bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–12–29
forty-six papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Light-Inducible Deformation of Mitochondria in Live Cells.
  2. Mitochondrial tRNA modifications: functions, diseases caused by their loss, and treatment strategies.
  3. Functionally conserved inner mitochondrial membrane proteins CCDC51 and Mdm33 demarcate a subset of fission events.
  4. Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster.
  5. Risk Factors Associated With Leber Hereditary Optic Neuropathy due to Rare Mutations in Mitochondrial DNA-Encoded Respiratory Complex I Subunits.
  6. BCKDK loss impairs mitochondrial Complex I activity and drives alpha-synuclein aggregation in models of Parkinson's disease.
  7. Coenzyme Q improves mitochondrial and muscle dysfunction caused by CUG expanded repeats in Caenorhabditis elegans.
  8. The Mitochondrial Lactate Oxidation Complex: endpoint for carbohydrate carbon disposal.
  9. Expanding the phenotypic and genetic spectrum of GTPBP3 deficiency: findings from nine Chinese pedigrees.
  10. Effects of Aging on Glucose and Lipid Metabolism in Mice.
  11. A transcription network underlies the dual genomic coordination of mitochondrial biogenesis.
  12. Reprogramming patient-iPSC specific retinal organoids for deciphering epigenetic modifications of RNA methylation.
  13. Liver transplantation in a boy with TFAM mutation associated mtDNA depletion syndrome.
  14. Biallelic variants in the NDUFAF6 cause mitochondrial respiratory complex assembly defects associated with Leigh syndrome in probands.
  15. Cyclosporine A Delays the Terminal Disease Stage in the Tfam KO Mitochondrial Myopathy Mouse Model Without Improving Mitochondrial Energy Production.
  16. SLP2 and MIC13 synergistically coordinate MICOS assembly and crista junction formation.
  17. PCNA and Rnh1 independently participate in the protection of mitochondrial genome against UV-induced mutagenesis in yeast cells.
  18. Deafness-associated mitochondrial 12S rRNA mutation reshapes mitochondrial and cellular homeostasis.
  19. Aging through the lens of mitochondrial DNA mutations and inheritance paradoxes.
  20. Mitochondrial quality control: the real dawn of intervertebral disc degeneration?
  21. Mitochondrial ROS modulate presynaptic plasticity in the drosophila neuromuscular junction.
  22. Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.
  23. Alternating Cellular Functions by Optogenetic Control of Organelles.
  24. A subcellular selective APEX2-based proximity labeling used for identifying mitochondrial G-quadruplex DNA binding proteins.
  25. Nuclear Control of Mitochondrial Homeostasis and Venetoclax Efficacy in AML via COX4I1.
  26. Mitochondrial deletion4977 abundance in melanoma-adjacent skin.
  27. Mitonuclear Communication in Stem Cell Function.
  28. Mitochondrial DNA mutations in human oocytes undergo frequency-dependent selection but do not increase with age.
  29. Mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicing.
  30. The Mitochondrial Blueprint: Unlocking Secondary Metabolite Production.
  31. Different effects of fatty acid oxidation on hematopoietic stem cells based on age and diet.
  32. Nuclear respiratory factor-1 (NRF1) induction drives mitochondrial biogenesis and attenuates amyloid beta-induced mitochondrial dysfunction and neurotoxicity.
  33. The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses.
  34. The Vsr-like protein FASTKD4 regulates the stability and polyadenylation of the MT-ND3 mRNA.
  35. Mitochondria-targeting materials and therapies for regenerative engineering.
  36. Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma.
  37. Single Cell Sequencing Traces Mitochondrial Transfers.
  38. Disruption of deoxyribonucleotide triphosphate biosynthesis leads to RAS proto-oncogene activation and perturbation of mitochondrial metabolism.
