Piero Barboni, Chiara La Morgia.
      PURPOSE: Heterozygous mutations in AFG3L2 gene (encoding a mitochondrial protease indirectly reflecting on OPA1 cleavage) and ACO2 gene (encoding the mitochondrial enzyme aconitase) are associated to isolated forms of Dominant Optic Atrophy (DOA). We aimed at describing their neuro-ophthalmological phenotype as compared with classic OPA1-related DOA.DESIGN: Cross-sectional study.
    METHODS: The following neuro-ophthalmological parameters were collected: Log MAR visual acuity (VA), color vision, mean deviation and foveal threshold at visual fields, average and sectorial retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness at optic coherence tomography. ACO2 and AFG3L2 patients were compared with an age- and gender-matched group of OPA1 patients with 1:2 ratio. All eyes were analysed using Clustered Wilcoxon rank sum test using Rosner-Glynn-Lee method.
    RESULTS: 44 eyes from 23 ACO2 and 26 eyes from 13 AFG3L2 patients were compared with 143 eyes from 72 OPA1 patients. All cases presented with bilateral temporal-predominant optic atrophy with various degree of visual impairment. Comparison between AFG3L2 and OPA1 failed to reveal any significant difference. ACO2 patients compared to both AFG3L2 and OPA1 presented overall higher values of nasal RNFL thickness (p=0.029, p=0.023), average (p=0.012, p=0.0007) and sectorial GCL thickness. These results were confirmed also comparing separately affected and subclinical patients.
    CONCLUSIONS: Clinically, DOA remains a fairly homogeneous entity despite the growing genetic heterogeneity. ACO2 seems associated to an overall better preservation of retinal ganglion cells, probably depending on the different pathogenic mechanism involving mtDNA maintenance, as opposed to AFG3L2, which is involved in OPA1 processing and resulted virtually indistinguishable from classic OPA1-DOA.
    Keywords:  Clinical Genetics; Dominant Optic Atrophy; Genotype-phenotype; Mitochondrial Optic Neuropathies; Neuro-ophthalmology; Optic Coherence Tomography
    DOI:  https://doi.org/10.1016/j.ajo.2024.01.011
  7. Neurotherapeutics. 2024 Jan 19. pii: S1878-7479(24)00009-6. [Epub ahead of print]21(1): e00323
    Applications of near-infrared spectroscopy in epilepsy, with a focus on mitochondrial disorders.
    Kosar Khaksari, Wei-Liang Chen, Mongkol Chanvanichtrakool, Alexa Taylor, Rohan Kotla, Andrea L Gropman.
      Mitochondrial diseases are inherited disorders that impede the mitochondria's ability to produce sufficient energy for the cells. They can affect different parts of the body, notably the brain. Neurological symptoms and epilepsy are prevalent in patients with mitochondrial disorders. The epileptogenicity of mitochondrial disorder is a complex process involving the intricate interplay between abnormal energy metabolism and neuronal activity. Several modalities have been used to detect seizures in different disorders including mitochondrial disorders. EEG serve as the gold standard for diagnosis and localization, commonly complemented by additional imaging modalities to enhance source localization. In the current work, we propose the use of functional near-infrared spectroscopy (fNIRS) to identify the occurrence of epilepsy and seizure in patients with mitochondrial disorders. fNIRS proves an advantageous imaging technique due to its portability and insensitivity to motion especially for imaging infants and children. It has added a valuable factor to our understanding of energy metabolism and neuronal activity. Its real-time monitoring with high spatial resolution supplements traditional diagnostic tools such as EEG and provides a comprehensive understanding of seizure and epileptogenesis. The utility of fNIRS extends to its ability to detect changes in Cytochrome c oxidase (CcO) which is a crucial enzyme in cellular respiration. This facet enhances our insight into the metabolic dimension of epilepsy related to mitochondrial dysfunction. By providing valuable insights into both energy metabolism and neuronal activity, fNIRS emerges as a promising imaging technique for unveiling the complexities of mitochondrial disorders and their neurological manifestations.
    Keywords:  Brain biomarkers; Epilepsy; Mitochondrial disease; Near-infrared spectroscopy; Neuromonitoring; Seizure
    DOI:  https://doi.org/10.1016/j.neurot.2024.e00323
  8. Trends Mol Med. 2024 Jan 10. pii: S1471-4914(23)00281-2. [Epub ahead of print]
    Omaveloxolone: a groundbreaking milestone as the first FDA-approved drug for Friedreich ataxia.
    Federica Pilotto, Deepika M Chellapandi, Hélène Puccio.
      Friedreich ataxia (FA) is an inherited autosomal recessive neurodegenerative disease (NDD) characterized primarily by progressive sensory and spinocerebellar ataxia associated with hypertrophic cardiomyopathy. FA is due to an intronic GAA repeat expansion within the frataxin gene (FXN) leading to reduced levels of frataxin (FXN) which causes mitochondrial dysfunction, production of reactive oxygen species (ROS), and altered iron metabolism. To date there is no resolutive cure for FA; however, the FDA has recently approved omaveloxolone - a potent activator of nuclear factor erythroid 2-related factor 2 (NRF2) - as the first treatment for FA. We discuss herein the urgency to find a resolutive cure for NDDs that will most probably be achieved via combinatorial therapy targeting multiple disease pathways, and how omavaloxolone serves as an example for future treatments.
    Keywords:  Friedreich’s ataxia; NRF2 pathway; ferroptosis; neurodegenerative diseases; omaveloxolone; oxidative stress
    DOI:  https://doi.org/10.1016/j.molmed.2023.12.002
  9. Life Sci Alliance. 2024 Apr;pii: e202302177. [Epub ahead of print]7(4):
    Drosophila MIC10b can polymerize into cristae-shaping filaments.
    Till Stephan, Stefan Stoldt, Mariam Barbot, Travis D Carney, Felix Lange, Mark Bates, Peter Bou Dib, Kaushik Inamdar, Halyna R Shcherbata, Michael Meinecke, Dietmar Riedel, Sven Dennerlein, Peter Rehling, Stefan Jakobs.
      Cristae are invaginations of the mitochondrial inner membrane that are crucial for cellular energy metabolism. The formation of cristae requires the presence of a protein complex known as MICOS, which is conserved across eukaryotic species. One of the subunits of this complex, MIC10, is a transmembrane protein that supports cristae formation by oligomerization. In Drosophila melanogaster, three MIC10-like proteins with different tissue-specific expression patterns exist. We demonstrate that CG41128/MINOS1b/DmMIC10b is the major MIC10 orthologue in flies. Its loss destabilizes MICOS, disturbs cristae architecture, and reduces the life span and fertility of flies. We show that DmMIC10b has a unique ability to polymerize into bundles of filaments, which can remodel mitochondrial crista membranes. The formation of these filaments relies on conserved glycine and cysteine residues, and can be suppressed by the co-expression of other Drosophila MICOS proteins. These findings provide new insights into the regulation of MICOS in flies, and suggest potential mechanisms for the maintenance of mitochondrial ultrastructure.
    DOI:  https://doi.org/10.26508/lsa.202302177
  10. J Cell Biol. 2024 Mar 04. pii: e202305087. [Epub ahead of print]223(3):
    CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex.
    Megan J Baker, Kai Uwe Blau, Alexander J Anderson, Catherine S Palmer, Laura F Fielden, Jordan J Crameri, Dusanka Milenkovic, David R Thorburn, Ann E Frazier, Thomas Langer, Diana Stojanovski.
