bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–03–10
fifty-one papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Identification of a novel MT-ND3 variant and restoring mitochondrial function by allotopic expression of MT-ND3 gene.
  2. The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.
  3. A case of mitochondrial myopathy and chronic progressive external ophthalmoplegia.
  4. Expanded clinical phenotype and untargeted metabolomics analysis in RARS2-related mitochondrial disorder: a case report.
  5. Hallmark Molecular and Pathological Features of POLG Disease are Recapitulated in Cerebral Organoids.
  6. Mitochondrial metabolism in neural stem cells and implications for neurodevelopmental and neurodegenerative diseases.
  7. Miro-mediated mitochondrial transport: A new dimension for disease-related abnormal cell metabolism?
  8. Two ancient membrane pores mediate mitochondrial-nucleus membrane contact sites.
  9. Mitochondrial DNA mutations in Korean patients with Leber's hereditary optic neuropathy.
  10. Mitochondrial DNA marks multiple sclerosis.
  11. How and When to Measure Mitochondrial Inner Membrane Potentials.
  12. Generation of a human induced pluripotent stem cell line NTUHi004-A from a patient with Leigh syndrome harboring a homozygous missense mutation c.836 T > G (p.Met279Arg) in NDUFAF5 gene.
  13. Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization.
  14. Charcot-Marie-tooth disease type 2A: An update on pathogenesis and therapeutic perspectives.
  15. Mitochondrial dysfunction in the pathophysiology of renal diseases.
  16. Mitochondrial calcium: An essential element for skeletal muscle performance and function.
  17. The lysosomal β-glucocerebrosidase strikes mitochondria: implications for Parkinson's therapeutics.
  18. How mitochondrial cristae illuminate the important role of oxygen during eukaryogenesis.
  19. A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.
  20. Activity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo.
  21. Kinase signalling adaptation supports dysfunctional mitochondria in disease.
  22. The Mst1/2-BNIP3 axis is required for mitophagy induction and neuronal viability under mitochondrial stress.
  23. Intraoperative management during liver transplantation in the child with mitochondrial depletion syndrome: A case report.
  24. Mitochondrial myopathies diagnosed in adulthood: clinico-genetic spectrum and long-term outcomes.
  25. Sudden death in non-syndromic mitochondrial disorders due to m.3243A > G may not only be cardiogenic.
  26. Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders.
  27. Ribosome Profiling and Mass Spectrometry Reveal Widespread Mitochondrial Translation Defects in a Striatal Cell Model of Huntington Disease.
  28. Absence of both MGME1 and POLG EXO abolishes mtDNA whereas absence of either creates unique mtDNA duplications.
  29. ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes.
  30. Exome and genome sequencing in a heterogeneous population of patients with rare disease: Identifying predictors of a diagnosis.
  31. A review of fatty acid oxidation disorder mouse models.
  32. Localization of RNAs to the Mitochondria - Mechanisms and Functions.
  33. Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.
  34. Mechanism of proton-powered c-ring rotation in a mitochondrial ATP synthase.
  35. Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options.
  36. Mitochondrial DNA mutations in extremely preterm infants with bronchopulmonary dysplasia.
  37. Loss of CHCHD2 Stability Coordinates with C1QBP/CHCHD2/CHCHD10 Complex Impairment to Mediate PD-Linked Mitochondrial Dysfunction.
  38. NDUFS4 regulates cristae remodeling in diabetic kidney disease.
  39. Loss of WIPI4 in neurodegeneration causes autophagy-independent ferroptosis.
  40. International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis.
  41. Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome.
  42. LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling in C. elegans.
  43. An unexpected journey for BNIP3.
  44. Interplay between mitochondrial dysfunction and lysosomal storage: challenges in genetic metabolic muscle diseases with a focus on infantile onset Pompe disease.
  45. Nanopore DNA sequencing technologies and their applications towards single-molecule proteomics.
  46. A Mammalian-Based Synthetic Biology Toolbox to Engineer Membrane-Membrane Interfaces.
  47. The mystery of methylmercury-perturbed calcium homeostasis: AMPK-DRP1-dependent mitochondrial fission initiates ER-mitochondria contact formation.
  48. Fat infiltration in skeletal muscle: Influential triggers and regulatory mechanism.
  49. Genebe.net: Implementation and validation of an automatic ACMG variant pathogenicity criteria assignment.
  50. Organoids grown from amniotic fluid could shed light on rare diseases.
  51. Developing a GNN-based AI model to predict mitochondrial toxicity using the bagging method.
  1. Mitochondrion. 2024 Mar 02. pii: S1567-7249(24)00016-3. [Epub ahead of print] 101858
    Identification of a novel MT-ND3 variant and restoring mitochondrial function by allotopic expression of MT-ND3 gene.
    Nurun Nahar Borna, Yoshihito Kishita, Masaru Shimura, Kei Murayama, Akira Ohtake, Yasushi Okazaki.
      Mitochondrial diseases are caused by nuclear, or mitochondrial DNA (mtDNA) variants and related co-factors. Here, we report a novel m.10197G > C variant in MT-ND3 in a patient, and two other patients with m.10191 T > C. MT-ND3 variants are known to cause Leigh syndrome or mitochondrial complex I deficiency. We performed the functional analyses of the novel m.10197G > C variant that significantly lowered MT-ND3 protein levels, causing complex I assembly and activity deficiency, and reduction of ATP synthesis. We adapted a previously described re-engineering technique of delivering mitochondrial genes into mitochondria through codon optimization for nuclear expression and translation by cytoplasmic ribosomes to rescue defects arising from the MT-ND3 variants. We constructed mitochondrial targeting sequences along with the codon-optimized MT-ND3 and imported them into the mitochondria. To achieve the goal, we imported codon-optimized MT-ND3 into mitochondria in three patients with m.10197G > C and m.10191 T > C missense variants in the MT-ND3. Nuclear expression of the MT-ND3 gene partially restored protein levels, complex I deficiency, and significant improvement of ATP production indicating a functional rescue of the mutant phenotype. The codon-optimized nuclear expression of mitochondrial protein and import inside the mitochondria can supplement the requirements for ATP in energy-deficient mitochondrial disease patients.
    Keywords:  Allotopic expression; Codon-optimization; Leigh Syndrome; MT-ND3; Mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.mito.2024.101858
  2. Semin Cell Dev Biol. 2024 Mar 01. pii: S1084-9521(24)00022-3. [Epub ahead of print]161-162 1-19
    The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.
    Alice Lacombe, Luca Scorrano.
      The complex relationship between mitochondrial dynamics and autophagy illustrates how two cellular housekeeping processes are intimately linked, illuminating fundamental principles of cellular homeostasis and shedding light on disparate pathological conditions including several neurodegenerative disorders. Here we review the basic tenets of mitochondrial dynamics i.e., the concerted balance between fusion and fission of the organelle, and its interplay with macroautophagy and selective mitochondrial autophagy, also dubbed mitophagy, in the maintenance of mitochondrial quality control and ultimately in cell viability. We illustrate how conditions of altered mitochondrial dynamics reverberate on autophagy and vice versa. Finally, we illustrate how altered interplay between these two key cellular processes participates in the pathogenesis of human disorders affecting multiple organs and systems.
    Keywords:  Mitochondria; autophagy; diseases; fusion-fission; mitophagy
    DOI:  https://doi.org/10.1016/j.semcdb.2024.02.001
  3. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2023 Nov 28. pii: 1672-7347(2023)11-1760-09. [Epub ahead of print]48(11): 1760-1768
    A case of mitochondrial myopathy and chronic progressive external ophthalmoplegia.
    Haokun Liu, Ming Gao, Qiying Sun, Si Chen, Yuebei Luo, Huan Yang, Qiuxiang Li, Jing Li, Guang Yang.
      Mitochondrial myopathy is a group of multi-system diseases in which mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) defects lead to structural and functional dysfunction of mitochondria. The clinical manifestations of mitochondrial myopathy are complex and varied, and the testing for mtDNA and nDNA is not widely available, so misdiagnosis or missed diagnosis is common. Chronic progressive external ophthalmoplegia (CPEO) is a common type of mitochondrial myopathy, which is characterized by blepharoptosis. Here we report a 38-year-old female with mitochondrial myopathy presented with chronic numbness and weakness of the limbs, accompanied by blepharoptosis that was recently noticed. Laboratory and head magnetic resonance imaging (MRI) examinations showed no obvious abnormalities. Muscle and nerve biopsies showed characteristic ragged red fibers (RRFs) and large aggregates of denatured mitochondria. Testing for mtDNA and nDNA showed a known mutation c.2857C>T (p.R953C) and a novel variant c.2391G>C (p.M797I) in the polymerase gamma (POLG)gene, so the patient was diagnosed as mitochondrial myopathy. Clinicians should pay more attention to long-term unexplained skeletal muscle diseases with recent onset blepharoptosis. Histopathologic examination and genetic testing are of great value in the early diagnosis and therapeutic intervention.
    Keywords:  blepharoptosis; histopathologic examination; mitochondrial DNA; mitochondrial myopathy; nuclear DNA
    DOI:  https://doi.org/10.11817/j.issn.1672-7347.2023.220605
  4. BMC Neurol. 2024 Mar 04. 24(1): 87
    Expanded clinical phenotype and untargeted metabolomics analysis in RARS2-related mitochondrial disorder: a case report.
    Ameya S Walimbe, Keren Machol, Stephen F Kralik, Elizabeth A Mizerik, Yoel Gofin, Mir Reza Bekheirnia, Charul Gijavanekar, Sarah H Elsea, Lisa T Emrick, Fernando Scaglia.
       BACKGROUND: RARS2-related mitochondrial disorder is an autosomal recessive mitochondrial encephalopathy caused by biallelic pathogenic variants in the gene encoding the mitochondrial arginyl-transfer RNA synthetase 2 (RARS2, MIM *611524, NM_020320.5). RARS2 catalyzes the transfer of L-arginine to its cognate tRNA during the translation of mitochondrially-encoded proteins. The classical presentation of RARS2-related mitochondrial disorder includes pontocerebellar hypoplasia (PCH), progressive microcephaly, profound developmental delay, feeding difficulties, and hypotonia. Most patients also develop severe epilepsy by three months of age, which consists of focal or generalized seizures that frequently become pharmacoresistant and lead to developmental and epileptic encephalopathy (DEE).