  39. Base editing of Ptbp1 in neurons alleviates symptoms in a mouse model of Parkinson's disease.
  40. Nuclear respiratory factor-1 (NRF1) induction as a powerful strategy to deter mitochondrial dysfunction and senescence in mesenchymal stem cells.
  41. Advancing mitochondrial therapeutics: Synthesis and pharmacological evaluation of pyrazole-based inhibitors targeting the mitochondrial pyruvate carrier.
  42. Ndufs4 inactivation in glutamatergic neurons reveals swallow-breathing discoordination in a mouse model of Leigh syndrome.
  43. Non-viral gene therapy for Leber's congenital amaurosis: progress and possibilities.
  44. Thoughts for the future.
  45. Targeting mitochondrial RNAs enhances the efficacy of the DNA-demethylating agents.
  46. Optimizing regulatory frameworks for gene therapies in rare diseases: Challenges and solutions.
  1. Methods Mol Biol. 2025 ;2840 185-200
    Light-Inducible Deformation of Mitochondria in Live Cells.
    Yutong Song, Peiyuan Huang, Liting Duan.
      Mitochondria are dynamic organelles with constantly changing morphologies. Despite recent reports indicating that mechanical cues modulate mitochondrial morphologies and functions, there is a lack of methods that can exclusively and precisely exert mechanical forces to and deform mitochondria in live cells. Therefore, how mitochondria sense and respond to mechanical forces remains largely elusive. Optogenetic methods open up new venues for remote and precise manipulation of intracellular activities using light, providing an unprecedented opportunity to establish targeted mechano-stimulation toward mitochondria. This chapter describes the development of a novel optogenetic approach to optically mechanostimulate and induce the deformation of mitochondria. In this approach, light-gated protein-protein heterodimerization recruits force-generating molecular motors to the outer mitochondrial membrane, enabling direct exertion of mechanical force on mitochondria. Details for the design, application, and experimental procedures are laid out in this chapter. This method presents a mitochondria-specific mechano-stimulator for studying the correlation between mitochondrial morphology and functions as well as mitochondrial mechanobiology.
    Keywords:  Mitochondria; Mitochondrial morphology; Molecular motor; Optogenetics; Organelle mechanobiology
    DOI:  https://doi.org/10.1007/978-1-0716-4047-0_14
  2. RNA. 2024 Dec 24. pii: rna.080257.124. [Epub ahead of print]
    Mitochondrial tRNA modifications: functions, diseases caused by their loss, and treatment strategies.
    Takeshi Chujo, Kazuhito Tomizawa.
      Mitochondrial tRNA (mt-tRNA) modifications play pivotal roles in decoding and sustaining tRNA stability, thereby enabling synthesis of essential respiratory complex proteins in mitochondria. Consequently, loss of human mt-tRNA modifications caused by mutations in the mitochondrial or nuclear genome can cause life-threatening mitochondrial diseases such as encephalopathy and cardiomyopathy. In this article, we first provide a comprehensive overview of the functions of mt-tRNA modifications, the responsible modification enzymes, and the diseases caused by loss of mt-tRNA modifications. We then discuss progress and potential strategies to treat these diseases, including taurine supplementation for MELAS patients, targeted deletion of mtDNA variants, and overexpression of modification-related proteins. Finally, we discuss factors that need to be overcome to cure 'mitochondrial tRNA modopathies'.
    Keywords:  MELAS; mitoTALEN; mitochondrial disease; tRNA modification; tRNA modopathy
    DOI:  https://doi.org/10.1261/rna.080257.124
  3. J Cell Biol. 2025 Mar 03. pii: e202403140. [Epub ahead of print]224(3):
    Functionally conserved inner mitochondrial membrane proteins CCDC51 and Mdm33 demarcate a subset of fission events.
    Alia R Edington, Olivia M Connor, Abigail C Love, Madeleine Marlar-Pavey, Jonathan R Friedman.