      CLPB is a mitochondrial intermembrane space AAA+ domain-containing disaggregase. CLPB mutations are associated with 3-methylglutaconic aciduria and neutropenia; however, the molecular mechanism underscoring disease and the contribution of CLPB substrates to disease pathology remains unknown. Interactions between CLPB and mitochondrial quality control (QC) factors, including PARL and OPA1, have been reported, hinting at dysregulation of organelle QC in disease. Utilizing proteomic and biochemical approaches, we show a stress-specific aggregation phenotype in a CLPB-null environment and define the CLPB substrate profile. We illustrate an interplay between intermembrane space proteins including CLPB, HAX1, HTRA2, and the inner membrane quality control proteins (STOML2, PARL, YME1L1; SPY complex), with CLPB deficiency impeding SPY complex function by virtue of protein aggregation in the intermembrane space. We conclude that there is an interdependency of mitochondrial QC components at the intermembrane space/inner membrane interface, and perturbations to this network may underscore CLPB disease pathology.
    DOI:  https://doi.org/10.1083/jcb.202305087
  11. Front Cell Dev Biol. 2023 ;11 1356278
    Editorial: Mitochondria at the nexus of metabolism, aging, and disease.
    Karthik Babu Mallilankaraman, Brian K Kennedy, Vincenzo Sorrentino, Alessandro Luciani.
      
    Keywords:  ageing; dietary intervention; drug discovery; metabolic disease; metabolic signaling; metabolism; mitochondrial dysfuncion; mitophagy
    DOI:  https://doi.org/10.3389/fcell.2023.1356278
  12. Mitochondrion. 2024 Jan 19. pii: S1567-7249(24)00005-9. [Epub ahead of print]75 101847
    Mitochondrial dynamics and mitochondrial autophagy: Molecular structure, orchestrating mechanism and related disorders.
    Haoran Wang, Wenjun Luo, Haoyu Chen, Zhiduan Cai, Guibin Xu.
      Mitochondrial dynamics and autophagy play essential roles in normal cellular physiological activities, while abnormal mitochondrial dynamics and mitochondrial autophagy can cause cancer and related disorders. Abnormal mitochondrial dynamics usually occur in parallel with mitochondrial autophagy. Both have been reported to have a synergistic effect and can therefore complement or inhibit each other. Progress has been made in understanding the classical mitochondrial PINK1/Parkin pathway and mitochondrial dynamical abnormalities. Still, the mechanisms and regulatory pathways underlying the interaction between mitophagy and mitochondrial dynamics remain unexplored. Like other existing reviews, we review the molecular structure of proteins involved in mitochondrial dynamics and mitochondrial autophagy, and how their abnormalities can lead to the development of related diseases. We will also review the individual or synergistic effects of abnormal mitochondrial dynamics and mitophagy leading to cellular proliferation, differentiation and invasion. In addition, we explore the mechanisms underlying mitochondrial dynamics and mitochondrial autophagy to contribute to targeted and precise regulation of mitochondrial function. Through the study of abnormal mitochondrial dynamics and mitochondrial autophagy regulation mechanisms, as well as the role of early disease development, effective targets for mitochondrial function regulation can be proposed to enable accurate diagnosis and treatment of the associated disorders.
    Keywords:  Mitochondrial autophagy; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Orchestrating mechanism
    DOI:  https://doi.org/10.1016/j.mito.2024.101847
  13. Mitochondrion. 2024 Jan 20. pii: S1567-7249(24)00006-0. [Epub ahead of print]75 101848
    Decoding the nature and complexity of extracellular mtDNA: Types and implications for health and disease.
    Andrés Caicedo, Abigail Benavides-Almeida, Alissen Haro-Vinueza, José Peña-Cisneros, Álvaro A Pérez-Meza, Jeremy Michelson, Sebastian Peñaherrera, Martin Picard.
      The mitochondrial DNA (mtDNA) is replicated and canonically functions within intracellular mitochondria, but recent discoveries reveal that the mtDNA has another exciting extracellular life. mtDNA fragments and mitochondria-containing vesicular structures are detected at high concentrations in cell-free forms, in different biofluids. Commonly referred to as cell-free mtDNA (cf-mtDNA), the field is currently without a comprehensive classification system that acknowledges the various biological forms of mtDNA and whole mitochondria existing outside the cell. This absence of classification hampers the creation of precise and consistent quantification methods across different laboratories, which is crucial for unraveling the molecular and biological characteristics of mtDNA. In this article, we integrate recent findings to propose a classification for different types of Extracellular mtDNA [ex-mtDNA]. The major biologically distinct types include: Naked mtDNA [N-mtDNA], mtDNA within non-mitochondrial Membranes [M-mtDNA], Extracellular mitochondria [exM-mtDNA], and mtDNA within Mitochondria enclosed in a Membrane [MM-mtDNA]. We outline the challenges associated with accurately quantifying these ex-mtDNA types, suggest potential physiological roles for each ex-mtDNA type, and explore how this classification could establish a foundation for future research endeavors and further analysis and definitions for ex-mtDNA. By proposing this classification of circulating mtDNA forms, we draw a parallel with the clinically recognized forms of cholesterol, such as HDL and LDL, to illustrate potential future significance in a similar manner. While not directly analogous, these mtDNA forms may one day be as biologically relevant in clinical interpretation as cholesterol fractions are currently. We also discuss how advancing methodologies to reliably quantify distinct ex-mtDNA forms could significantly enhance their utility as health or disease biomarkers, and how their application may offer innovative therapeutic approaches.
    Keywords:  Aging; Biomarker; Classification; Extracellular mitochondria (ex-mito); Extracellular mitochondrial DNA (ex-mtDNA); Health; Identification methods; Stress; Therapeutic agent
    DOI:  https://doi.org/10.1016/j.mito.2024.101848
  14. Front Pharmacol. 2023 ;14 1332567
    The potential influence of melatonin on mitochondrial quality control: a review.
    Xudan Lei, Zhenni Xu, Lingxiao Huang, Yujun Huang, Siyu Tu, Lu Xu, Dengqun Liu.
      Mitochondria are critical for cellular energetic metabolism, intracellular signaling orchestration and programmed death regulation. Therefore, mitochondrial dysfunction is associated with various pathogeneses. The maintenance of mitochondrial homeostasis and functional recovery after injury are coordinated by mitochondrial biogenesis, dynamics and autophagy, which are collectively referred to as mitochondrial quality control. There is increasing evidence that mitochondria are important targets for melatonin to exert protective effects under pathological conditions. Melatonin, an evolutionarily conserved tryptophan metabolite, can be synthesized, transported and metabolized in mitochondria. In this review, we summarize the important role of melatonin in the damaged mitochondria elimination and mitochondrial energy supply recovery by regulating mitochondrial quality control, which may provide new strategies for clinical treatment of mitochondria-related diseases.
    Keywords:  autophagy; melatonin; mitochondria-related diseases; mitochondrial dynamics; oxidative phosphorylation
    DOI:  https://doi.org/10.3389/fphar.2023.1332567
  15. Biomolecules. 2023 Dec 21. pii: 12. [Epub ahead of print]14(1):
    Mitochondria in Multi-Directional Differentiation of Dental-Derived Mesenchymal Stem Cells.
    Haotian Liu, Ke Xu, Yifan He, Fang Huang.