    CASE PRESENTATION: Here, we describe a six-year-old boy with developmental delay, hypotonia, and failure to thrive who developed an early-onset DEE consistent with Lennox-Gastaut Syndrome (LGS), which has not previously been observed in this disorder. He had dysmorphic features including bilateral macrotia, overriding second toes, a depressed nasal bridge, retrognathia, and downslanting palpebral fissures, and he did not demonstrate progressive microcephaly. Whole genome sequencing identified two variants in RARS2, c.36 + 1G > T, a previously unpublished variant that is predicted to affect splicing and is, therefore, likely pathogenic and c.419 T > G (p.Phe140Cys), a known pathogenic variant. He exhibited significant, progressive generalized brain atrophy and ex vacuo dilation of the supratentorial ventricular system on brain MRI and did not demonstrate PCH. Treatment with a ketogenic diet (KD) reduced seizure frequency and enabled him to make developmental progress. Plasma untargeted metabolomics analysis showed increased levels of lysophospholipid and sphingomyelin-related metabolites.
    CONCLUSIONS: Our work expands the clinical spectrum of RARS2-related mitochondrial disorder, demonstrating that patients can present with dysmorphic features and an absence of progressive microcephaly, which can help guide the diagnosis of this condition. Our case highlights the importance of appropriate seizure phenotyping in this condition and indicates that patients can develop LGS, for which a KD may be a viable therapeutic option. Our work further suggests that analytes of phospholipid metabolism may serve as biomarkers of mitochondrial dysfunction.
    Keywords:   RARS2 ; Dysmorphic features; Lennox-Gastaut Syndrome; Mitochondrial disease; Untargeted metabolomics analysis
    DOI:  https://doi.org/10.1186/s12883-024-03571-w
  5. Adv Sci (Weinh). 2024 Mar 06. e2307136
    Hallmark Molecular and Pathological Features of POLG Disease are Recapitulated in Cerebral Organoids.
    Anbin Chen, Tsering Yangzom, Yu Hong, Bjørn Christian Lundberg, Gareth John Sullivan, Charalampos Tzoulis, Laurence A Bindoff, Kristina Xiao Liang.
      In this research, a 3D brain organoid model is developed to study POLG-related encephalopathy, a mitochondrial disease stemming from POLG mutations. Induced pluripotent stem cells (iPSCs) derived from patients with these mutations is utilized to generate cortical organoids, which exhibited typical features of the diseases with POLG mutations, such as altered morphology, neuronal loss, and mitochondiral DNA (mtDNA) depletion. Significant dysregulation is also identified in pathways crucial for neuronal development and function, alongside upregulated NOTCH and JAK-STAT signaling pathways. Metformin treatment ameliorated many of these abnormalities, except for the persistent affliction of inhibitory dopamine-glutamate (DA GLU) neurons. This novel model effectively mirrors both the molecular and pathological attributes of diseases with POLG mutations, providing a valuable tool for mechanistic understanding and therapeutic screening for POLG-related disorders and other conditions characterized by compromised neuronal mtDNA maintenance and complex I deficiency.
    Keywords:  POLG; cortical organoids; iPSC; mitochondrial function; neuron
    DOI:  https://doi.org/10.1002/advs.202307136
  6. J Transl Med. 2024 Mar 04. 22(1): 238
    Mitochondrial metabolism in neural stem cells and implications for neurodevelopmental and neurodegenerative diseases.
    C Garone, F De Giorgio, S Carli.
      Mitochondria are cytoplasmic organelles having a fundamental role in the regulation of neural stem cell (NSC) fate during neural development and maintenance.During embryonic and adult neurogenesis, NSCs undergo a metabolic switch from glycolytic to oxidative phosphorylation with a rise in mitochondrial DNA (mtDNA) content, changes in mitochondria shape and size, and a physiological augmentation of mitochondrial reactive oxygen species which together drive NSCs to proliferate and differentiate. Genetic and epigenetic modifications of proteins involved in cellular differentiation (Mechanistic Target of Rapamycin), proliferation (Wingless-type), and hypoxia (Mitogen-activated protein kinase)-and all connected by the common key regulatory factor Hypoxia Inducible Factor-1A-are deemed to be responsible for the metabolic shift and, consequently, NSC fate in physiological and pathological conditions.Both primary mitochondrial dysfunction due to mutations in nuclear DNA or mtDNA or secondary mitochondrial dysfunction in oxidative phosphorylation (OXPHOS) metabolism, mitochondrial dynamics, and organelle interplay pathways can contribute to the development of neurodevelopmental or progressive neurodegenerative disorders.This review analyses the physiology and pathology of neural development starting from the available in vitro and in vivo models and highlights the current knowledge concerning key mitochondrial pathways involved in this process.
    Keywords:  HIF-1A; Mitochondrial metabolism; Neurodegenerative disorders; Neuronal development; Stem cells; Wnt; mTOR
    DOI:  https://doi.org/10.1186/s12967-024-05041-w
  7. Biochem Biophys Res Commun. 2024 Feb 27. pii: S0006-291X(24)00273-0. [Epub ahead of print]705 149737
    Miro-mediated mitochondrial transport: A new dimension for disease-related abnormal cell metabolism?
    Yanxing Li, Zhen Yang, Shumei Zhang, Jianjun Li.
      Mitochondria are versatile and highly dynamic organelles found in eukaryotic cells that play important roles in a variety of cellular processes. The importance of mitochondrial transport in cell metabolism, including variations in mitochondrial distribution within cells and intercellular transfer, has grown in recent years. Several studies have demonstrated that abnormal mitochondrial transport represents an early pathogenic alteration in a variety of illnesses, emphasizing its significance in disease development and progression. Mitochondrial Rho GTPase (Miro) is a protein found on the outer mitochondrial membrane that is required for cytoskeleton-dependent mitochondrial transport, mitochondrial dynamics (fusion and fission), and mitochondrial Ca2+ homeostasis. Miro, as a critical regulator of mitochondrial transport, has yet to be thoroughly investigated in illness. This review focuses on recent developments in recognizing Miro as a crucial molecule in controlling mitochondrial transport and investigates its roles in diverse illnesses. It also intends to shed light on the possibilities of targeting Miro as a therapeutic method for a variety of diseases.
    Keywords:  Cancer; Cell metabolism; Central nervous system disease; Miro; Mitochondrial transport; Tunneling nanotuble
    DOI:  https://doi.org/10.1016/j.bbrc.2024.149737
  8. J Cell Biol. 2024 Apr 01. pii: e202304075. [Epub ahead of print]223(4):
    Two ancient membrane pores mediate mitochondrial-nucleus membrane contact sites.
    Jana Ovciarikova, Shikha Shikha, Alice Lacombe, Flavie Courjol, Rosalind McCrone, Wasim Hussain, Andrew Maclean, Leandro Lemgruber, Erica S Martins-Duarte, Mathieu Gissot, Lilach Sheiner.
      Coordination between nucleus and mitochondria is essential for cell survival, and thus numerous communication routes have been established between these two organelles over eukaryotic cell evolution. One route for organelle communication is via membrane contact sites, functional appositions formed by molecular tethers. We describe a novel nuclear-mitochondrial membrane contact site in the protozoan Toxoplasma gondii. We have identified specific contacts occurring at the nuclear pore and demonstrated an interaction between components of the nuclear pore and the mitochondrial protein translocon, highlighting them as molecular tethers. Genetic disruption of the nuclear pore or the TOM translocon components, TgNup503 or TgTom40, respectively, result in contact site reduction, supporting their potential involvement in this tether. TgNup503 depletion further leads to specific mitochondrial morphology and functional defects, supporting a role for nuclear-mitochondrial contacts in mediating their communication. The discovery of a contact formed through interaction between two ancient mitochondrial and nuclear complexes sets the ground for better understanding of mitochondrial-nuclear crosstalk in eukaryotes.
    DOI:  https://doi.org/10.1083/jcb.202304075
  9. Sci Rep. 2024 Mar 08. 14(1): 5702
    Mitochondrial DNA mutations in Korean patients with Leber's hereditary optic neuropathy.
    Hee Kyung Yang, Moon-Woo Seong, Jeong-Min Hwang.
      In order to explore the spectrum of mitochondrial DNA (mtDNA) mutations in Korean patients with Leber's hereditary optic neuropathy (LHON), we investigated the spectrum of mtDNA mutations in 145 Korean probands confirmed with the diagnosis of LHON. Total genomic DNA was isolated from the peripheral blood leukocytes of the patients with suspected LHON, and mtDNA mutations were identified by direct sequencing. Analysis of mtDNA mutations revealed seven primary LHON mutations including the nucleotide positions (nps) 11778A (101 probands, 69.2%), 14484C (31 probands, 21.2%), 3460A (5 probands, 3.4%), and G3635A, G3733A, C4171A, and G13051A mutations in one proband each. In addition, two provisional mtDNA mutations at nps T3472C, and G13259A were each found in one proband, respectively. Another provisional mtDNA mutation at np T3394C was found in two probands. In conclusion, the spectrum of mtDNA mutations in Korean patients with LHON may differ from other ethnicities, which is characterized by high prevalence of 11778A and 14484C mutations, and a low prevalence of the 3460A mutation.
    Keywords:  Koreans; Leber’s hereditary optic neuropathy; Mitochondrial DNA mutation; Spectrum
    DOI:  https://doi.org/10.1038/s41598-024-56215-x
  10. Nat Rev Neurol. 2024 Mar 05.
    Mitochondrial DNA marks multiple sclerosis.
    Ian Fyfe.
      
    DOI:  https://doi.org/10.1038/s41582-024-00948-w
  11. Biophys J. 2024 Mar 06. pii: S0006-3495(24)00176-0. [Epub ahead of print]
    How and When to Measure Mitochondrial Inner Membrane Potentials.
    Alicia J Kowaltowski, Fernando Abdulkader.
      The scientific literature on mitochondria has increased significantly over the years, due to findings that these organelles have widespread roles in the onset and progression of pathological conditions such as metabolic disorders, neurodegenerative and cardiovascular diseases, inflammation, and cancer. Researchers have extensively explored how mitochondrial properties and functions are modified in different models, often using fluorescent inner mitochondrial membrane potential (ΔΨm) probes to assess functional mitochondrial aspects such as protonmotive force and oxidative phosphorylation. This review provides an overview of existing techniques to measure ΔpH and ΔΨm, highlighting their advantages, limitations, and applications. It discusses drawbacks of ΔΨm probes, especially when used without calibration, and conditions where alternative methods should replace ΔΨm measurements for the benefit of the specific scientific objectives entailed. Studies investigating mitochondria and their vast biological roles would be significantly advanced by the understanding of the correct applications as well as limitations of protonmotive force measurements and use of fluorescent ΔΨm probes, adopting more precise, artifact-free, sensitive, and quantitative measurements of mitochondrial functionality.
    DOI:  https://doi.org/10.1016/j.bpj.2024.03.011
  12. Stem Cell Res. 2024 Mar 05. pii: S1873-5061(24)00077-1. [Epub ahead of print]76 103379
    Generation of a human induced pluripotent stem cell line NTUHi004-A from a patient with Leigh syndrome harboring a homozygous missense mutation c.836 T > G (p.Met279Arg) in NDUFAF5 gene.