      While extensive work has examined the mechanisms of mitochondrial fission, it remains unclear whether internal mitochondrial proteins in metazoans play a direct role in the process. Previously, the yeast inner membrane protein Mdm33 was shown to be required for normal mitochondrial morphology and has been hypothesized to be involved in mitochondrial fission. However, it is unknown whether Mdm33 plays a direct role, and it is not thought to have a mammalian homolog. Here, we use a bioinformatic approach to identify a structural ortholog of Mdm33 in humans, CCDC51 (also called MITOK), whose depletion phenocopies loss of Mdm33. We find that knockdown of CCDC51 also leads to reduced rates of mitochondrial fission. Further, we spatially and temporally resolve Mdm33 and CCDC51 to a subset of mitochondrial fission events. Finally, we show that CCDC51 overexpression promotes its spatial association with Drp1 and induces mitochondrial fragmentation, suggesting it is a positive effector of mitochondrial fission. Together, our data reveal that Mdm33 and CCDC51 are functionally conserved and suggest that internal mitochondrial proteins are directly involved in at least a subset of mitochondrial fission events in human cells.
    DOI:  https://doi.org/10.1083/jcb.202403140
  4. Nat Commun. 2024 Dec 23. 15(1): 10719
    Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster.
    Najla El Fissi, Florian A Rosenberger, Kai Chang, Alissa Wilhalm, Tom Barton-Owen, Fynn M Hansen, Zoe Golder, David Alsina, Anna Wedell, Matthias Mann, Patrick F Chinnery, Christoph Freyer, Anna Wredenberg.
      Aberration of mitochondrial function is a shared feature of many human pathologies, characterised by changes in metabolic flux, cellular energetics, morphology, composition, and dynamics of the mitochondrial network. While some of these changes serve as compensatory mechanisms to maintain cellular homeostasis, their chronic activation can permanently affect cellular metabolism and signalling, ultimately impairing cell function. Here, we use a Drosophila melanogaster model expressing a proofreading-deficient mtDNA polymerase (POLγexo-) in a genetic screen to find genes that mitigate the harmful accumulation of mtDNA mutations. We identify critical pathways associated with nutrient sensing, insulin signalling, mitochondrial protein import, and autophagy that can rescue the lethal phenotype of the POLγexo- flies. Rescued flies, hemizygous for dilp1, atg2, tim14 or melted, normalise their autophagic flux and proteasome function and adapt their metabolism. Mutation frequencies remain high with the exception of melted-rescued flies, suggesting that melted may act early in development. Treating POLγexo- larvae with the autophagy activator rapamycin aggravates their lethal phenotype, highlighting that excessive autophagy can significantly contribute to the pathophysiology of mitochondrial diseases. Moreover, we show that the nucleation process of autophagy is a critical target for intervention.
    DOI:  https://doi.org/10.1038/s41467-024-55559-2
  5. Clin Genet. 2024 Dec 23.
    Risk Factors Associated With Leber Hereditary Optic Neuropathy due to Rare Mutations in Mitochondrial DNA-Encoded Respiratory Complex I Subunits.
    Pilar Bayona-Bafaluy, Javier Sanz-Pons, Olivia Esteban, Luca Bueno-Borghi, Eduardo Ruiz-Pesini.
      An in-depth analysis of susceptibility factors modifying the penetrance of rare Leber hereditary optic neuropathy-causing mutations in respiratory complex I genes encoded in mitochondrial deoxyribonucleic acid has not been performed. To bridge this gap, we conducted a review of the literature on rare mutations associated with LHON, selected those with substantial evidence of pathogenicity, and performed an in-depth analysis of the various pedigrees. Examining the influences that modify the penetrance of the classical mutations associated with this disease may offer insights into susceptibility factors in individuals carrying the rare mutations.
    Keywords:  Leber hereditary optic neuropathy; incomplete penetrance; mitochondrial deoxyribonucleic acid; rare mutation; respiratory complex I genes
    DOI:  https://doi.org/10.1111/cge.14683
  6. Acta Neuropathol Commun. 2024 Dec 21. 12(1): 198
    BCKDK loss impairs mitochondrial Complex I activity and drives alpha-synuclein aggregation in models of Parkinson's disease.