      The pursuit of tissue regeneration has fueled decades of research in regenerative medicine. Among the numerous types of mesenchymal stem cells (MSCs), dental-derived mesenchymal stem cells (DMSCs) have recently emerged as a particularly promising candidate for tissue repair and regeneration. In recent years, evidence has highlighted the pivotal role of mitochondria in directing and orchestrating the differentiation processes of DMSCs. Beyond mitochondrial energy metabolism, the multifaceted functions of mitochondria are governed by the mitochondrial quality control (MQC) system, encompassing biogenesis, autophagy, and dynamics. Notably, mitochondrial energy metabolism not only governs the decision to differentiate but also exerts a substantial influence on the determination of differentiation directions. Furthermore, the MQC system exerts a nuanced impact on the differentiation of DMSCs by finely regulating the quality and mass of mitochondria. The review aims to provide a comprehensive overview of the regulatory mechanisms governing the multi-directional differentiation of DMSCs, mediated by both mitochondrial energy metabolism and the MQC system. We also focus on a new idea based on the analysis of data from many research groups never considered before, namely, DMSC-based regenerative medicine applications.
    Keywords:  dental-derived mesenchymal stem cells; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial energy metabolism; mitophagy; multi-directional differentiation
    DOI:  https://doi.org/10.3390/biom14010012
  16. Neuron. 2024 Jan 17. pii: S0896-6273(23)00978-9. [Epub ahead of print]
    Direct neuronal reprogramming of NDUFS4 patient cells identifies the unfolded protein response as a novel general reprogramming hurdle.
    Giovanna Sonsalla, Ana Belen Malpartida, Therese Riedemann, Mirjana Gusic, Ejona Rusha, Giorgia Bulli, Sonia Najas, Aleks Janjic, Bob A Hersbach, Pawel Smialowski, Micha Drukker, Wolfgang Enard, Jochen H M Prehn, Holger Prokisch, Magdalena Götz, Giacomo Masserdotti.
      Mitochondria account for essential cellular pathways, from ATP production to nucleotide metabolism, and their deficits lead to neurological disorders and contribute to the onset of age-related diseases. Direct neuronal reprogramming aims at replacing neurons lost in such conditions, but very little is known about the impact of mitochondrial dysfunction on the direct reprogramming of human cells. Here, we explore the effects of mitochondrial dysfunction on the neuronal reprogramming of induced pluripotent stem cell (iPSC)-derived astrocytes carrying mutations in the NDUFS4 gene, important for Complex I and associated with Leigh syndrome. This led to the identification of the unfolded protein response as a major hurdle in the direct neuronal conversion of not only astrocytes and fibroblasts from patients but also control human astrocytes and fibroblasts. Its transient inhibition potently improves reprogramming by influencing the mitochondria-endoplasmic-reticulum-stress-mediated pathways. Taken together, disease modeling using patient cells unraveled novel general hurdles and ways to overcome these in human astrocyte-to-neuron reprogramming.
    Keywords:  Leigh syndrome; astrocytes; direct neuronal reprogramming; mitochondria; unfolded protein response
    DOI:  https://doi.org/10.1016/j.neuron.2023.12.020
  17. Stem Cell Rev Rep. 2024 Jan 24.
    Mitochondria in Mesenchymal Stem Cells: Key to Fate Determination and Therapeutic Potential.
    Yang Liu, Lingjuan Wang, Jihui Ai, Kezhen Li.
      Mesenchymal stem cells (MSCs) have become popular tool cells in the field of transformation and regenerative medicine due to their function of cell rescue and cell replacement. The dynamically changing mitochondria serve as an energy metabolism factory and signal transduction platform, adapting to different cell states and maintaining normal cell activities. Therefore, a clear understanding of the regulatory mechanism of mitochondria in MSCs is profit for more efficient clinical transformation of stem cells. This review highlights the cutting-edge knowledge regarding mitochondrial biology from the following aspects: mitochondrial morphological dynamics, energy metabolism and signal transduction. The manuscript mainly focuses on mitochondrial mechanistic insights in the whole life course of MSCs, as well as the potential roles played by mitochondria in MSCs treatment of transplantation, for seeking pivotal targets of stem cell fate regulation and stem cell therapy.
    Keywords:  Mesenchymal stem cells; Mitochondria; Mitochondrial morphology; Mitochondrial transfer; Regenerative therapy; Signal transduction
    DOI:  https://doi.org/10.1007/s12015-024-10681-y
  18. Antioxid Redox Signal. 2024 Jan 22.
    Is mitochondrial DNA copy number from human blood associated with iron deposits in the brain?
    Qu Tian, David A Zweibaum, Luke C Pilling, Francesco Casanova, Yong Qian, Janice L Atkins, David Melzer, Jun Ding, Luigi Ferrucci.
      Iron overload is implicated in mitochondrial dysfunction. Some iron and mitochondria-related measures show sex differences. It is unclear whether mitochondrial DNA copy number (mtDNAcn) from blood associated with iron depositions in the brain or liver and whether the relationship differs by sex. In this population-based study, we find that among community-dwelling adults, lower mtDNAcn assessed in blood is associated with higher brain iron in basal ganglia and hippocampus and more liver fat, and not with brain volumes or liver iron. Interestingly, the association between mtDNAcn and brain iron in basal ganglia is prominent in men. Our observations lead to the hypothesis that mechanisms connecting mitochondrial dysfunction and iron overload may differ between brain and liver and differ by sex.
    DOI:  https://doi.org/10.1089/ars.2023.0529
  19. STAR Protoc. 2024 Jan 18. pii: S2666-1667(24)00007-8. [Epub ahead of print]5(1): 102842
    Protocol for measuring mitochondrial size in mouse and human liver tissues.
    Balamurugan Ramatchandirin, Miho Iijima, Arisa Ikeda, Alexia Pearah, Sally Radovick, Fredric E Wondisford, Hiromi Sesaki, Ling He.
      Mitochondrial dynamic process is important for cell viability, metabolic activity, and mitochondria health. Here, we present a protocol for measuring mitochondrial size through immunofluorescence staining, confocal imaging, and analysis in ImageJ. We describe the steps for tissue processing, antigen retrieval, mitochondrial staining using an integrating immunofluorescence assay, and computerized image analysis to measure each mitochondrial size in mouse and human liver tissues. This protocol reduces tissue sample volume and processing time for the preparation of primary cells. For complete details on the use and execution of this protocol, please refer to Pearah et al.1.
    Keywords:  Cell Biology; Health Sciences; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2024.102842
  20. Free Radic Biol Med. 2024 Jan 22. pii: S0891-5849(24)00042-X. [Epub ahead of print]
    Cardiomyocyte maturation alters molecular stress response capacities and determines cell survival upon mitochondrial dysfunction.
    Nina Schraps, Michaela Tirre, Simon Pyschny, Anna Reis, Hannah Schlierbach, Matthias Seidl, Hans-Gerd Kehl, Anne Schänzer, Jacqueline Heger, Christian Jux, Jörg-Detlef Drenckhahn.
      Cardiomyocyte maturation during pre- and postnatal development requires multiple intertwined processes, including a switch in energy generation from glucose utilization in the embryonic heart towards fatty acid oxidation after birth. This is accompanied by a boost in mitochondrial mass to increase capacities for oxidative phosphorylation and ATP generation required for efficient contraction. Whether cardiomyocyte differentiation is paralleled by augmented capacities to deal with reactive oxygen species (ROS), physiological byproducts of the mitochondrial electron transport chain (ETC), is less clear. Here we show that expression of genes and proteins involved in redox homeostasis and protein quality control within mitochondria increases after birth in the mouse and human heart. Using primary embryonic, neonatal and adult mouse cardiomyocytes in vitro we investigated how excessive ROS production induced by mitochondrial dysfunction affects cell survival and stress response at different stages of maturation. Embryonic and neonatal cardiomyocytes largely tolerate inhibition of ETC complex III by antimycin A (AMA) as well as ATP synthase (complex V) by oligomycin but are susceptible to complex I inhibition by rotenone. All three inhibitors alter the intracellular distribution and ultrastructure of mitochondria in neonatal cardiomyocytes. In contrast, adult cardiomyocytes treated with AMA undergo rapid morphological changes and cellular disintegration. At the molecular level embryonic cardiomyocytes activate antioxidative defense mechanisms, the integrated stress response (ISR) and ER stress but not the mitochondrial unfolded protein response upon complex III inhibition. In contrast, adult cardiomyocytes fail to activate the ISR and antioxidative proteins following AMA treatment. In conclusion, our results identified fundamental differences in cell survival and stress response in differentiated compared to immature cardiomyocytes subjected to mitochondrial dysfunction. The high stress tolerance of immature cardiomyocytes might allow outlasting unfavorable intrauterine conditions thereby preventing fetal or perinatal heart disease and may contribute to the regenerative capacity of the embryonic and neonatal mammalian heart.