    Chih-Hsin Ou-Yang, Pin-Shiuan Chen, Chin-Hsien Lin.
      Leigh syndrome is a rare autosomal recessive disorder showcasing a diverse range of neurological symptoms. Classical Leigh syndrome is associated with mitochondrial complex I deficiency, primarily resulting from biallelic mutations in the NDUFAF5 gene, encoding the NADH:ubiquinone oxidoreductase complex assembly factor 5. Using the Sendai virus delivery system, we generated an induced pluripotent stem cell line from peripheral blood mononuclear cells of a 47-years-old female patient who carried a homozygous NDUFAF5 c.836 T > G (p.Met279Arg) mutation. This cellular model serves as a tool for investigating the underlying pathogenic mechanisms and for the development of potential treatments for Leigh syndrome.
    DOI:  https://doi.org/10.1016/j.scr.2024.103379
  13. Cell Metab. 2024 Mar 01. pii: S1550-4131(24)00057-3. [Epub ahead of print]
    Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization.
    Dingfeng Li, Xinyi Gao, Xiaolin Ma, Ming Wang, Chuandong Cheng, Tian Xue, Feng Gao, Yong Shen, Juan Zhang, Qiang Liu.
      Mitochondrial cristae, infoldings of the mitochondrial inner membrane, undergo aberrant changes in their architecture with age. However, the underlying molecular mechanisms and their contribution to brain aging are largely elusive. Here, we observe an age-dependent accumulation of Glu-5'tsRNA-CTC, a transfer-RNA-derived small RNA (tsRNA), derived from nuclear-encoded tRNAGlu in the mitochondria of glutaminergic neurons. Mitochondrial Glu-5'tsRNA-CTC disrupts the binding of mt-tRNALeu and leucyl-tRNA synthetase2 (LaRs2), impairing mt-tRNALeu aminoacylation and mitochondria-encoded protein translation. Mitochondrial translation defects disrupt cristae organization, leading to damaged glutaminase (GLS)-dependent glutamate formation and reduced synaptosomal glutamate levels. Moreover, reduction of Glu-5'tsRNA-CTC protects aged brains from age-related defects in mitochondrial cristae organization, glutamate metabolism, synaptic structures, and memory. Thus, beyond illustrating a physiological role for normal mitochondrial cristae ultrastructure in maintaining glutamate levels, our study defines a pathological role for tsRNAs in brain aging and age-related memory decline.
    Keywords:  angiogenin; brain aging; cristae organization; glutamate metabolism; memory decline; mitochondria; mitochondrial translation; tRNA-derived small RNAs
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.011
  14. Neurobiol Dis. 2024 Mar 05. pii: S0969-9961(24)00066-4. [Epub ahead of print] 106467
    Charcot-Marie-tooth disease type 2A: An update on pathogenesis and therapeutic perspectives.
    Claudia Alberti, Federica Rizzo, Alessia Anastasia, Giacomo Comi, Stefania Corti, Elena Abati.
      Mutations in the gene encoding MFN2 have been identified as associated with Charcot-Marie-Tooth disease type 2A (CMT2A), a neurological disorder characterized by a broad clinical phenotype involving the entire nervous system. MFN2, a dynamin-like GTPase protein located on the outer mitochondrial membrane, is well-known for its involvement in mitochondrial fusion. Numerous studies have demonstrated its participation in a network crucial for various other mitochondrial functions, including mitophagy, axonal transport, and its controversial role in endoplasmic reticulum (ER)-mitochondria contacts. Considerable progress has been made in the last three decades in elucidating the disease pathogenesis, aided by the generation of animal and cellular models that have been instrumental in studying disease physiology. A review of the literature reveals that, up to now, no definitive pharmacological treatment for any CMT2A variant has been established; nonetheless, recent years have witnessed substantial progress. Many treatment approaches, especially concerning molecular therapy, such as histone deacetylase inhibitors, peptide therapy to increase mitochondrial fusion, the new therapeutic strategies based on MF1/MF2 balance, and SARM1 inhibitors, are currently in preclinical testing. The literature on gene silencing and gene replacement therapies is still limited, except for a recent study by Rizzo et al.(Rizzo et al., 2023), which recently first achieved encouraging results in in vitro and in vivo models of the disease. The near-future goal for these promising therapies is to progress to the stage of clinical translation.
    Keywords:  CMT2A; MFN2; Mitofusin 2; Pathogenesis; Treatment
    DOI:  https://doi.org/10.1016/j.nbd.2024.106467
  15. Am J Physiol Renal Physiol. 2024 Mar 07.
    Mitochondrial dysfunction in the pathophysiology of renal diseases.
    Yuxian Guo, Ruochen Che, Peipei Wang, Aihua Zhang.
      Mitochondria are essential organelles in the human body, serving as the metabolic factory of the whole organism. When mitochondria are dysfunctional, it can affect all organs of the body. The kidney is rich in mitochondria, and its function is closely related to the development of kidney diseases. Studying the relationship between mitochondria and kidney disease progression is of great interest. In the past decade, scientists have made inspiring progress in investigating the role of mitochondria in the pathophysiology of renal diseases. This article discusses various mechanisms for maintaining mitochondrial quality, including mitochondrial energetics, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial DNA repair, mitochondrial proteolysis and UPR, mitochondrial autophagy, mitochondria-derived vesicles, and mitocytosis. The article also highlights the crosstalk between mitochondria and other organelles, with a focus on kidney diseases. Finally, the article concludes with an overview of mitochondrial-related clinical research.
    DOI:  https://doi.org/10.1152/ajprenal.00189.2023
  16. J Physiol. 2024 Mar 04.
    Mitochondrial calcium: An essential element for skeletal muscle performance and function.
    Jaydeep Sharma, Somnath Mondal, Mahima Kumari.
      
    Keywords:  MCU; MICU; calcium; fibre type; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1113/JP286218
  17. Brain. 2024 Mar 04. pii: awae070. [Epub ahead of print]
    The lysosomal β-glucocerebrosidase strikes mitochondria: implications for Parkinson's therapeutics.
    Juan Carlos Rubilar, Tiago Fleming Outeiro, Andrés D Klein.
      Parkinson's disease (PD) is a neurodegenerative disorder primarily known for typical motor features that arise due to the loss of dopaminergic neurons in the substantia nigra. However, the precise molecular etiology of the disease is still unclear. Several cellular pathways have been linked to PD, including the autophagy-lysosome pathway (ALP), α-synuclein (α-syn) aggregation, and mitochondrial function. Interestingly, the mechanistic link between GBA1, the gene that encodes for lysosomal β-glucocerebrosidase (GCase), and PD lies in the interplay between GCase functions in the lysosome and mitochondria. GCase mutations alter mitochondria-lysosome contact sites. In the lysosome, reduced GCase activity leads to glycosphingolipid buildup, disrupting lysosomal function and autophagy, thereby triggering α-syn accumulation. Additionally, α-syn aggregates reduce GCase activity, creating a self-perpetuating cycle of lysosomal dysfunction and α-syn accumulation. GCase can also be imported into the mitochondria, where it promotes the integrity and function of mitochondrial complex I. Thus, GCase mutations that impair its normal function increase oxidative stress in mitochondria, the compartment where dopamine is oxidized. In turn, the accumulation of oxidized dopamine-adducts further impairs GCase activity, creating a second cycle of GCase dysfunction. The oxidative state triggered by GCase dysfunction can also induce mitochondrial DNA damage which, in turn, can cause dopaminergic cell death. In this review, we highlight the pivotal role of GCase in PD pathogenesis and discuss promising examples of GCase-based therapeutics such as gene and enzyme replacement therapies, small molecule chaperones, and substrate reduction therapies, among others, as potential therapeutic interventions.
    Keywords:  Gaucher’s disease; Parkinson’s disease; lysosome; mitochondria; neurodegeneration; therapeutics
    DOI:  https://doi.org/10.1093/brain/awae070
  18. Bioessays. 2024 Mar 06. e2300193
    How mitochondrial cristae illuminate the important role of oxygen during eukaryogenesis.
    Dave Speijer.
      Inner membranes of mitochondria are extensively folded, forming cristae. The observed overall correlation between efficient eukaryotic ATP generation and the area of internal mitochondrial inner membranes both in unicellular organisms and metazoan tissues seems to explain why they evolved. However, the crucial use of molecular oxygen (O2 ) as final acceptor of the electron transport chain is still not sufficiently appreciated. O2 was an essential prerequisite for cristae development during early eukaryogenesis and could be the factor allowing cristae retention upon loss of mitochondrial ATP generation. Here I analyze illuminating bacterial and unicellular eukaryotic examples. I also discuss formative influences of intracellular O2 consumption on the evolution of the last eukaryotic common ancestor (LECA). These considerations bring about an explanation for the many genes coming from other organisms than the archaeon and bacterium merging at the start of eukaryogenesis.
    Keywords:  ROS; cristae; eukaryogenesis; mitochondria; molecular oxygen; symbiogenesis
    DOI:  https://doi.org/10.1002/bies.202300193
  19. Cell Stem Cell. 2024 Mar 07. pii: S1934-5909(24)00047-X. [Epub ahead of print]31(3): 359-377.e10
    A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.
    Massimo Bonora, Claudia Morganti, Nick van Gastel, Kyoko Ito, Enrica Calura, Ilaria Zanolla, Letizia Ferroni, Yang Zhang, Yookyung Jung, Gabriele Sales, Paolo Martini, Takahisa Nakamura, Francesco Massimo Lasorsa, Toren Finkel, Charles P Lin, Barbara Zavan, Paolo Pinton, Irene Georgakoudi, Chiara Romualdi, David T Scadden, Keisuke Ito.
      Mitochondrial fatty acid oxidation (FAO) is essential for hematopoietic stem cell (HSC) self-renewal; however, the mechanism by which mitochondrial metabolism controls HSC fate remains unknown. Here, we show that within the hematopoietic lineage, HSCs have the largest mitochondrial NADPH pools, which are required for proper HSC cell fate and homeostasis. Bioinformatic analysis of the HSC transcriptome, biochemical assays, and genetic inactivation of FAO all indicate that FAO-generated NADPH fuels cholesterol synthesis in HSCs. Interference with FAO disturbs the segregation of mitochondrial NADPH toward corresponding daughter cells upon single HSC division. Importantly, we have found that the FAO-NADPH-cholesterol axis drives extracellular vesicle (EV) biogenesis and release in HSCs, while inhibition of EV signaling impairs HSC self-renewal. These data reveal the existence of a mitochondrial NADPH-cholesterol axis for EV biogenesis that is required for hematopoietic homeostasis and highlight the non-stochastic nature of HSC fate determination.