    Aya Jishi, Di Hu, Yutong Shang, Rihua Wang, Steven A Gunzler, Xin Qi.
      Mitochondrial dysfunction and α-synuclein (αSyn) aggregation are key contributors to Parkinson's Disease (PD). While genetic and environmental risk factors, including mutations in mitochondrial-associated genes, are implicated in PD, the precise mechanisms linking mitochondrial defects to αSyn pathology remain incompletely understood, hindering the development of effective therapeutic interventions. Here, we identify the loss of branched chain ketoacid dehydrogenase kinase (BCKDK) as a mitochondrial risk factor that exacerbates αSyn pathology by disrupting Complex I function. Our findings reveal a consistent downregulation of BCKDK in dopaminergic (DA) neurons from A53T-αSyn mouse models, PD patient-derived induced pluripotent stem (iPS) cells, and postmortem brain tissues. BCKDK deficiency leads to mitochondrial dysfunction, including reduced membrane potential and increased reactive oxygen species (ROS) production upon administration of a stressor, which in turn promotes αSyn oligomerization. Mechanistically, BCKDK interacts with the NDUFS1 subunit of Complex I to stabilize its function. Loss of BCKDK disrupts this interaction, leading to Complex I destabilization and enhanced αSyn aggregation. Notably, restoring BCKDK expression in neuron-like cells rescues mitochondrial integrity and restores Complex I activity. Similarly, in patient-derived iPS cells differentiated to form dopaminergic neurons, NDUFS1 and phosphorylated aSyn levels are partially restored upon BCKDK expression. These findings establish a mechanistic link between BCKDK deficiency, mitochondrial dysfunction, and αSyn pathology in PD, positioning BCKDK as a potential therapeutic target to mitigate mitochondrial impairment and neurodegeneration in PD.
    DOI:  https://doi.org/10.1186/s40478-024-01915-8
  7. Genetics. 2024 Dec 27. pii: iyae208. [Epub ahead of print]
    Coenzyme Q improves mitochondrial and muscle dysfunction caused by CUG expanded repeats in Caenorhabditis elegans.
    Joana Teixeira, Anu-Mari Harju, Alaa Othman, Ove Eriksson, Brendan J Battersby, Susana M D A Garcia.
      Expansion of nucleotide repeat sequences is associated with more than 40 human neuromuscular disorders. The different pathogenic mechanisms associated with the expression of nucleotide repeats are not well understood. We use a Caenorhabditis elegans model that expresses expanded CUG repeats only in cells of the body wall muscle and recapitulate muscle dysfunction and impaired organismal motility to identify the basis by which expression of RNA repeats is toxic to muscle function. Here, we performed 2 consecutive RNA interference screens and uncovered coenzyme Q metabolism and mitochondrial dysfunction as critical genetic modifiers of the motility phenotype. Furthermore, coenzyme Q supplementation reduced the toxic phenotypes, ameliorating the motility impairment and mitochondrial phenotypes. Together our data show how the expression of expanded RNA repeats can be toxic to mitochondrial homeostasis.
    Keywords:   Caenorhabditis elegans ; CUG repeats; RNA repeat toxicity; coenzyme Q; mitochondrial dysfunction; myotonic dystrophy
    DOI:  https://doi.org/10.1093/genetics/iyae208
  8. Am J Physiol Endocrinol Metab. 2024 Dec 23.
    The Mitochondrial Lactate Oxidation Complex: endpoint for carbohydrate carbon disposal.
    Robert G Leija, Jose A Arevalo, Dianna Xing, José Pablo Vázquez-Medina, George A Brooks.