    Keywords:  Cardiomyocyte differentiation; Cardiomyocyte survival; Cellular stress response; Mitochondrial dysfunction; Oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.034
  21. Front Psychiatry. 2023 ;14 1301272
    Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implications.
    Peter Balicza, Andras Gezsi, Mariann Fedor, Judit C Sagi, Aniko Gal, Noemi Agnes Varga, Maria Judit Molnar.
      We present a male patient carrying a pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial dysfunction who responded to the cariprazine treatment. He had delayed speech development and later experienced severe social anxiety, learning disabilities, cognitive slowing, and predominant negative psychiatric symptoms associated with rigidity. Clinical examinations showed multisystemic involvement. Together with elevated ergometric lactate levels, the clinical picture suggested mitochondrial disease, which was also supported by muscle histopathology. Exploratory transcriptome analysis also revealed the involvement of metabolic and oxidative phosphorylation pathways. Whole-exome sequencing identified a pathogenic MECP2 variant, which can explain both the dopamine imbalance and mitochondrial dysfunction in this patient. Mitochondrial dysfunction was previously suggested in classical Rett syndrome, and we detected related phenotype evidence on multiple consistent levels for the first time in a MECP2 variant carrier male. This study further supports the importance of the MECP2 gene in the mitochondrial pathways, which can open the gate for more personalized therapeutic interventions. Good cariprazine response highlights the role of dopamine dysfunction in the complex psychiatric symptoms of Rett syndrome. This can help identify the optimal treatment strategy from a transdiagnostic perspective instead of a classical diagnostic category.
    Keywords:  MECP2 mutation; RNA sequencing; Rett syndrome; anxiety; cariprazine; learning disability; mitochondrial dysfunction; negative symptoms
    DOI:  https://doi.org/10.3389/fpsyt.2023.1301272
  22. Front Physiol. 2023 ;14 1279548
    Mitochondrial-related microRNAs and their roles in cellular senescence.
    Ling Luo, Xingna An, Yinghui Xiao, Xiguang Sun, Sijie Li, Yingzhao Wang, Weixia Sun, Dehai Yu.
      Aging is a natural aspect of mammalian life. Although cellular mortality is inevitable, various diseases can hasten the aging process, resulting in abnormal or premature senescence. As cells age, they experience distinctive morphological and biochemical shifts, compromising their functions. Research has illuminated that cellular senescence coincides with significant alterations in the microRNA (miRNA) expression profile. Notably, a subset of aging-associated miRNAs, originally encoded by nuclear DNA, relocate to mitochondria, manifesting a mitochondria-specific presence. Additionally, mitochondria themselves house miRNAs encoded by mitochondrial DNA (mtDNA). These mitochondria-residing miRNAs, collectively referred to as mitochondrial miRNAs (mitomiRs), have been shown to influence mtDNA transcription and protein synthesis, thereby impacting mitochondrial functionality and cellular behavior. Recent studies suggest that mitomiRs serve as critical sensors for cellular senescence, exerting control over mitochondrial homeostasis and influencing metabolic reprogramming, redox equilibrium, apoptosis, mitophagy, and calcium homeostasis-all processes intimately connected to senescence. This review synthesizes current findings on mitomiRs, their mitochondrial targets, and functions, while also exploring their involvement in cellular aging. Our goal is to shed light on the potential molecular mechanisms by which mitomiRs contribute to the aging process.
    Keywords:  cellular senescence; epigenetics; mitochondria; mitomiRs; noncoding RNA
    DOI:  https://doi.org/10.3389/fphys.2023.1279548
  23. Neurotherapeutics. 2024 Jan 19. pii: S1878-7479(23)02027-5. [Epub ahead of print]21(1): e00311
    Challenges and opportunities to bridge translational to clinical research for personalized mitochondrial medicine.
    Andrea L Gropman, Martine N Uittenbogaard, Anne E Chiaramello.
      Mitochondrial disorders are a group of rare and heterogeneous genetic diseases characterized by dysfunctional mitochondria leading to deficient adenosine triphosphate synthesis and chronic energy deficit in patients. The majority of these patients exhibit a wide range of phenotypic manifestations targeting several organ systems, making their clinical diagnosis and management challenging. Bridging translational to clinical research is crucial for improving the early diagnosis and prognosis of these intractable mitochondrial disorders and for discovering novel therapeutic drug candidates and modalities. This review provides the current state of clinical testing in mitochondrial disorders, discusses the challenges and opportunities for converting basic discoveries into clinical settings, explores the most suited patient-centric approaches to harness the extraordinary heterogeneity among patients affected by the same primary mitochondrial disorder, and describes the current outlook of clinical trials.
    Keywords:  Clinical trial; Energy metabolism; Mitochondrial medicine; Next generation therapeutics; Patient-centric approach
    DOI:  https://doi.org/10.1016/j.neurot.2023.e00311
  24. Elife. 2024 Jan 22. pii: e84282. [Epub ahead of print]13
    Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms.
    Yeyun Ouyang, Mi-Young Jeong, Corey N Cunningham, Jordan A Berg, Ashish G Toshniwal, Casey E Hughes, Kristina Seiler, Jonathan G Van Vranken, Ahmad A Cluntun, Geanette Lam, Jacob M Winter, Emel Akdoǧan, Katja K Dove, Sara M Nowinski, Matthew West, Greg Odorizzi, Steven P Gygi, Cory D Dunn, Dennis R Winge, Jared Rutter.
      Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential, both through inducing the electron transport chain and the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited simply by phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of mitochondrial membrane potential is observed in primary and immortalized mammalian cells as well as in Drosophila. These data suggest that mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement of mitochondrial function even in defective mitochondria.
    Keywords:  D. melanogaster; S. cerevisiae; cell biology; human
    DOI:  https://doi.org/10.7554/eLife.84282
  25. Int J Mol Sci. 2024 Jan 18. pii: 1175. [Epub ahead of print]25(2):
    The Research Progress of Mitochondrial Transplantation in the Treatment of Mitochondrial Defective Diseases.
    Cuilan Hu, Zheng Shi, Xiongxiong Liu, Chao Sun.
      Mitochondria are double-membrane organelles that are involved in energy production, apoptosis, and signaling in eukaryotic cells. Several studies conducted over the past decades have correlated mitochondrial dysfunction with various diseases, including cerebral ischemia, myocardial ischemia-reperfusion, and cancer. Mitochondrial transplantation entails importing intact mitochondria from healthy tissues into diseased tissues with damaged mitochondria to rescue the injured cells. In this review, the different mitochondrial transplantation techniques and their clinical applications have been discussed. In addition, the challenges and future directions pertaining to mitochondrial transplantation and its potential in the treatment of diseases with defective mitochondria have been summarized.