    Keywords:  HSC self-renewal; NADPH; cholesterol; exosomes; extracellular vesicles; fate determination; fatty acid oxidation; hematopoietic stem cell; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.stem.2024.02.004
  20. Nat Commun. 2024 Mar 08. 15(1): 2142
    Activity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo.
    Daniel M Virga, Stevie Hamilton, Bertha Osei, Abigail Morgan, Parker Kneis, Emiliano Zamponi, Natalie J Park, Victoria L Hewitt, David Zhang, Kevin C Gonzalez, Fiona M Russell, D Grahame Hardie, Julien Prudent, Erik Bloss, Attila Losonczy, Franck Polleux, Tommy L Lewis.
      Neuronal mitochondria play important roles beyond ATP generation, including Ca2+ uptake, and therefore have instructive roles in synaptic function and neuronal response properties. Mitochondrial morphology differs significantly between the axon and dendrites of a given neuronal subtype, but in CA1 pyramidal neurons (PNs) of the hippocampus, mitochondria within the dendritic arbor also display a remarkable degree of subcellular, layer-specific compartmentalization. In the dendrites of these neurons, mitochondria morphology ranges from highly fused and elongated in the apical tuft, to more fragmented in the apical oblique and basal dendritic compartments, and thus occupy a smaller fraction of dendritic volume than in the apical tuft. However, the molecular mechanisms underlying this striking degree of subcellular compartmentalization of mitochondria morphology are unknown, precluding the assessment of its impact on neuronal function. Here, we demonstrate that this compartment-specific morphology of dendritic mitochondria requires activity-dependent, Ca2+ and Camkk2-dependent activation of AMPK and its ability to phosphorylate two direct effectors: the pro-fission Drp1 receptor Mff and the recently identified anti-fusion, Opa1-inhibiting protein, Mtfr1l. Our study uncovers a signaling pathway underlying the subcellular compartmentalization of mitochondrial morphology in dendrites of neurons in vivo through spatially precise and activity-dependent regulation of mitochondria fission/fusion balance.
    DOI:  https://doi.org/10.1038/s41467-024-46463-w
  21. Front Mol Biosci. 2024 ;11 1354682
    Kinase signalling adaptation supports dysfunctional mitochondria in disease.
    George L Skalka, Mina Tsakovska, Daniel J Murphy.
      Mitochondria form a critical control nexus which are essential for maintaining correct tissue homeostasis. An increasing number of studies have identified dysregulation of mitochondria as a driver in cancer. However, which pathways support and promote this adapted mitochondrial function? A key hallmark of cancer is perturbation of kinase signalling pathways. These pathways include mitogen activated protein kinases (MAPK), lipid secondary messenger networks, cyclic-AMP-activated (cAMP)/AMP-activated kinases (AMPK), and Ca2+/calmodulin-dependent protein kinase (CaMK) networks. These signalling pathways have multiple substrates which support initiation and persistence of cancer. Many of these are involved in the regulation of mitochondrial morphology, mitochondrial apoptosis, mitochondrial calcium homeostasis, mitochondrial associated membranes (MAMs), and retrograde ROS signalling. This review will aim to both explore how kinase signalling integrates with these critical mitochondrial pathways and highlight how these systems can be usurped to support the development of disease. In addition, we will identify areas which require further investigation to fully understand the complexities of these regulatory interactions. Overall, this review will emphasize how studying the interaction between kinase signalling and mitochondria improves our understanding of mitochondrial homeostasis and can yield novel therapeutic targets to treat disease.
    Keywords:  apoptosis; disease adaptation; kinase; mitochondria; mitochondrial associated endoplasmic reticulum membranes (MAMs); mitochondrial morphology; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.3389/fmolb.2024.1354682
  22. Exp Mol Med. 2024 Mar 05.
    The Mst1/2-BNIP3 axis is required for mitophagy induction and neuronal viability under mitochondrial stress.
    Dae Jin Jeong, Jee-Hyun Um, Young Yeon Kim, Dong Jin Shin, Sangwoo Im, Kang-Min Lee, Yun-Hee Lee, Dae-Sik Lim, Donghoon Kim, Jeanho Yun.
      Mitophagy induction upon mitochondrial stress is critical for maintaining mitochondrial homeostasis and cellular function. Here, we found that Mst1/2 (Stk3/4), key regulators of the Hippo pathway, are required for the induction of mitophagy under various mitochondrial stress conditions. Knockdown of Mst1/2 or pharmacological inhibition by XMU-MP-1 treatment led to impaired mitophagy induction upon CCCP and DFP treatment. Mechanistically, Mst1/2 induces mitophagy independently of the PINK1-Parkin pathway and the canonical Hippo pathway. Moreover, our results suggest the essential involvement of BNIP3 in Mst1/2-mediated mitophagy induction upon mitochondrial stress. Notably, Mst1/2 knockdown diminishes mitophagy induction, exacerbates mitochondrial dysfunction, and reduces cellular survival upon neurotoxic stress in both SH-SY5Y cells and Drosophila models. Conversely, Mst1 and Mst2 expression enhances mitophagy induction and cell survival. In addition, AAV-mediated Mst1 expression reduced the loss of TH-positive neurons, ameliorated behavioral deficits, and improved mitochondrial function in an MPTP-induced Parkinson's disease mouse model. Our findings reveal the Mst1/2-BNIP3 regulatory axis as a novel mediator of mitophagy induction under conditions of mitochondrial stress and suggest that Mst1/2 play a pivotal role in maintaining mitochondrial function and neuronal viability in response to neurotoxic treatment.
    DOI:  https://doi.org/10.1038/s12276-024-01198-y
  23. Int J Surg Case Rep. 2024 Feb 23. pii: S2210-2612(24)00213-X. [Epub ahead of print]116 109432
    Intraoperative management during liver transplantation in the child with mitochondrial depletion syndrome: A case report.
    Lu Che, Yuli Wu, Mingwei Sheng, Jiangang Xu, Wenli Yu, Yiqi Weng.
       INTRODUCTION: Mitochondrial DNA depletion syndrome (MDS) is a kind of autosomal recessive genetic disorder associated with a reduction in mitochondrial DNA (mtDNA) copy number caused by mutations in nuclear genes during nucleotide synthesis, which affects the energy production of tissues and organs. Changes in hemodynamics during liver transplantation may lead to high energy-demanding organs and tissues being vulnerable. This report described the intraoperative management during liver transplantation in a child with MDS. Ultimately, the child was discharged smoothly without any complications.
    PRESENTATION OF THE CASE: A five-year-old boy was diagnosed with mitochondrial depletion syndrome preoperatively and scheduled for living donor liver transplantation. The incidence of postreperfusion syndrome (PRS) could not be avoided for 30 min after opening, despite our best efforts to aggressively prevent it before opening. While ensuring hemodynamic stability, we actively prevented and adopted high-energy-demand organ protection strategies to reduce the incidence of postoperative complications. Finally, the child was discharged 28 days after the operation, and no other complications were found.
    DISCUSSION: Liver transplantation can be performed for liver failure in this disease to improve the quality of life and prolong the life of patients. As this child has mitochondrial DNA depletion syndrome, the disruption of cellular energy generation caused by mitochondrial malfunction puts high-energy-demanding organs and tissues at risk during surgery. It motivates us to pay closer attention to the prevention and treatment of PRS in anesthetic management to minimize damage to the child's organs and tissues with high energy demands.
    CONCLUSIONS: This report describes the intraoperative management during liver transplantation in a child with mitochondrial depletion syndrome. To increase the safety of perioperative anesthesia and reduce mortality in patients with mitochondrial disease, for such patients, maintaining an acid-base balance and a stable internal environment is essential. We should also pay attention to protecting body temperature, using vasoactive drugs beforehand to lessen the incidence of PRS, and protecting high-energy-demanding organs afterward.
    Keywords:  Case report; Intraoperative management; Liver transplantation; Mitochondrial depletion syndrome
    DOI:  https://doi.org/10.1016/j.ijscr.2024.109432
  24. Brain Commun. 2024 ;6(2): fcae041
    Mitochondrial myopathies diagnosed in adulthood: clinico-genetic spectrum and long-term outcomes.
    Grayson Beecher, Ralitza H Gavrilova, Jay Mandrekar, Elie Naddaf.
      Mitochondrial myopathies are frequently recognized in childhood as part of a broader multisystem disorder and often overlooked in adulthood. Herein, we describe the phenotypic and genotypic spectrum and long-term outcomes of mitochondrial myopathies diagnosed in adulthood, focusing on neuromuscular features, electrodiagnostic and myopathological findings and survival. We performed a retrospective chart review of adult patients diagnosed with mitochondrial myopathy at Mayo Clinic (2005-21). We identified 94 patients. Median time from symptom onset to diagnosis was 11 years (interquartile range 4-21 years). Median age at diagnosis was 48 years (32-63 years). Primary genetic defects were identified in mitochondrial DNA in 48 patients (10 with single large deletion, 38 with point mutations) and nuclear DNA in 29. Five patients had multiple mitochondrial DNA deletions or depletion without nuclear DNA variants. Twelve patients had histopathological features of mitochondrial myopathy without molecular diagnosis. The most common phenotypes included multisystem disorder (n = 30); mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (14); limb myopathy (13); chronic progressive external ophthalmoplegia (12); and chronic progressive external ophthalmoplegia-plus (12). Isolated skeletal muscle manifestations occurred in 27%. Sixty-nine per cent had CNS and 21% had cardiac involvement. Mutations most frequently involved MT-TL1 (27) and POLG (17); however, a wide spectrum of established and novel molecular defects, with overlapping phenotypes, was identified. Electrodiagnostic studies identified myopathy (77%), fibrillation potentials (27%) and axonal peripheral neuropathy (42%, most common with nuclear DNA variants). Among 42 muscle biopsies available, median percentage counts were highest for cytochrome C oxidase negative fibres (5.1%) then ragged blue (1.4%) and ragged red fibres (0.5%). Skeletal muscle weakness was mild and slowly progressive (decline in strength summated score of 0.01/year). Median time to gait assistance was 5.5 years from diagnosis and 17 years from symptom onset. Thirty patients died, with median survival of 33.4 years from symptom onset and 10.9 years from diagnosis. Median age at death was 55 years. Cardiac involvement was associated with increased mortality [hazard ratio 2.36 (1.05, 5.29)]. There was no difference in survival based on genotype or phenotype. Despite the wide phenotypic and genotypic spectrum, mitochondrial myopathies in adults share similar features with slowly progressive limb weakness, contrasting with common multiorgan involvement and high mortality.