      The Lactate Shuttle concept has revolutionized our understanding and study of metabolism in physiology, biochemistry, metabolism, nutrition, and medicine. Seminal findings of the Mitochondrial Lactate Oxidation Complex (mLOC) elucidated the architectural structure of its components. Here, we report that the mitochondrial pyruvate carrier (mPC) is an additional member of the mLOC in mouse muscle and C2C12 myoblasts and myotubes. Immunoblots, mass spectrometry, and co-immunoprecipitation experiments of mitochondrial preparations revealed abundant amounts of mitochondrial lactate dehydrogenase (mLDH), monocarboxylate transporter (mMCT), basigin (CD147), cytochrome oxidase (COx), and pyruvate carriers 1 and 2 (mPC1 and 2). Additionally, using confocal laser scanning microscopy (CLSM) and in situ proximity ligation, we also demonstrated planar and 3D colocalization of pyruvate and lactate transporters with COx in fixed skeletal muscle sections, myotubes, and C2C12 myoblasts. This work serves as a landmark for configuring the final pathway of carbohydrate oxidation.
    Keywords:  Lactate; Lactate Shuttle; Mitochondral Reticulum; Pyruvate; Skeletal Muscle
    DOI:  https://doi.org/10.1152/ajpendo.00306.2024
  9. Orphanet J Rare Dis. 2024 Dec 24. 19(1): 488
    Expanding the phenotypic and genetic spectrum of GTPBP3 deficiency: findings from nine Chinese pedigrees.
    Yaojun Xie, Keyi Li, Li Yang, Xiaofei Zeng, Zhehui Chen, Xue Ma, Luyi Zhang, Yuwei Zhou, Liqin Jin, Yanling Yang, Xiaoting Lou.
       BACKGROUND: GTPBP3 catalyzes τm5(s2) U biosynthesis at the 34th wobble position of mitochondrial tRNAs, the hypomodification of τm5U leads to mitochondrial disease. While twenty-three variants of GTPBP3 have been reported worldwide, the genetic landscape in China remains uncertain.
    METHODS: By using whole-exome sequencing, the candidate individuals carrying GTPBP3 variants were screened and identified. Pathogenicity analysis of variants was biochemically verified by patients-derived immortalized lymphocytes and cell models.
    RESULTS: Through whole-exome sequencing, thirteen variants associated with GTPBP3 were identified in nine Chinese pedigrees, with eight of these variants being newly reported. Affected individuals displayed classic neurologic phenotypes and heart complications including developmental delay, seizures, hypotonia, exercise intolerance, and hypertrophic cardiomyopathy. Additionally, they displayed new symptoms such as eye problems like strabismus and heart issues related to valve function. Studies conducted on patient-derived cells provided evidence of reduced levels of GTPBP3 and impairment in mitochondrial energetic biogenesis. Re-expressing GTPBP3 variants in knockout cell lines further defined the pathogenicity of the novel variants. Analysis of the genetic spectrum in the Chinese population highlighted a concentration in exons 4 and 6, with c.689A > C being the prominent hotspot.
    CONCLUSION: Our findings emphasize the extensive clinical and genetic implications of GTPBP3-related mitochondrial disorders, particularly within the Chinese population, but further investigations are needed to explore the phenotype-genotype correlation.
    Keywords:   GTPBP3 ; Genetic hotspot; Mitochondrial diseases; Oxidative phosphorylation; τm5(s2)U modification
    DOI:  https://doi.org/10.1186/s13023-024-03469-3
  10. Aging Cell. 2024 Dec 27. e14462
    Effects of Aging on Glucose and Lipid Metabolism in Mice.
    Evan C Lien, Ngoc Vu, Anna M Westermark, Laura V Danai, Allison N Lau, Yetiş Gültekin, Matthew A Kukurugya, Bryson D Bennett, Matthew G Vander Heiden.
      Aging is accompanied by multiple molecular changes that contribute to aging associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part, because mitochondria are central to cellular metabolism. Moreover, the cofactor NAD+, which is reported to decline across multiple tissues during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and diversity outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of upregulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. These data suggest that NAD+-generating lipid metabolism reactions may help to maintain the NAD+/NADH ratio during healthy aging.