    Keywords:  cancer; cerebral ischemia; mitochondrial defective diseases; mitochondrial transplantation; myocardial ischemia-reperfusion
    DOI:  https://doi.org/10.3390/ijms25021175
  26. J Reprod Dev. 2024 Jan 25.
    Effect of paternal aging and vitrification on mitochondrial DNA copy number and telomere length of mouse blastocysts.
    Nao Aburada, Jun Ito, Yuki Inoue, Taiyo Yamamoto, Masamune Hayashi, Noko Teramoto, Yuri Okada, Yuichi Koshiishi, Koumei Shirasuna, Hisataka Iwata.
      In this study, we examined the effects of paternal aging on the mitochondrial DNA copy number (mt-cn), telomere length (TL), and gene expression in mouse embryos. The effects of vitrification on the mt-cn and TL of the embryos derived from young and aged male parents (YF and AF, respectively) were examined. C57BL/6N male mice were used for embryo production at 13-23 and 50-55 weeks of age. Two-cell stage embryos were collected from the oviducts of superovulated female mice (8-15 weeks old) and cultured for 24 h until the 8-cell stage, followed by embryo vitrification. Fresh and vitrified-warmed embryos were incubated for 2 days until the blastocyst stage, and mt-cn and TL were investigated. The cell-free mitochondrial DNA copy number (cf-mt-cn) in the spent culture medium (SCM) of the embryos was then investigated. RNA sequencing of blastocysts revealed that metabolic pathways, including oxidative phosphorylation and mTOR pathways, were enriched in differentially expressed genes. The mt-cn and TL of AF-derived blastocysts were lower and shorter, respectively, than those of YF-derived blastocysts. Paternal aging did not affect the blastocyst rate after vitrification. Vitrification of the 8-cell stage embryos did not affect the mt-cn of the blastocysts. However, it increased the cf-mt-cn (cell-free mt-cn) in the SCM of both YF- and AF-derived embryos. Vitrification did not affect the TL of either YF- or AF-derived embryos. Thus, paternal aging affected the mt-cn and TL of the embryos, but vitrification did not affect these parameters in either age groups.
    Keywords:  Mitochondrial DNA copy number; Mouse embryos; Paternal aging; Telomere length; Vitrification
    DOI:  https://doi.org/10.1262/jrd.2023-079
  27. Heliyon. 2024 Jan 15. 10(1): e24029
    Advances in crosstalk among innate immune pathways activated by mitochondrial DNA.
    Guangwei Tao, Wenyan Liao, Jiafeng Hou, Xinmiao Jiang, Xin Deng, Guodong Chen, Chengming Ding.
      Mitochondria are not only the power plant for intracellular oxidative phosphorylation and ATP synthesis, but also involved in cell proliferation, differentiation, signaling and apoptosis. Recent studies have shown that mitochondria play an important role in other pathophysiological functions in addition to cellular energy metabolism. Mitochondria release mitochondrial DNA (mtDNA) as a damage-associated molecular pattern (DAMP) to activate Toll-like receptor 9 (TLR9), NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune signaling pathways against foreign pathogenic microorganisms. The innate immune response not only promotes antimicrobial immune defense and regulates antiviral signaling, but their overactivation also induces the onset and progression of inflammatory diseases. In this paper, we review the role of mtDNA in the activation of innate immune signaling pathways and the crosstalk among innate immune signaling pathways activated by mtDNA, providing clues for the study of inflammatory diseases caused by mtDNA cytoplasmic translocation.
    Keywords:  NLRP3 inflammasome; TLR9; cGAS-STING signaling pathway; mtDNA
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e24029
  28. EMBO J. 2024 Jan 24.
    Shared structural features of Miro binding control mitochondrial homeostasis.
    Christian Covill-Cooke, Brian Kwizera, Guillermo López-Doménech, Caleb Od Thompson, Ngaam J Cheung, Ema Cerezo, Martin Peterka, Josef T Kittler, Benoît Kornmann.
      Miro proteins are universally conserved mitochondrial calcium-binding GTPases that regulate a multitude of mitochondrial processes, including transport, clearance, and lipid trafficking. The exact role of Miro in these functions is unclear but involves binding to a variety of client proteins. How this binding is operated at the molecular level and whether and how it is important for mitochondrial health, however, remains unknown. Here, we show that known Miro interactors-namely, CENPF, Trak, and MYO19-all use a similar short motif to bind the same structural element: a highly conserved hydrophobic pocket in the first calcium-binding domain of Miro. Using these Miro-binding motifs, we identified direct interactors de novo, including MTFR1/2/1L, the lipid transporters Mdm34 and VPS13D, and the ubiquitin E3-ligase Parkin. Given the shared binding mechanism of these functionally diverse clients and its conservation across eukaryotes, we propose that Miro is a universal mitochondrial adaptor coordinating mitochondrial health.
    Keywords:  AlphaFold; ERMES; Lipid Transport; Mitophagy; Organelle Transport
    DOI:  https://doi.org/10.1038/s44318-024-00028-1
  29. Nat Med. 2024 Jan 22.
    Early interventions improve child neurodevelopment.
    Sonia Muliyil.
      
    Keywords:  Clinical trials; Developmental biology; Neurological disorders
    DOI:  https://doi.org/10.1038/d41591-024-00005-5
  30. bioRxiv. 2024 Jan 13. pii: 2024.01.12.575075. [Epub ahead of print]
    Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling.
    Mateus Prates Mori, Oswaldo Lozoya, Ashley M Brooks, Dagoberto Grenet, Cristina A Nadalutti, Birgitta Ryback, Kai Ting Huang, Prottoy Hasan, Gyӧrgy Hajnóczky, Janine H Santos.
      Maintenance of the mitochondrial inner membrane potential (ΔΨM) is critical for many aspects of mitochondrial function, including mitochondrial protein import and ion homeostasis. While ΔΨM loss and its consequences are well studied, little is known about the effects of increased ΔΨM. In this study, we used cells deleted of ATPIF1 , a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of mitochondrial hyperpolarization. Our data show that chronic ΔΨM increase leads to nuclear DNA hypermethylation, regulating transcription of mitochondria, carbohydrate and lipid metabolism genes. Surprisingly, remodeling of phospholipids, but not metabolites or redox changes, mechanistically links the ΔΨM to the epigenome. These changes were also observed upon chemical exposures and reversed by decreasing the ΔΨM, highlighting them as hallmark adaptations to chronic mitochondrial hyperpolarization. Our results reveal the ΔΨM as the upstream signal conveying the mitochondrial status to the epigenome to regulate cellular biology, providing a new framework for how mitochondria can influence health outcomes in the absence of canonical dysfunction.Highlights: Mitochondria hyperpolarization leads to nuclear DNA hypermethylationDNA methylation regulates expression of mitochondrial and lipid metabolism genesPhospholipid remodeling mediates the epigenetic effects of mitochondrial hyperpolarization.
    DOI:  https://doi.org/10.1101/2024.01.12.575075
  31. FEBS Lett. 2024 Jan 24.
    Functional interplay of lipid droplets and mitochondria.
    Ludovic Enkler, Anne Spang.
      Our body stores energy mostly in form of fatty acids (FAs) in lipid droplets (LDs). From there the FAs can be mobilized and transferred to peroxisomes and mitochondria. This transfer is dependent on close opposition of LDs and mitochondria and peroxisomes and happens at membrane contact sites. However, the composition and the dynamics of these contact sites is not well understood, which is in part due to the dependence on the metabolic state of the cell and on the cell- and tissue-type. Here, we summarize the current knowledge on the contacts between lipid droplets and mitochondria both in mammals and in the yeast Saccharomyces cerevisiae, in which various contact sites are well studied. We discuss possible functions of the contact site and their implication in disease.