    Keywords:  MELAS; POLG; chronic progressive external ophthalmoplegia; inherited myopathies; mitochondrial myopathies
    DOI:  https://doi.org/10.1093/braincomms/fcae041
  25. Cardiol Young. 2024 Mar 06. 1-2
    Sudden death in non-syndromic mitochondrial disorders due to m.3243A > G may not only be cardiogenic.
    Josef Finsterer, Sounira Mehri, Sinda Zarrouk.
      
    Keywords:  Mitochondrial DNA; cardiomyopathy; heteroplasmy; m.3243A > G; sudden death
    DOI:  https://doi.org/10.1017/S1047951124000234
  26. Genet Med. 2024 Mar 05. pii: S1098-3600(24)00050-9. [Epub ahead of print] 101117
    Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders.
    Camila Armirola-Ricaurte, Noortje Zonnekein, Georgios Koutsis, Silvia Amor-Barris, Ana Lara Pelayo-Negro, Derek Atkinson, Stephanie Efthymiou, Valentina Turchetti, Argyris Dinopoulos, Antonio Garcia, Mert Karakaya, German Moris, Ayşe Ipek Polat, Uluc Yis, Carmen Espinos, Liedewei Van de Vondel, Els De Vriendt, Georgia Karadima, Brunhilde Wirth, Michael Hanna, Henry Houlden, Jose Berciano, Albena Jordanova.
       PURPOSE: We describe three families with Charcot-Marie-Tooth neuropathy (CMT), harboring a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant previously linked to fatal Leigh syndrome. We aimed to characterize clinically and molecularly the newly identified patients and understand the mechanism underlying their milder phenotype.
    METHODS: The patients underwent extensive clinical examinations. Exome sequencing was done in four affected individuals. The functional effect of the c.309+5G>A variant was investigated in patient-derived EBV-transformed lymphoblasts at the cDNA, protein and mitochondrial level. Alternative splicing was evaluated using cDNA long-read sequencing.
    RESULTS: All patients presented with early-onset, slowly progressive axonal CMT and nystagmus; some exhibited additional central nervous system symptoms. The c.309+5G>A substitution caused the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Immunoblotting showed reduced levels of mutant isoforms. No detectable defects in mitochondrial complex stability or bioenergetics were found.
    CONCLUSION: We expand the clinical spectrum of NDUFS6-related mitochondrial disorders to include axonal CMT, emphasizing the clinical and pathophysiologic overlap between these two clinical entities. This work demonstrates the critical role that alternative splicing may play in modulating the severity of a genetic disorder, emphasizing the need for careful consideration when interpreting splice variants and their implications on disease prognosis.
    Keywords:  Charcot-Marie-Tooth; NDUFS6; mitochondrial disorders; peripheral neuropathy; splicing
    DOI:  https://doi.org/10.1016/j.gim.2024.101117
  27. Mol Cell Proteomics. 2024 Mar 04. pii: S1535-9476(24)00036-7. [Epub ahead of print] 100746
    Ribosome Profiling and Mass Spectrometry Reveal Widespread Mitochondrial Translation Defects in a Striatal Cell Model of Huntington Disease.
    Sunayana Dagar, Manish Sharma, George Tsaprailis, Catherina Scharager Tapia, Gogce Crynen, Preksha Sandipkumar Joshi, Neelam Shahani, Srinivasa Subramaniam.
      Huntington disease (HD) is caused by an expanded polyglutamine mutation in huntingtin (mHTT) that promotes prominent atrophy in the striatum and subsequent psychiatric, cognitive, and choreiform movements. Multiple lines of evidence point to an association between HD and aberrant striatal mitochondrial functions; however, the present knowledge about whether (or how) mitochondrial mRNA translation is differentially regulated in HD remains unclear. We found that protein synthesis is diminished in HD mitochondria compared to healthy control striatal cell models. We utilized ribosome profiling (Ribo-Seq) to analyze detailed snapshots of ribosome occupancy of the mitochondrial mRNA transcripts in control and HD striatal cell models. The Ribo-Seq data revealed almost unaltered ribosome occupancy on the nuclear-encoded mitochondrial transcripts involved in oxidative phosphorylation (OXPHOS) (SDHA, Ndufv1, Timm23, Tomm5, Mrps22) in HD cells. By contrast, ribosome occupancy was dramatically increased for mitochondrially encoded OXPHOS mRNAs (mtNd-1, mtNd-2, mtNd-4, mtNd-4l, mtNd-5, mtNd-6, mt-Co1, mtCyt b, and mt-ATP8). We also applied tandem mass tag-based mass spectrometry (TMT-MS) identification of mitochondrial proteins to derive correlations between ribosome occupancy and actual mature mitochondrial protein products. We found many mitochondrial transcripts with comparable or higher ribosome occupancy, but diminished mitochondrial protein products, in HD. Thus, our study provides the first evidence of a widespread dichotomous effect on ribosome occupancy and protein turnover of mitochondria-related genes in HD.
    Keywords:  Dichotomy; abnormality; brain disease; cytoribosome; energy metabolism; mRNA translation; mitoribosome; oxidative stress; vulnerability
    DOI:  https://doi.org/10.1016/j.mcpro.2024.100746
  28. J Biol Chem. 2024 Mar 01. pii: S0021-9258(24)01623-5. [Epub ahead of print] 107128
    Absence of both MGME1 and POLG EXO abolishes mtDNA whereas absence of either creates unique mtDNA duplications.
    Christian D Gonzalez, Nadee Nissanka, Derek Van Booven, Anthony J Griswold, Carlos T Moraes.
      Both POLG and MGME1 are needed for mitochondrial DNA (mtDNA) maintenance in animal cells. POLG, the primary replicative polymerase of the mitochondria, has an exonuclease activity (3'→5') that corrects for the misincorporation of bases. MGME1 serves as an exonuclease (5'→3'), producing ligatable DNA ends. Although both have a critical role in mtDNA replication and elimination of linear fragments, these mechanisms are still not fully understood. Using digital PCR to evaluate and compare mtDNA integrity, we show that Mgme1 knock out (Mgme1 KK) tissue mtDNA is more fragmented than POLG exonuclease deficient "Mutator" (Polg MM) or WT tissue. In addition, next generation sequencing of mutant hearts showed abundant duplications in/nearby the D-loop region and unique 100bp duplications evenly spaced throughout the genome only in Mgme1 KK hearts. However, despite these unique mtDNA features at steady-state, we observed a similar delay in the degradation of mtDNA after an induced double strand DNA break in both Mgme1 KK and Polg MM models. Lastly, we characterized double mutant (Polg MM/Mgme1 KK) cells and show that mtDNA cannot be maintained without at least one of these enzymatic activities. We propose a model for the generation of these genomic abnormalities which suggests a role for MGME1 outside of nascent mtDNA end ligation. Our results highlight the role of MGME1 in and outside of the D-loop region during replication, support the involvement of MGME1 in dsDNA degradation and demonstrate that POLG EXO and MGME1 can partially compensate for each other in maintaining mtDNA.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107128
  29. Mol Genet Metab. 2024 Mar 02. pii: S1096-7192(24)00247-6. [Epub ahead of print]142(1): 108362
    ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes.
    Jennifer Goldstein, Amanda Thomas-Wilson, Emily Groopman, Vimla Aggarwal, Simona Bianconi, Raquel Fernandez, Kim Hart, Nicola Longo, Nicole Liang, Daniel Reich, Heidi Wallis, Meredith Weaver, Sarah Young, Saadet Mercimek-Andrews.
      Cerebral creatine deficiency syndromes (CCDS) are inherited metabolic phenotypes of creatine synthesis and transport. There are two enzyme deficiencies, guanidinoacetate methyltransferase (GAMT), encoded by GAMT and arginine-glycine amidinotransferase (AGAT), encoded by GATM, which are involved in the synthesis of creatine. After synthesis, creatine is taken up by a sodium-dependent membrane bound creatine transporter (CRTR), encoded by SLC6A8, into all organs. Creatine uptake is very important especially in high energy demanding organs such as the brain, and muscle. To classify the pathogenicity of variants in GAMT, GATM, and SLC6A8, we developed the CCDS Variant Curation Expert Panel (VCEP) in 2018, supported by The Clinical Genome Resource (ClinGen), a National Institutes of Health (NIH)-funded resource. We developed disease-specific variant classification guidelines for GAMT-, GATM-, and SLC6A8-related CCDS, adapted from the American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant interpretation guidelines. We applied specific variant classification guidelines to 30 pilot variants in each of the three genes that have variants associated with CCDS. Our CCDS VCEP was approved by the ClinGen Sequence Variant Interpretation Working Group (SVI WG) and Clinical Domain Oversight Committee in July 2022. We curated 181 variants including 72 variants in GAMT, 45 variants in GATM, and 64 variants in SLC6A8 and submitted these classifications to ClinVar, a public variant database supported by the National Center for Biotechnology Information. Missense variants were the most common variant type in all three genes. We submitted 32 new variants and reclassified 34 variants with conflicting interpretations. We report specific phenotype (PP4) using a points system based on the urine and plasma guanidinoacetate and creatine levels, brain magnetic resonance spectroscopy (MRS) creatine level, and enzyme activity or creatine uptake in fibroblasts ranging from PP4, PP4_Moderate and PP4_Strong. Our CCDS VCEP is one of the first panels applying disease specific variant classification algorithms for an X-linked disease. The availability of these guidelines and classifications can guide molecular genetics and genomic laboratories and health care providers to assess the molecular diagnosis of individuals with a CCDS phenotype.
    Keywords:  ACMG/AMP; Brain magnetic resonance spectroscopy; Cerebral creatine deficiency syndromes; Creatine; GAMT; GATM; Guanidinoacetate; SLC6A8
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108362
  30. Genet Med. 2024 Mar 01. pii: S1098-3600(24)00048-0. [Epub ahead of print] 101115
    Exome and genome sequencing in a heterogeneous population of patients with rare disease: Identifying predictors of a diagnosis.
    Undiagnosed Diseases Network
       PURPOSE: Exome (ES) and genome sequencing (GS) are increasingly being utilized for individuals with rare and undiagnosed diseases; however, guidelines on their use remain limited. This study aimed to identify factors associated with diagnosis by ES and/or GS in a heterogeneous population of patients with rare and undiagnosed diseases.
    METHODS: In this case control study, we reviewed data from 400 diagnosed and 400 undiagnosed randomly selected participants in the Undiagnosed Diseases Network (UDN), all of whom had undergone ES and/or GS. We analyzed factors associated with receiving a diagnosis by ES and/or GS.
    RESULTS: Factors associated with a decreased odds of being diagnosed included adult symptom onset, singleton sequencing, and having undergone ES and/or GS prior to acceptance to the UDN (48%, 51%, and 32% lower odds, respectively). Factors that increased the odds of being diagnosed by ES and/or GS included having primarily neurological symptoms and having undergone prior chromosomal microarray testing (44% and 59% higher odds, respectively).