    Keywords:  NAD; aging; metabolic rate; mice
    DOI:  https://doi.org/10.1111/acel.14462
  11. Elife. 2024 Dec 27. pii: RP96536. [Epub ahead of print]13
    A transcription network underlies the dual genomic coordination of mitochondrial biogenesis.
    Fan Zhang, Annie Lee, Anna V Freitas, Jake T Herb, Zong-Heng Wang, Snigdha Gupta, Zhe Chen, Hong Xu.
      Mitochondrial biogenesis requires the expression of genes encoded by both the nuclear and mitochondrial genomes. However, aside from a handful transcription factors regulating specific subsets of mitochondrial genes, the overall architecture of the transcriptional control of mitochondrial biogenesis remains to be elucidated. The mechanisms coordinating these two genomes are largely unknown. We performed a targeted RNAi screen in developing eyes with reduced mitochondrial DNA content, anticipating a synergistic disruption of tissue development due to impaired mitochondrial biogenesis and mitochondrial DNA (mtDNA) deficiency. Among 638 transcription factors annotated in the Drosophila genome, 77 were identified as potential regulators of mitochondrial biogenesis. Utilizing published ChIP-seq data of positive hits, we constructed a regulatory network revealing the logic of the transcription regulation of mitochondrial biogenesis. Multiple transcription factors in core layers had extensive connections, collectively governing the expression of nearly all mitochondrial genes, whereas factors sitting on the top layer may respond to cellular cues to modulate mitochondrial biogenesis through the underlying network. CG1603, a core component of the network, was found to be indispensable for the expression of most nuclear mitochondrial genes, including those required for mtDNA maintenance and gene expression, thus coordinating nuclear genome and mtDNA activities in mitochondrial biogenesis. Additional genetic analyses validated YL-1, a transcription factor upstream of CG1603 in the network, as a regulator controlling CG1603 expression and mitochondrial biogenesis.
    Keywords:  ChIP-seq; D. melanogaster; RNA-seq; SDHA; TFAM; genetics; genomics; mitochondrial biogenesis; transcription factors
    DOI:  https://doi.org/10.7554/eLife.96536
  12. J Chin Med Assoc. 2024 Dec 23.
    Reprogramming patient-iPSC specific retinal organoids for deciphering epigenetic modifications of RNA methylation.
    Yueh Chien, Yi-Ping Yang, Tai-Chi Lin, Guang-Yuh Chiou, Aliaksandr A Yarmishyn, Chia-Hao Wang, Lo-Jei Ching, Yi-Ying Lin, Shih-Jen Chen, De-Kuang Hwang, Chih-Chien Hsu.
       BACKGROUND: Induced pluripotent stem cell (iPSC) technology has emerged as a powerful tool for disease modeling, providing an innovative platform for investigating disease mechanisms. iPSC-derived organoids, including retinal organoids, offer patient-specific models that closely replicate in vivo cellular environments, making them ideal for studying retinal neurodegenerative diseases where retinal ganglion cells (RGCs) are impacted. N6-methyladenosine (m6A), a prevalent internal modification in eukaryotic mRNAs, plays a critical role in RNA metabolic processes such as splicing, stability, translation, and transport. Given the high energy demands of RGCs, mitochondrial dysfunction, which leads to impaired ATP production and increased ROS levels, is often central to the progression of retinal neurodegenerative disorders. However, the epigenetic mechanisms underlying m6A modification and their contributions to these conditions remain unclear.
    METHODS: Patient-specific iPSCs were generated from individuals with Leber's hereditary optic neuropathy (LHON) and differentiated into retinal ganglion cells (RGCs) within retinal organoids. To analyze m6A methylation, we employed quantitative PCR and focused on differential expression of key m6A-modifying enzymes.