    Keywords:  disease; fatty acids; mammals; metabolism; stress; yeast; β-oxidation
    DOI:  https://doi.org/10.1002/1873-3468.14809
  32. Theranostics. 2024 ;14(3): 954-972
    Endometrial organoids: a reservoir of functional mitochondria for uterine repair.
    Sun-Young Hwang, Danbi Lee, Gaeun Lee, Jungho Ahn, Yu-Gyeong Lee, Hwa Seon Koo, Youn-Jung Kang.
      Background: Asherman's syndrome (AS) is a dreadful gynecological disorder of the uterus characterized by intrauterine adhesion with severe fibrotic lesions, resulting in a damaged basalis layer with infertility. Despite extensive research on overcoming AS, evidence-based effective and reproducible treatments to improve the structural and functional morphology of the AS endometrium have not been established. Methods: Endometrial organoids generated from human or mouse endometrial tissues were transplanted into the uterine cavity of a murine model of AS to evaluate their transplantable feasibility to improve the AS uterine environment. The successful engraftment of organoid was confirmed by detection of human mitochondria and cytosol (for human endometrial organoid) or enhanced green fluorescent protein signals (for mouse endometrial organoid) in the recipient endometrium. The therapeutic effects mediated by organoid transplantation were examined by the measurements of fibrotic lesions, endometrial receptivity and angiogenesis, and fertility assessment by recording the number of implantation sites and weighing the fetuses and placenta. To explore the cellular and molecular mechanisms underlying the recovery of AS endometrium, we evaluated the status of mitochondrial movement and biogenetics in organoid transplanted endometrium. Results: Successfully engrafted endometrial organoids with similar morphological and molecular features to the parental tissues dramatically repaired the AS-induced damaged endometrium, significantly reducing fibrotic lesions and increasing fertility outcomes in mice. Moreover, dysfunctional mitochondria in damaged tissues, which we propose might be a key cellular feature of the AS endometrium, was fully recovered by functional mitochondria transferred from engrafted endometrial organoids. Endometrial organoid-originating mitochondria restored excessive collagen accumulation in fibrotic lesions and shifted uterine metabolic environment to levels observed in the normal endometrium. Conclusions: Our findings suggest that endometrial organoid-originating mitochondria might be key players to mediate uterine repair resulting in fertility enhancement by recovering abrogated metabolic circumstance of the endometrium with AS. Further studies addressing the clinical applicability of endometrial organoids may aid in identifying new therapeutic strategies for infertility in patients with AS.
    Keywords:  Asherman's syndrome; Endometrial organoid; Infertility; Mitochondria; Uterine repair
    DOI:  https://doi.org/10.7150/thno.90538
  33. Mol Ther Methods Clin Dev. 2024 Mar 14. 32(1): 101179
    Perspectives of the Friedreich ataxia community on gene therapy clinical trials.
    Shandra J Trantham, Mackenzi A Coker, Samantha Norman, Emma Crowley, Julie Berthy, Barry J Byrne, Sub Subramony, XiangYang Lou, Manuela Corti.
      Gene therapy is a potential treatment for Friedreich ataxia, with multiple programs on the horizon. The purpose of this study was to collect opinions about gene therapy from individuals 14 years or older with Friedreich ataxia or parents/caregivers of Friedreich ataxia patients who were diagnosed as children 17 or younger. Participants were asked to complete a survey after reading brief educational materials regarding gene therapy. Most of the patients captured in this survey have an early-onset (classical) presentation of the disease. Participants expressed urgency in participating in gene therapy clinical trials despite the associated risks. About half of the respondents believed that gene therapy would cease progression or minimize symptoms, whereas nearly one-fourth expected to be cured. The survey also revealed how participants perceive their symptom burden, because a substantial majority reported that balance/walking issues most interfere with their quality of life and would be the symptom they would prioritize treating. Although not statistically significant, more caregivers prioritized treating cardiomyopathy than patients. This study provides valuable information on priorities, beliefs, and expectations regarding gene therapy and serves to guide future gene therapy opinion studies and gene therapy trial design.
    Keywords:  Friedreich ataxia; caregivers; gene therapy; patient preference study; patients; survey
    DOI:  https://doi.org/10.1016/j.omtm.2023.101179
  34. Nature. 2024 Jan 22.
    Deciphering cell states and genealogies of human hematopoiesis.
    Chen Weng, Fulong Yu, Dian Yang, Michael Poeschla, L Alexander Liggett, Matthew G Jones, Xiaojie Qiu, Lara Wahlster, Alexis Caulier, Jeffrey A Hussmann, Alexandra Schnell, Kathryn E Yost, Luke Koblan, Jorge D Martin-Rufino, Joseph Min, Alessandro Hammond, Daniel Ssozi, Raphael Bueno, Hari Mallidi, Antonia Kreso, Javier Escabi, William M Rideout, Tyler Jacks, Sahand Hormoz, Peter van Galen, Jonathan S Weissman, Vijay G Sankaran.
      The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived hematopoietic stem cells (HSCs)1. Perturbations to this process underlie diverse diseases, but the clonal contributions to human hematopoiesis and how this changes with age remain incompletely understood. While recent insights have emerged from barcoding studies in model systems4,5,16,17, simultaneous detection of cell states and phylogenies from natural barcodes in humans has been challenging. Here, we introduce an improved single-cell lineage tracing system based on deep detection of naturally-occurring mitochondrial DNA (mtDNA) mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs and map the physiological state and output of clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as differences in total HSC output as well as biases toward the production of different mature cell types. We also find that the diversity of HSC clones decreases dramatically with age leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides the first clonally-resolved and cell-state aware atlas of human hematopoiesis at single-cell resolution revealing an unappreciated functional diversity of human HSC clones and more broadly paves the way for refined studies of clonal dynamics across a range of tissues in human health and disease.
    DOI:  https://doi.org/10.1038/s41586-024-07066-z
  35. Hum Genome Var. 2024 Jan 25. 11(1): 6
    Epigenetic regulation of the nuclear genome associated with mitochondrial dysfunction in Leber's hereditary optic neuropathy (LHON).
    Aswathy P Nair, Ambika Selvakumar, Janani Gopalarethinam, B Abishek Kumar, Balachandar Vellingiri, Mohana Devi Subramaniam.
      Leber's hereditary optic neuropathy (LHON) is a mitochondrial hereditary disease in which visual loss affects complex 1 activity of the electron transport chain of mitochondria. It first manifests as painless dulling or blurry in one or even both eyes, and as it develops, sharpness and color perception are lost. In addition to primary mitochondrial DNA (mtDNA) mutations, there are also other environmental and epigenetic factors involved in the pathogenesis of LHON. One of the most common locations for deadly pathogenic mutations in humans is the human complex I accessory NDUFS4 subunit gene. The iron-sulfur clusters of the electron input domain were distorted in the absence of NDUFS4, which reduced complex I function and elevated the production of reactive oxygen species. Therefore, here, we studied the epigenetic alterations of NDUFS4 by focusing on histone activation and repressive markers. We isolated peripheral blood mononuclear cells (PBMCs) from LHON patients and healthy individuals and examined epigenetic modifications in ND4 mutant cells and control cells. Chromatin immunoprecipitation-qRT PCR (ChIP-qRT PCR) assays were performed to investigate the modifications of histones. In comparison to their controls, both LHON patients and ND4 mutant cells exhibited a significant enrichment in activation and repressive markers. This finding indicates that these modifications might mitigate the impact of LHON mutations on complex 1 and aid in elucidating the mechanism underlying the progression of LHON disease.