    CONCLUSION: We identified several factors that were associated with receiving a diagnosis by ES and/or GS. This will ideally inform the utilization of ES and/or GS and help manage expectations of individuals and families undergoing these tests.
    Keywords:  exome sequencing; genome sequencing; predictors of a diagnosis; rare disease; undiagnosed disease
    DOI:  https://doi.org/10.1016/j.gim.2024.101115
  31. Mol Genet Metab. 2024 Feb 23. pii: S1096-7192(24)00236-1. [Epub ahead of print]142(1): 108351
    A review of fatty acid oxidation disorder mouse models.
    Shannon J Babcock, Sander M Houten, Melanie B Gillingham.
      Fatty acid oxidation disorders (FAODs) are a family of rare, genetic disorders that affect any part of the fatty acid oxidation pathway. Patients present with severe phenotypes, such as hypoketotic hypoglycemia, cardiomyopathy, and rhabdomyolysis, and currently manage these symptoms by the avoidance of fasting and maintaining a low-fat, high-carbohydrate diet. Because knowledge about FAODs is limited due to the small number of patients, rodent models have been crucial in learning more about these disorders, particularly in studying the molecular mechanisms involved in different phenotypes and in evaluating treatments for patients. The purpose of this review is to present the different FAOD mouse models and highlight the benefits and limitations of using these models. Specifically, we discuss the phenotypes of the available FAOD mouse models, the potential molecular causes of prominent FAOD phenotypes that have been studied using FAOD mouse models, and how FAOD mouse models have been used to evaluate treatments for patients.
    Keywords:  Cardiomyopathy; Exercise; Fatty acid β-oxidation; Gene addition; Hypoglycemia; Inborn errors of metabolism; Mouse models
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108351
  32. RNA. 2024 Mar 06. pii: rna.079999.124. [Epub ahead of print]
    Localization of RNAs to the Mitochondria - Mechanisms and Functions.
    Surbhi Sharma, Furqan M Fazal.
      The mammalian mitochondrial proteome comprises over 1000 proteins, with the majority translated from nuclear-encoded messenger RNAs (mRNAs). Mounting evidence suggests many of these mRNAs are localized to the outer mitochondrial membrane (OMM) in a pre-or co-translational state. Upon reaching the mitochondrial surface, these mRNAs are locally translated to produce proteins that are co-translationally imported into mitochondria. Here, we summarize various mechanisms cells employ to localize RNAs, including transfer RNAs (tRNAs), to the OMM and recent technological advancements in the field to study these processes. While most early studies in the field were carried out in yeast, recent studies reveal RNA localization to the OMM and their regulation in higher organisms. Various factors regulate this localization process, including RNA sequence elements, RNA binding proteins (RBPs), cytoskeletal motors, and translation machinery. In this review, we also highlight the role of RNA structures and modifications in mitochondrial RNA localization and discuss how these features can alter the binding properties of RNAs. Finally, in addition to RNAs related to mitochondrial function, RNAs involved in other cellular processes can also localize to the OMM, including those implicated in the innate immune response and piRNA biogenesis. As impairment of mRNA localization and regulation compromise mitochondrial function, future studies will undoubtedly expand our understanding of how RNAs localize to the OMM and investigate the consequences of their mislocalization in disorders, particularly neurodegenerative diseases, muscular dystrophies, and cancers.
    Keywords:  Imaging; Mitochondrial Biology; RNA Subcellular Localization; Technologies; Transcriptomics
    DOI:  https://doi.org/10.1261/rna.079999.124
  33. Nat Commun. 2024 Mar 02. 15(1): 1931
    Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.
    Martha M Zarou, Kevin M Rattigan, Daniele Sarnello, Engy Shokry, Amy Dawson, Angela Ianniciello, Karen Dunn, Mhairi Copland, David Sumpton, Alexei Vazquez, G Vignir Helgason.
      Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells. Consequently, changes in purine nucleotide levels lead to activation of AMPK signalling and suppression of mTORC1 activity. Notably, suppression of mitochondrial 1C metabolism increases expression of erythroid differentiation markers. Moreover, we find that increased differentiation occurs independently of AMPK signalling and can be reversed through reconstitution of purine levels and reactivation of mTORC1. Of clinical relevance, we identify that combination of 1C metabolism inhibition with imatinib, a frontline treatment for CML patients, decreases the number of therapy-resistant CML LSCs in a patient-derived xenograft model. Our results highlight a role for folate metabolism and purine sensing in stem cell fate decisions and leukaemogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-46114-0
  34. Proc Natl Acad Sci U S A. 2024 Mar 12. 121(11): e2314199121
    Mechanism of proton-powered c-ring rotation in a mitochondrial ATP synthase.
    Florian E C Blanc, Gerhard Hummer.
      Proton-powered c-ring rotation in mitochondrial ATP synthase is crucial to convert the transmembrane protonmotive force into torque to drive the synthesis of adenosine triphosphate (ATP). Capitalizing on recent cryo-EM structures, we aim at a structural and energetic understanding of how functional directional rotation is achieved. We performed multi-microsecond atomistic simulations to determine the free energy profiles along the c-ring rotation angle before and after the arrival of a new proton. Our results reveal that rotation proceeds by dynamic sliding of the ring over the a-subunit surface, during which interactions with conserved polar residues stabilize distinct intermediates. Ordered water chains line up for a Grotthuss-type proton transfer in one of these intermediates. After proton transfer, a high barrier prevents backward rotation and an overall drop in free energy favors forward rotation, ensuring the directionality of c-ring rotation required for the thermodynamically disfavored ATP synthesis. The essential arginine of the a-subunit stabilizes the rotated configuration through a salt bridge with the c-ring. Overall, we describe a complete mechanism for the rotation step of the ATP synthase rotor, thereby illuminating a process critical to all life at atomic resolution.
    Keywords:  ATP synthase; bioenergetics; c-ring; molecular dynamics simulations; rotary motor
    DOI:  https://doi.org/10.1073/pnas.2314199121
  35. JIMD Rep. 2024 Mar;65(2): 102-109
    Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options.
    Parith Wongkittichote, Cassandra Pantano, Miao He, Xinying Hong, Matthew M Demczko.
      Ferredoxin-2 (FDX2) is an electron transport protein required for iron-sulfur clusters biosynthesis. Pathogenic variants in FDX2 have been associated with autosomal recessive FDX2-related disorder characterized by mitochondrial myopathy with or without optic atrophy and leukoencephalopathy. We described a new case harboring compound heterozygous variants in FDX2 who presented with recurrent rhabdomyolysis with severe episodes affecting respiratory muscle. Biochemical analysis of the patients revealed hyperexcretion of 2-hydroxyadipic acid, along with previously reported biochemical abnormalities. The proband demonstrated increased lactate and creatine kinase (CK) with increased amount of glucose infusion. Lactate and CK drastically decreased when parenteral nutrition containing high protein and lipid contents with low glucose was initiated. Overall, we described a new case of FDX2-related disorder and compare clinical, biochemical and molecular findings with previously reported cases. We demonstrated that 2-hydroxyadipic acid biomarker could be used as an adjunct biomarker for FDX2-related disorder and the use of parenteral nutrition as a treatment option for the patient with FDX2-related disorder during rhabdomyolysis episode.
    Highlights: 2-Hydroxyadipic acid can serve as a potential adjunct biomarker for iron-sulfur assembly defects and lipoic acid biosynthesis disorders. Parenteral nutrition containing high lipid and protein content could be used to reverse acute rhabdomyolysis episodes in the patients with FDX2-related disorder.
    Keywords:  episodic; ferredoxin‐2; iron‐sulfur clusters; mitochondrial disorders; mitochondrial myopathy; urine organic acid analysis; with optic atrophy and reversible leukoencephalopathy
    DOI:  https://doi.org/10.1002/jmd2.12408
  36. Gene. 2024 Mar 01. pii: S0378-1119(24)00218-X. [Epub ahead of print]910 148337
    Mitochondrial DNA mutations in extremely preterm infants with bronchopulmonary dysplasia.
    Jiyoon Jeong, Yeonmi Lee, Jongsuk Han, Eunju Kang, Deokhoon Kim, Ki-Soo Kim, Ellen Ai-Rhan Kim, Byong Sop Lee, Euiseok Jung.
      Bronchopulmonary dysplasia (BPD) is a serious chronic lung disease affecting extremely preterm infants. While mitochondrial dysfunction has been investigated in various medical conditions, limited research has explored mitochondrial DNA (mtDNA) gene mutations, specifically in BPD. This study aimed to evaluate mitochondrial mtDNA gene mutations in extremely preterm infants with BPD. In this prospective observational study, we enrolled a cohort of extremely preterm infants diagnosed with BPD. Clinical data were collected to provide comprehensive patient profiles. Peripheral blood mononuclear cells were isolated from whole-blood samples obtained within a defined timeframe. Subsequently, mtDNA extraction and sequencing using next-generation sequencing technology were performed to identify mtDNA gene mutations. Among the cohort of ten extremely preterm infants with BPD, mtDNA sequencing revealed the presence of mutations in seven patients, resulting in a total of twenty-one point mutations. Notably, many of these mutations were identified in loci associated with critical components of the respiratory chain complexes, vital for proper mitochondrial function and cellular energy production. This pilot study provides evidence of mtDNA point mutations in a subset of extremely preterm infants with BPD. These findings suggest a potential association between mitochondrial dysfunction and the pathogenesis of BPD. Further extensive investigations are warranted to unravel the mechanisms underlying mtDNA mutations in BPD.
    Keywords:  Bronchopulmonary dysplasia; Chronic lung disease; Electron transport chain; Gene mutations; Mitochondrial DNA; Preterm infants
    DOI:  https://doi.org/10.1016/j.gene.2024.148337
  37. Mol Neurobiol. 2024 Mar 07.
    Loss of CHCHD2 Stability Coordinates with C1QBP/CHCHD2/CHCHD10 Complex Impairment to Mediate PD-Linked Mitochondrial Dysfunction.
    Yan-Lin Ren, Zheng Jiang, Jia-Yi Wang, Qin He, Si-Xu Li, Xiao-Jing Gu, Yang-Ran Qi, Min Zhang, Wen-Jie Yang, Bei Cao, Jing-Yu Li, Yi Wang, Yong-Ping Chen.