    RESULTS: iPSC-derived retinal organoids are adaptable for studying and investigating the epigenetic mechanisms of retinal neurodegenerative diseases. Our data demonstrated the profiling of global m6A-related gene expression levels in LHON patient-derived iPSC-RGCs compared with controls, highlighting specific disruptions in m6A modification pathways.
    CONCLUSION: These findings suggest that differential m6A modifications may play pivotal roles in the pathogenesis of retinal neurodegenerative diseases and affect the progression of the disease in affected individuals.
    DOI:  https://doi.org/10.1097/JCMA.0000000000001198
  13. Orphanet J Rare Dis. 2024 Dec 23. 19(1): 486
    Liver transplantation in a boy with TFAM mutation associated mtDNA depletion syndrome.
    Jing Zhao, Lian Chen, Ni Wang, Xin-Bao Xie.
      Mitochondrial transcription factor A (TFAM) deficiency may cause mtDNA depletion syndrome, which manifests as neonatal liver failure or primary ovarian insufficiency, hearing loss, seizures, and intellectual disability. Treatment focusing on symptomatic management, and the clinical prognosis remains poor. Here, we describe a novel case of TFAM mutation presenting with progressive neonatal cholestasis, hypoglycemia and abnormal amino acid profiling. The patient progressed to liver failure at 6 months of age but did not exhibit neurological involvement. No morphologic abnormalities were observed in muscle biopsy, while mtDNA copy number was reduced in comparison to age- and tissue-matched controls. After liver transplantation, liver biochemistries and blood amino acid profiling normalized three weeks later. Moreover, the boy was doing well post-transplant without any clinical concerns, and his development and neurological examination remain normal 33 months after liver transplantation. Our report suggests that liver transplantation appears to have a favorable profile in such patients.
    Keywords:  Liver transplantation; MtDNA depletion syndrome; Neonatal liver failure; TFAM
    DOI:  https://doi.org/10.1186/s13023-024-03487-1
  14. Mol Genet Metab Rep. 2024 Dec;41 101168
    Biallelic variants in the NDUFAF6 cause mitochondrial respiratory complex assembly defects associated with Leigh syndrome in probands.
    Yuwei Zhou, Xiaofei Zeng, Luyi Zhang, Xiaojie Yin, Xue Ma, Keyi Li, Peijing Qiu, Xiaoting Lou, Liqin Jin, Ya Wang, Yanling Yang, Ting Shen.
       Background: Variants in NDUFAF6 have been reported to be associated with Leigh syndrome. However, further expansion of the NDUFAF6-phenotype and variants spectrum of NDUFAF6-related Leigh syndrome are still required.
    Methods: Two patients diagnosed with Leigh syndrome were recruited, and whole-exome sequencing was performed to identify the genetic variants responsible for the abnormal gait, dystonia, and bilateral basal ganglia lesions, followed by validation using Sanger sequencing. Detailed medical records of the patients were collected and reviewed. Patient-derived immortalized B lymphocytes were generalized for functional assays. The clinical manifestations of the patients in this study and previously reported studies are summarized.
    Results: Two patients developed gait dystonia followed by rapid progression to generalized dystonia and psychomotor regression. Brain magnetic resonance images showed lesions in bilateral symmetric basal ganglia. We identified that patient 1 and patient 2 had two missense changes (NM_152416 c.371 T > C, c.923 T > C and c.371 T > C, c.920 A > T) in NDUFAF6, respectively. The deficiency of mature super complex of complex I was confirmed in patient-derived immortalized B lymphocytes. Meanwhile, cellular ATP production was decreased, and mitochondrial ROS was increased. A literature review of 18 patients carrying variants in NDUFAF6 was conducted, focusing on neurological presentation.
    Conclusions: NDUFAF6-related Leigh syndrome is a relevant cause of initial symptoms with abnormal gait, dystonia, and bilateral basal ganglia lesions. Two novel genetic variants, c.923 T > C and c.920 A > T were reported, which expands NDUFAF6-related Leigh syndrome and is advantageous for genetic counseling.