    DOI:  https://doi.org/10.1038/s41439-023-00258-5
  36. Antioxidants (Basel). 2024 Jan 18. pii: 121. [Epub ahead of print]13(1):
    Maintaining the Mitochondrial Quality Control System Was a Key Event of Tanshinone IIA against Deoxynivalenol-Induced Intestinal Toxicity.
    Cong Zhang, Youshuang Wang, Xinyu Zhang, Kefei Zhang, Fengjuan Chen, Jiayan Fan, Xuebing Wang, Xu Yang.
      Deoxynivalenol (DON) is the one of the most common mycotoxins, widely detected in various original foods and processed foods. Tanshinone IIA (Tan IIA) is a fat-soluble diterpene quinone extracted from Salvia miltiorrhiza Bunge, which has multi-biological functions and pharmacological effects. However, whether Tan IIA has a protective effect against DON-induced intestinal toxicity is unknown. In this study, the results showed Tan IIA treatment could attenuate DON-induced IPEC-J2 cell death. DON increased oxidation product accumulation, decreased antioxidant ability and disrupted barrier function, while Tan IIA reversed DON-induced barrier function impairment and oxidative stress. Furthermore, Tan IIA dramatically improved mitochondrial function via mitochondrial quality control. Tan IIA could upregulate mitochondrial biogenesis and mitochondrial fusion as well as downregulate mitochondrial fission and mitochondrial unfolded protein response. In addition, Tan IIA significantly attenuated mitophagy caused by DON. Collectively, Tan IIA presented a potential protective effect against DON toxicity and the underlying mechanisms were involved in mitochondrial quality control-mediated mitophagy.
    Keywords:  IPEC-J2 cells; Tanshinone IIA; deoxynivalenol; mitochondrial quality control
    DOI:  https://doi.org/10.3390/antiox13010121
  37. Expert Rev Neurother. 2024 Jan 25.
    Omaveloxolone for the treatment of Friedreich Ataxia: clinical trial results and practical considerations.
    David R Lynch, Susan Perlman, Kim Schadt.
      INTRODUCTION: Omavaloxolone, an NRF2 activator recently became the first drug approved specifically for the treatment of Friedreich ataxia (FRDA). This landmark achievement provides a background for a review of the detailed data leading to the approval.AREAS COVERED: The authors review the data from the 4 major articles on FRDA in the context of the authors' considerable (>1000 patients) experience in treating individuals with FRDA. The data is presented in the context not only of its scientific meaning but also in the practical context of therapy in FRDA.
    EXPERT OPINION: Omaveloxolone provides a significant advance in treatment of FRDA that is likely to be beneficial in a majority of the FRDA population. The data suggesting a benefit is consistent, and adverse issues are relatively modest. The major remaining questions are the subgroups that are most responsive and how long the beneficial effects will remain significant in FRDA patients.
    Keywords:  Antioxidant; Friedrech Ataxia; KEAP1; clinical trial; ferritin; mFARS
    DOI:  https://doi.org/10.1080/14737175.2024.2310617
  38. Cell Death Discov. 2024 Jan 26. 10(1): 54
    Caspase-dependent apoptosis in Ribloflavin transporter deficiency iPSCs and derived motor neurons.
    Chiara Marioli, Maurizio Muzzi, Fiorella Colasuonno, Cristian Fiorucci, Nicolò Cicolani, Stefania Petrini, Enrico Bertini, Marco Tartaglia, Claudia Compagnucci, Sandra Moreno.
      Riboflavin Transporter Deficiency (RTD) is a rare genetic, childhood-onset disease. This pathology has a relevant neurological involvement, being characterized by motor symptoms, ponto-bulbar paralysis and sensorineural deafness. Such clinical presentation is associated with muscle weakness and motor neuron (MN) degeneration, so that RTD is considered part of the MN disease spectrum. Based on previous findings demonstrating energy dysmetabolism and mitochondrial impairment in RTD induced Pluripotent Stem cells (iPSCs) and iPSC-derived MNs, here we address the involvement of intrinsic apoptotic pathways in disease pathogenesis using these patient-specific in vitro models by combined ultrastructural and confocal analyses. We show impaired neuronal survival of RTD iPSCs and MNs. Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) documents severe alterations in patients' cells, including deranged mitochondrial ultrastructure, and altered plasma membrane and nuclear organization. Occurrence of aberrantly activated apoptosis is confirmed by immunofluorescence and TUNEL assays. Overall, our work provides evidence of a role played by mitochondrial dysfunction in RTD, and identifies neuronal apoptosis as a contributing event in disease pathogenesis, indicating intrinsic apoptosis pathways as possible relevant targets for more effective therapeutical approaches.
    DOI:  https://doi.org/10.1038/s41420-024-01812-y
  39. Int J Mol Sci. 2024 Jan 12. pii: 963. [Epub ahead of print]25(2):
    Mitochondrial and Cellular Function in Fibroblasts, Induced Neurons, and Astrocytes Derived from Case Study Patients: Insights into Major Depression as a Mitochondria-Associated Disease.
    Iseline Cardon, Sonja Grobecker, Selin Kücükoktay, Stefanie Bader, Tatjana Jahner, Caroline Nothdurfter, Kevin Koschitzki, Mark Berneburg, Bernhard H F Weber, Heidi Stöhr, Marcus Höring, Gerhard Liebisch, Frank Braun, Tanja Rothammer-Hampl, Markus J Riemenschneider, Rainer Rupprecht, Vladimir M Milenkovic, Christian H Wetzel.
      The link between mitochondria and major depressive disorder (MDD) is increasingly evident, underscored both by mitochondria's involvement in many mechanisms identified in depression and the high prevalence of MDD in individuals with mitochondrial disorders. Mitochondrial functions and energy metabolism are increasingly considered to be involved in MDD's pathogenesis. This study focused on cellular and mitochondrial (dys)function in two atypical cases: an antidepressant non-responding MDD patient ("Non-R") and another with an unexplained mitochondrial disorder ("Mito"). Skin biopsies from these patients and controls were used to generate various cell types, including astrocytes and neurons, and cellular and mitochondrial functions were analyzed. Similarities were observed between the Mito patient and a broader MDD cohort, including decreased respiration and mitochondrial function. Conversely, the Non-R patient exhibited increased respiratory rates, mitochondrial calcium, and resting membrane potential. In conclusion, the Non-R patient's data offered a new perspective on MDD, suggesting a detrimental imbalance in mitochondrial and cellular processes, rather than simply reduced functions. Meanwhile, the Mito patient's data revealed the extensive effects of mitochondrial dysfunctions on cellular functions, potentially highlighting new MDD-associated impairments. Together, these case studies enhance our comprehension of MDD.
    Keywords:  iPS-astrocytes; iPS-neurons; major depressive disorder; mitochondrial functions; mitochondriopathy; treatment-resistant depression
    DOI:  https://doi.org/10.3390/ijms25020963
  40. Int J Mol Sci. 2024 Jan 13. pii: 1024. [Epub ahead of print]25(2):
    Mitochondrial Dysfunction in Periodontitis and Associated Systemic Diseases: Implications for Pathomechanisms and Therapeutic Strategies.
    Yifei Deng, Junhong Xiao, Li Ma, Chuan Wang, Xiaoxuan Wang, Xin Huang, Zhengguo Cao.