      Novel CHCHD2 mutations causing C-terminal truncation and interrupted CHCHD2 protein stability in Parkinson's disease (PD) patients were previously found. However, there is limited understanding of the underlying mechanism and impact of subsequent CHCHD2 loss-of-function on PD pathogenesis. The current study further identified the crucial motif (aa125-133) responsible for diminished CHCHD2 expression and the molecular interplay within the C1QBP/CHCHD2/CHCHD10 complex to regulate mitochondrial functions. Specifically, CHCHD2 deficiency led to decreased neural cell viability and mitochondrial structural and functional impairments, paralleling the upregulation of autophagy under cellular stresses. Meanwhile, as a binding partner of CHCHD2, C1QBP was found to regulate the stability of CHCHD2 and CHCHD10 proteins to maintain the integrity of the C1QBP/CHCHD2/CHCHD10 complex. Moreover, C1QBP-silenced neural cells displayed severe cell death phenotype along with mitochondrial damage that initiated a significant mitophagy process. Taken together, the evidence obtained from our in vitro and in vivo studies emphasized the critical role of CHCHD2 in regulating mitochondria functions via coordination among CHCHD2, CHCHD10, and C1QBP, suggesting the potential mechanism by which CHCHD2 function loss takes part in the progression of neurodegenerative diseases.
    Keywords:  C1QBP; CHCHD10; CHCHD2; Mitochondrial Functions; Parkinson's Disease
    DOI:  https://doi.org/10.1007/s12035-024-04090-y
  38. Nat Commun. 2024 Mar 04. 15(1): 1965
    NDUFS4 regulates cristae remodeling in diabetic kidney disease.
    Koki Mise, Jianyin Long, Daniel L Galvan, Zengchun Ye, Guizhen Fan, Rajesh Sharma, Irina I Serysheva, Travis I Moore, Collene R Jeter, M Anna Zal, Motoo Araki, Jun Wada, Paul T Schumacker, Benny H Chang, Farhad R Danesh.
      The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generate diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that conditional male mice with genetic overexpression of Ndufs4 exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping protein STOML2 in linking NDUFS4 with improved cristae morphology. Together, we provide the evidence on the central role of NDUFS4 as a regulator of cristae remodeling and mitochondrial function in kidney podocytes. We propose that targeting NDUFS4 represents a promising approach to slow the progression of DKD.
    DOI:  https://doi.org/10.1038/s41467-024-46366-w
  39. Nat Cell Biol. 2024 Mar 07.
    Loss of WIPI4 in neurodegeneration causes autophagy-independent ferroptosis.
    Ye Zhu, Motoki Fujimaki, Louisa Snape, Ana Lopez, Angeleen Fleming, David C Rubinsztein.
      β-Propeller protein-associated neurodegeneration (BPAN) is a rare X-linked dominant disease, one of several conditions that manifest with neurodegeneration and brain iron accumulation. Mutations in the WD repeat domain 45 (WDR45) gene encoding WIPI4 lead to loss of function in BPAN but the cellular mechanisms of how these trigger pathology are unclear. The prevailing view in the literature is that BPAN is simply the consequence of autophagy deficiency given that WIPI4 functions in this degradation pathway. However, our data indicate that WIPI4 depletion causes ferroptosis-a type of cell death induced by lipid peroxidation-via an autophagy-independent mechanism, as demonstrated both in cell culture and in zebrafish. WIPI4 depletion increases ATG2A localization at endoplasmic reticulum-mitochondrial contact sites, which enhances phosphatidylserine import into mitochondria. This results in increased mitochondrial synthesis of phosphatidylethanolamine, a major lipid prone to peroxidation, thus enabling ferroptosis. This mechanism has minimal overlap with classical ferroptosis stimuli but provides insights into the causes of neurodegeneration in BPAN and may provide clues for therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41556-024-01373-3
  40. Autophagy. 2024 Mar 05.
    International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis.
    Xin Chen, Andrey S Tsvetkov, Han-Ming Shen, Ciro Isidoro, Nicholas T Ktistakis, Andreas Linkermann, Werner J H Koopman, Hans-Uwe Simon, Lorenzo Galluzzi, Shouqing Luo, Daqian Xu, Wei Gu, Olivier Peulen, Qian Cai, David C Rubinsztein, Jen-Tsan Chi, Donna D Zhang, Changfeng Li, Shinya Toyokuni, Jinbao Liu, Jong-Lyel Roh, Enyong Dai, Gabor Juhasz, Wei Liu, Jianhua Zhang, Minghua Yang, Jiao Liu, Ling-Qiang Zhu, Weiping Zou, Mauro Piacentini, Wen-Xing Ding, Zhenyu Yue, Yangchun Xie, Morten Petersen, David A Gewirtz, Michael A Mandell, Charleen T Chu, Debasish Sinha, Eftekhar Eftekharpour, Boris Zhivotovsky, Sébastien Besteiro, Dmitry I Gabrilovich, Do-Hyung Kim, Valerian E Kagan, Hülya Bayir, Guang-Chao Chen, Scott Ayton, Jan D Lünemann, Masaaki Komatsu, Stefan Krautwald, Ben Loos, Eric H Baehrecke, Jiayi Wang, Jon D Lane, Junichi Sadoshima, Wan Seok Yang, Minghui Gao, Christian Münz, Michael Thumm, Martin Kampmann, Di Yu, Marta M Lipinski, Jace W Jones, Xuejun Jiang, Herbert J Zeh, Rui Kang, Daniel J Klionsky, Guido Kroemer, Daolin Tang.
      Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results.
    Keywords:  Cell death; ferritinophagy; iron; lipid peroxidation; lipophagy; lysosome
    DOI:  https://doi.org/10.1080/15548627.2024.2319901
  41. Front Pediatr. 2024 ;12 1278047
    Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome.
    Ina Kirchberg, Elke Lainka, Andrea Gangfuß, Alma Kuechler, Fabian Baertling, Lea D Schlieben, Dominic Lenz, Eva Tschiedel.
       Background/purpose: MEGDHEL syndrome is a rare autosomal recessive metabolic disorder, which is characterized by 3-methylglutaconic aciduria with deafness-dystonia, hepatopathy, encephalopathy and Leigh-like syndrome. It is caused by biallelic pathogenic variants in the SERAC1 gene. Due to the unspecific symptoms and the diverse manifestations of the clinical phenotype, the diagnosis is challenging. Infantile MEGDHEL syndrome often has a severe disease course with acute liver failure. Differentiation from other metabolic disorders is difficult and requires a multidisciplinary approach.
    Case presentation: A two-day-old small for gestational age neonate was admitted to our pediatric intensive care unit (PICU) due to severe liver failure with distinct hyperammonemia and hypoglycemia without elevation of transaminases or cholestasis. Due to high ammonia level, continuous hemodialysis was established immediately after admission. In addition, protein intake was stopped, and the patient anabolized with intravenous glucose. Temporary stabilization could be achieved after four days. In the further course, severe neurological and cardiocirculatory complications occurred, which ultimately led to the infant's death. In the metabolic diagnostics, a pronounced lactate acidosis and in urine an increased excretion of 3-methylglutaconic acid as well as other metabolites of mitochondrial energy metabolism has been the leading findings besides the hyperammonemia. Post-mortem trio whole genome analysis detected a homozygous pathogenic variant in SERAC1 with evidence of SERAC1 deficiency leading to the diagnosis of infantile MEGDHEL syndrome.
    Conclusion: When pediatricians are faced with hepatopathy or even acute liver failure without elevation of transaminases or cholestasis in newborns, SERAC1 deficiency should be considered as a potential differential diagnosis. The initial treatment is based on the recommended management of suspected metabolic disorders. Even while no cure is available yet, patients should be offered proper supportive management through a multidisciplinary team. In addition, genetic confirmation of the diagnosis is important for the families, especially regarding further family planning.If a newborn presents with hyperammonemia, hypoglycemia and impaired liver synthesis function without elevation of transaminases or cholestasis, the possible presence of MEGDHEL syndrome due to a SERAC1 mutation should be considered.
    Keywords:  MEGDHEL syndrome; SERAC1; hyperammonemia; lactic acidosis; liver failure; neurometabolic disorder
    DOI:  https://doi.org/10.3389/fped.2024.1278047
  42. Cell Rep. 2024 Mar 05. pii: S2211-1247(24)00227-4. [Epub ahead of print]43(3): 113899
    LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling in C. elegans.
    Taruna Pandey, Bingying Wang, Changnan Wang, Jenny Zu, Huichao Deng, Kang Shen, Goncalo Dias do Vale, Jeffrey G McDonald, Dengke K Ma.
      Insulin-mechanistic target of rapamycin (mTOR) signaling drives anabolic growth during organismal development; its late-life dysregulation contributes to aging and limits lifespans. Age-related regulatory mechanisms and functional consequences of insulin-mTOR remain incompletely understood. Here, we identify LPD-3 as a megaprotein that orchestrates the tempo of insulin-mTOR signaling during C. elegans aging. We find that an agonist insulin, INS-7, is drastically overproduced from early life and shortens lifespan in lpd-3 mutants. LPD-3 forms a bridge-like tunnel megaprotein to facilitate non-vesicular cellular lipid trafficking. Lipidomic profiling reveals increased hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1. Reducing the abundance of HYL-1, insulin receptor/DAF-2 or mTOR/LET-363, normalizes INS-7 levels and rescues the lifespan of lpd-3 mutants. LPD-3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age. We propose that LPD-3 acts as a megaprotein brake for organismal aging and that its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.
    Keywords:  CP: Metabolism; CP: Molecular biology; Caenorhabditis elegans; IIS-mTOR; INS-7; LPD-3; aging; hexaceramide; hyperfunction; mitochondrial pathway; molecular damages; sphingolipid
    DOI:  https://doi.org/10.1016/j.celrep.2024.113899
  43. Autophagy. 2024 Mar 06. 1-2
    An unexpected journey for BNIP3.
    José M Delgado, Christopher J Shoemaker.
      Mitophagy is a cellular process that enables the selective degradation of damaged, dysfunctional, or superfluous mitochondria. During mitophagy, specific proteins recognize and tag mitochondria for degradation. These tagged mitochondria are engulfed by specialized structures called phagophores that then mature into autophagosomes/mitophagosomes. Mitophagosomes subsequently transport their mitochondrial cargo to lysosomes, where the mitochondria are broken down and recycled. While the PINK1-PRKN-dependent mitophagy pathway is well understood, mitophagy can also occur independently of this pathway. BNIP3 and BNIP3L/NIX, paralogous membrane proteins on the outer mitochondrial membrane (OMM), serve as ubiquitin-independent mitophagy receptors. Historically, BNIP3 regulation was thought to be primarily transcriptional through HIF1A (hypoxia inducible factor 1 subunit alpha). However, recent work has revealed a significant post-translational dimension, highlighting the strong role of the ubiquitin-proteasome system (UPS) in BNIP3 regulation. With these emerging concepts in mind, we aimed to develop a unified understanding of how steady-state levels of BNIP3 are established and maintained and how this regulation governs underlying cell physiology.