      Periodontitis is a chronic infectious disorder damaging periodontal tissues, including the gingiva, periodontal ligament, cementum, and alveolar bone. It arises from the complex interplay between pathogenic oral bacteria and host immune response. Contrary to the previous view of "energy factories", mitochondria have recently been recognized as semi-autonomous organelles that fine-tune cell survival, death, metabolism, and other functions. Under physiological conditions, periodontal tissue cells participate in dynamic processes, including differentiation, mineralization, and regeneration. These fundamental activities depend on properly functioning mitochondria, which play a crucial role through bioenergetics, dynamics, mitophagy, and quality control. However, during the initiation and progression of periodontitis, mitochondrial quality control is compromised due to a range of challenges, such as bacterial-host interactions, inflammation, and oxidative stress. Currently, mounting evidence suggests that mitochondria dysfunction serves as a common pathological mechanism linking periodontitis with systemic conditions like type II diabetes, obesity, and cardiovascular diseases. Therefore, targeting mitochondria to intervene in periodontitis and multiple associated systemic diseases holds great therapeutic potential. This review provides advanced insights into the interplay between mitochondria, periodontitis, and associated systemic diseases. Moreover, we emphasize the significance of diverse therapeutic modulators and signaling pathways that regulate mitochondrial function in periodontal and systemic cells.
    Keywords:  dentistry; mitochondria dysfunction; mitochondrial quality control; oxidative stress; periodontitis; periodontology; systemic disease; therapy
    DOI:  https://doi.org/10.3390/ijms25021024
  41. Sci Rep. 2024 01 20. 14(1): 1780
    Peroxisome proliferator-activated receptor γ coactivator 1α regulates downstream of tyrosine kinase-7 (Dok-7) expression important for neuromuscular junction formation.
    Takumi Sugimoto, Chihiro Sakamaki, Tokushi Kimura, Takahiro Eguchi, Shinji Miura, Yasutomi Kamei.
      The neuromuscular junction (NMJ)-formed between a motor nerve terminal and skeletal muscle fiber-plays an important role in muscle contraction and other muscle functions. Aging and neurodegeneration worsen NMJ formation and impair muscle function. Downstream of tyrosine kinase-7 (Dok-7), expressed in skeletal muscle fibers, is essential for the formation of NMJ. Exercise increases the expression of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) in skeletal muscles and restores NMJ formation. In this study, we used skeletal muscle-specific PGC1α knockout or overexpression mice to examine the role of PGC1α in regulating Dok-7 expression and NMJ formation. Our findings revealed that Dok-7 expression is regulated by PGC1α, and luciferase activity of the Dok-7 promoter is greatly increased by coexpressing PGC1α and estrogen receptor-related receptor α. Thus, we suggest PGC1α is involved in exercise-mediated restoration of NMJ formation.
    DOI:  https://doi.org/10.1038/s41598-024-52198-x
  42. Nature. 2024 Jan 24.
    Motion of VAPB molecules reveals ER-mitochondria contact site subdomains.
    Christopher J Obara, Jonathon Nixon-Abell, Andrew S Moore, Federica Riccio, David P Hoffman, Gleb Shtengel, C Shan Xu, Kathy Schaefer, H Amalia Pasolli, Jean-Baptiste Masson, Harald F Hess, Christopher P Calderon, Craig Blackstone, Jennifer Lippincott-Schwartz.
      To coordinate cellular physiology, eukaryotic cells rely on the rapid exchange of molecules at specialized organelle-organelle contact sites1,2. Endoplasmic reticulum-mitochondrial contact sites (ERMCSs) are particularly vital communication hubs, playing key roles in the exchange of signalling molecules, lipids and metabolites3,4. ERMCSs are maintained by interactions between complementary tethering molecules on the surface of each organelle5,6. However, due to the extreme sensitivity of these membrane interfaces to experimental perturbation7,8, a clear understanding of their nanoscale organization and regulation is still lacking. Here we combine three-dimensional electron microscopy with high-speed molecular tracking of a model organelle tether, Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), to map the structure and diffusion landscape of ERMCSs. We uncovered dynamic subdomains within VAPB contact sites that correlate with ER membrane curvature and undergo rapid remodelling. We show that VAPB molecules enter and leave ERMCSs within seconds, despite the contact site itself remaining stable over much longer time scales. This metastability allows ERMCSs to remodel with changes in the physiological environment to accommodate metabolic needs of the cell. An amyotrophic lateral sclerosis-associated mutation in VAPB perturbs these subdomains, likely impairing their remodelling capacity and resulting in impaired interorganelle communication. These results establish high-speed single-molecule imaging as a new tool for mapping the structure of contact site interfaces and reveal that the diffusion landscape of VAPB at contact sites is a crucial component of ERMCS homeostasis.
    DOI:  https://doi.org/10.1038/s41586-023-06956-y
  43. Hum Gene Ther. 2024 Jan 22.
    Complement system response to adeno-associated virus (AAV) vector gene therapy.
    Elizabeth Kropf, David Markusic, Anna Majowicz, Federico Mingozzi, Klaudia Kuranda.
      Adeno-associated virus (AAV) vectors represent a novel tool for the delivery of genetic therapeutics and enable the treatment of a wide range of diseases. Success of this new modality is challenged, however, by cases of immune-related toxicities that complicate the clinical management of patients and potentially limit the therapeutic efficacy of AAV gene therapy. While significant progress has been made to manage immune-related liver enzyme elevations following systemic AAV delivery in humans, recent clinical trials utilizing high vector doses have highlighted a new challenge to AAV gene transfer - activation of the complement system. While current in vitro models implicate AAV-specific antibodies in the initiation of the classical complement pathway (CP), evidence from in vivo pre-clinical and clinical studies suggests that the alternative pathway (AP) also contributes to complement activation. A convergence of AAV-specific, environmental, and patient-specific factors shaping complement responses likely contribute to differential outcomes seen in clinical trials, from priming of the adaptive immune system to serious adverse events (SAEs) such as hepatotoxicity and thrombotic microangiopathy (TMA). Research focused on the interplay of patient-specific and AAV-related factors driving complement activation is needed, to understand and identify critical components in the complement cascade to target, and devise strategies to mitigate vector-related immune responses.
    DOI:  https://doi.org/10.1089/hum.2023.194
  44. Int J Biol Macromol. 2024 Jan 20. pii: S0141-8130(24)00410-0. [Epub ahead of print]260(Pt 2): 129607
    A comprehensive review on signaling attributes of serine and serine metabolism in health and disease.
    Di Wu, Kejia Zhang, Faheem Ahmed Khan, Nuruliarizki Shinta Pandupuspitasari, Kaifeng Guan, Fei Sun, Chunjie Huang.
      Serine is a metabolite with ever-expanding metabolic and non-metabolic signaling attributes. By providing one‑carbon units for macromolecule biosynthesis and functional modifications, serine and serine metabolism largely impinge on cellular survival and function. Cancer cells frequently have a preference for serine metabolic reprogramming to create a conducive metabolic state for survival and aggressiveness, making intervention of cancer-associated rewiring of serine metabolism a promising therapeutic strategy for cancer treatment. Beyond providing methyl donors for methylation in modulation of innate immunity, serine metabolism generates formyl donors for mitochondrial tRNA formylation which is required for mitochondrial function. Interestingly, fully developed neurons lack the machinery for serine biosynthesis and rely heavily on astrocytic l-serine for production of d-serine to shape synaptic plasticity. Here, we recapitulate recent discoveries that address the medical significance of serine and serine metabolism in malignancies, mitochondrial-associated disorders, and neurodegenerative pathologies. Metabolic control and epigenetic- and posttranslational regulation of serine metabolism are also discussed. Given the metabolic similarities between cancer cells, neurons and germ cells, we further propose the relevance of serine metabolism in testicular homeostasis. Our work provides valuable hints for future investigations that will lead to a deeper understanding of serine and serine metabolism in cellular physiology and pathology.
    Keywords:  Cancer therapeutics; Mitochondrial-associated disorders; Neurodegenerative pathologies; Serine; Serine metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.129607
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