    Keywords:  BNIP3; EMC; ER membrane protein complex; NIX; membrane trafficking; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2312038
  44. Front Cardiovasc Med. 2024 ;11 1367108
    Interplay between mitochondrial dysfunction and lysosomal storage: challenges in genetic metabolic muscle diseases with a focus on infantile onset Pompe disease.
    Mengjiao Zhang, Jiechao Niu, Mengmeng Xu, Erhu Wei, Peng Liu, Guangyao Sheng.
       Background: Pompe disease (PD) is a rare, progressive autosomal recessive lysosomal storage disorder that directly impacts mitochondrial function, leading to structural abnormalities and potentially culminating in heart failure or cardiogenic shock. The clinical course and molecular mechanisms of the disease remain incompletely understood.
    Methods: We performed a retrospective analysis to examine the clinical manifestations, genetic traits, and the relationship between PD and mitochondrial function in a pediatric patient. This comprehensive evaluation included the use of ultrasound echocardiograms, computed tomography (CT) scans, electrocardiograms, mutagenesis analysis, and structural analysis to gain insights into the patient's condition and the underlying mechanisms of PD. For structural analysis and visualization, the structure of protein data bank ID 5KZX of human GAA was used, and VMD software was used for visualization and analysis.
    Results: The study revealed that a 5-month-old male infant was admitted due to fever, with physical examination finding abnormal cardiopulmonary function and hepatomegaly. Laboratory tests and echocardiography confirmed heart failure and hypertrophic cardiomyopathy. Despite a week of treatment, which normalized body temperature and reduced pulmonary inflammation, cardiac abnormalities did not show significant improvement. Further genetic testing identified a homozygous mutation c.2662G>T (p.E888) in the GAA gene, leading to a diagnosis of Infantile-Onset Pompe Disease (IOPD).
    Conclusions: Although enzyme replacement therapy can significantly improve the quality of life for patients with PD, enhancing mitochondrial function may represent a new therapeutic strategy for treating PD.
    Keywords:  Pompe disease; alpha-glucosidase; enzyme replacement therapy; hereditary myopathy; lysosomal storage
    DOI:  https://doi.org/10.3389/fcvm.2024.1367108
  45. Nat Chem. 2024 Mar;16(3): 314-334
    Nanopore DNA sequencing technologies and their applications towards single-molecule proteomics.
    Adam Dorey, Stefan Howorka.
      Sequencing of nucleic acids with nanopores has emerged as a powerful tool offering rapid readout, high accuracy, low cost and portability. This label-free method for sequencing at the single-molecule level is an achievement on its own. However, nanopores also show promise for the technologically even more challenging sequencing of polypeptides, something that could considerably benefit biological discovery, clinical diagnostics and homeland security, as current techniques lack portability and speed. Here we survey the biochemical innovations underpinning commercial and academic nanopore DNA/RNA sequencing techniques, and explore how these advances can fuel developments in future protein sequencing with nanopores.
    DOI:  https://doi.org/10.1038/s41557-023-01322-x
  46. Methods Mol Biol. 2024 ;2774 43-58
    A Mammalian-Based Synthetic Biology Toolbox to Engineer Membrane-Membrane Interfaces.
    Hossein Moghimianavval, Sonisilpa Mohapatra, Allen P Liu.
      Intercellular membrane-membrane interfaces are compartments with specialized functions and unique biophysical properties that are essential in numerous cellular processes including cell signaling, development, and immunity. Using synthetic biology to engineer or to create novel cellular functions in the intercellular regions has led to an increasing need for a platform that allows generation of functionalized intercellular membrane-membrane interfaces. Here, we present a synthetic biology platform to engineer functional membrane-membrane interfaces using a pair of dimerizing proteins in both cell-free and cellular environments. We envisage this platform to be a helpful tool for synthetic biologists who wish to engineer novel intercellular signaling and communication systems.
    Keywords:  Cell-free expression; Membrane protein reconstitution; Membrane–membrane interfaces; Split protein reconstitution; SpyTag–SpyCatcher; Synthetic biology
    DOI:  https://doi.org/10.1007/978-1-0716-3718-0_4
  47. Sci Total Environ. 2024 Mar 04. pii: S0048-9697(24)01539-0. [Epub ahead of print] 171398
    The mystery of methylmercury-perturbed calcium homeostasis: AMPK-DRP1-dependent mitochondrial fission initiates ER-mitochondria contact formation.
    Yi Hu, Changsong Tian, Fang Chen, Aihua Zhang, Wenjuan Wang.
      Methylmercury (MeHg), as a global environmental pollutant, is of concern globally due to its neurodevelopmental toxicity. Mitochondria-associated membranes (MAMs) are highly dynamic sites of endoplasmic reticulum (ER)-haemocyte contact. MAMs are closely associated with the pathophysiology of neurological disorders due to their role in the transfer of calcium ions (Ca2+) between mitochondria and the ER. However, the molecular mechanisms that control these interactions in MeHg-induced neurotoxicity have not yet been characterized. In the current study, MeHg caused increases in the levels of both cytosolic and mitochondrial Ca2+ in PC12 cells and promoted MAMs formation in both in vivo and in vitro experiments. Of note, MeHg perturbed mitochondrial dynamics, promoting a shift toward a fission phenotype, and this was supported by the dysregulation of fission regulators. Interestingly, the MeHg-induced promotion of MAMs formation and increase in Ca2+ levels were effectively attenuated by the inhibition of mitochondrial fission using Mdivi-1, a DRP1 inhibitor. Furthermore, MeHg triggered the AMPK pathway, and most of the aforementioned changes were significantly rescued by Compound C. Mechanistic investigations revealed a reciprocal relationship between AMPK- and Ca2+-mediated mitochondrial fission. The specific inhibitor of Ca2+ uniporter, ruthenium-red (RuR), effectively abolished the feedback regulation of mitochondrial dynamics and MAMs formation mediated by AMPK in response to MeHg-induced Ca2+ overload. This study reveals a novel role of AMPK-DRP1-mediated mitochondrial fragmentation in the coupling of ER-mitochondrial calcium microdomains in MeHg-induced neurotoxicity. The findings provide valuable insights for the development of strategies to regulate mitochondrial imbalances in neurological diseases.
    Keywords:  Calcium; Endoplasmic reticulum; Methylmercury; Mitochondria; Neurotoxicity
    DOI:  https://doi.org/10.1016/j.scitotenv.2024.171398
  48. iScience. 2024 Mar 15. 27(3): 109221
    Fat infiltration in skeletal muscle: Influential triggers and regulatory mechanism.
    Liyi Wang, Teresa G Valencak, Tizhong Shan.
      Fat infiltration in skeletal muscle (also known as myosteatosis) is now recognized as a distinct disease from sarcopenia and is directly related to declining muscle capacity. Hence, understanding the origins and regulatory mechanisms of fat infiltration is vital for maintaining skeletal muscle development and improving human health. In this article, we summarized the triggering factors such as aging, metabolic diseases and metabolic syndromes, nonmetabolic diseases, and muscle injury that all induce fat infiltration in skeletal muscle. We discussed recent advances on the cellular origins of fat infiltration and found several cell types including myogenic cells and non-myogenic cells that contribute to myosteatosis. Furthermore, we reviewed the molecular regulatory mechanism, detection methods, and intervention strategies of fat infiltration in skeletal muscle. Based on the current findings, our review will provide new insight into regulating function and lipid metabolism of skeletal muscle and treating muscle-related diseases.
    Keywords:  Health sciences; Human metabolism; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2024.109221
  49. Clin Genet. 2024 Mar 05.
    Genebe.net: Implementation and validation of an automatic ACMG variant pathogenicity criteria assignment.
    Piotr Stawiński, Rafał Płoski.
      We present GeneBe, an online platform streamlining the automated application of American College of Medical Genetics and Genomics (ACMG), Association for Molecular Pathology (AMP), and the College of American Pathologists (CAP) criteria for assessment of pathogenicity of genetic variants. GeneBe utilizes automated algorithms that evaluate 17 criteria from 28, closely aligning with current guidelines and leveraging data from diverse sources, including ClinVar. The user-friendly web interface enables manual refinement of assignments for specific criteria based on site-collected data. Our algorithm demonstrates a high correlation (r = 0.90) of assigned pathogenicity scores compared to expert assessments from the ClinGen Evidence Repository and substantial concordance with ClinVar verdict assignments (κ = 0.69). Comparative analysis with other published tools reveals that GeneBe performs similarly to VarSome while being superior over TAPES and InterVar. In contrast to some other tools, GeneBe's web implementation is tracker-free and third-party request-free, safeguarding user privacy. Additionally, GeneBe offers an Application Programming Interface (API) for enhanced flexibility and integration into existing workflows and is provided free of charge for research purposes. GeneBe is available at https://genebe.net.
    Keywords:  ACMG; GeneBe; genetic diagnosis; variant annotation; variant interpretation
    DOI:  https://doi.org/10.1111/cge.14516
  50. Nature. 2024 Mar 04.
    Organoids grown from amniotic fluid could shed light on rare diseases.
    Lilly Tozer.
      
    Keywords:  Diseases; Stem cells
    DOI:  https://doi.org/10.1038/d41586-024-00656-x
  51. J Toxicol Sci. 2024 ;49(3): 117-126
    Developing a GNN-based AI model to predict mitochondrial toxicity using the bagging method.
    Yoshinobu Igarashi, Ryosuke Kojima, Shigeyuki Matsumoto, Hiroaki Iwata, Yasushi Okuno, Hiroshi Yamada.
      Mitochondrial toxicity has been implicated in the development of various toxicities, including hepatotoxicity. Therefore, mitochondrial toxicity has become a major screening factor in the early discovery phase of drug development. Several models have been developed to predict mitochondrial toxicity based on chemical structures. However, they only provide a binary classification of positive or negative results and do not provide the substructures that contribute to a positive decision. Therefore, we developed an artificial intelligence (AI) model to predict mitochondrial toxicity and visualize structural alerts. To construct the model, we used the open-source software library kMoL, which employs a graph neural network approach that allows learning from chemical structure data. We also utilized the integrated gradient method, which enables the visualization of substructures that contribute to positive results. The dataset used to construct the AI model exhibited a significant imbalance, with significantly more negative than positive data. To address this, we employed the bagging method, which resulted in a model with high predictive performance, as evidenced by an F1 score of 0.839. This model can also be used to visualize substructures that contribute to mitochondrial toxicity using the integrated gradient method. Our AI model predicts mitochondrial toxicity based on chemical structures and may contribute to screening mitochondrial toxicity in the early stages of drug discovery.
    Keywords:  Bagging method; Deep learning; Explainable artificial intelligence; Graph neural networks; Mitochondrial toxicity
    DOI:  https://doi.org/10.2131/jts.49.117
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