    Keywords:  Complex I deficiency; Leigh syndrome; Mitochondrial disease; NDUFAF6
    DOI:  https://doi.org/10.1016/j.ymgmr.2024.101168
  15. Muscle Nerve. 2024 Dec 23.
    Cyclosporine A Delays the Terminal Disease Stage in the Tfam KO Mitochondrial Myopathy Mouse Model Without Improving Mitochondrial Energy Production.
    Benjamin Chatel, Isabelle Varlet, Augustin C Ogier, Emilie Pecchi, Monique Bernard, Julien Gondin, Håkan Westerblad, David Bendahan, Charlotte Gineste.
       INTRODUCTION AND AIMS: Mitochondrial myopathies are rare genetic disorders for which no effective treatment exists. We previously showed that the pharmacological cyclophilin inhibitor cyclosporine A (CsA) extends the lifespan of fast-twitch skeletal muscle-specific mitochondrial transcription factor A knockout (Tfam KO) mice, lacking the ability to transcribe mitochondrial DNA and displaying lethal mitochondrial myopathy. Our present aim was to assess whether the positive effect of CsA was associated with improved in vivo mitochondrial energy production.
    METHODS: Mice were treated with CsA for 4 weeks, beginning at 12 weeks (i.e., before the terminal disease phase). Hindlimb plantar flexor muscles were fatigued by 80 contractions (40 Hz, 1.5 s on, 6 s off) while measuring force and energy metabolism using phosphorus-31 magnetic resonance spectroscopy.
    RESULTS: Force decreased at similar rates in Tfam KO mice with and without the CsA treatment, reaching 50% of the baseline value after ~14 ± 1 contractions, which was faster than in control mice (25 ± 1 contractions). Phosphocreatine (PCr) decreased to ~10% of the control concentration in Tfam KO mice, independent of the treatment, which was larger than the ~20% observed in control mice. The time constant of PCr recovery was higher in untreated Tfam KO than that in control muscle (+100%) and similar in untreated and CsA-treated Tfam KO mice.
    DISCUSSION: The results do not support improved mitochondrial energy production as a mechanism underlying the prolonged lifespan of Tfam KO mitochondrial myopathy mice treated with CsA. Thus, other mechanisms must be involved, such as the previously observed CsA-mediated protection against excessive mitochondrial Ca2+ accumulation.
    Keywords:  force production; mitochondrial function; muscle disease; pharmacological agent; preclinical model
    DOI:  https://doi.org/10.1002/mus.28315
  16. iScience. 2024 Dec 20. 27(12): 111467
    SLP2 and MIC13 synergistically coordinate MICOS assembly and crista junction formation.
    Ritam Naha, Rebecca Strohm, Yulia Schaumkessel, Jennifer Urbach, Ilka Wittig, Andreas S Reichert, Arun Kumar Kondadi, Ruchika Anand.
      The MICOS complex, essential for cristae organization, comprises MIC10 and MIC60 subcomplexes, with MIC13 as a crucial subunit. MIC13 mutations cause severe mitochondrial hepato-encephalopathy, cristae defects, and MIC10-subcomplex loss. We demonstrate that depletion of the mitochondrial protease YME1L in MIC13 KO stabilizes MIC10-subcomplex, restoring MIC60-MIC10 interaction and crista junction (CJ) defects, indicating MIC13 is crucial for MIC10-subcomplex stabilization rather than MIC60-MIC10 bridging. We identified stomatin-like protein 2 (SLP2) as a key MIC13 interaction partner, essential for cristae morphology and CJ formation. SLP2 serves as an interaction hub for MICOS subunits and stabilizes MIC26 by protecting it from YME1L-mediated degradation. Deleting both SLP2 and MIC13 impairs MIC60-subcomplex assembly and its nanoscale organization. Restoring the MIC10-subcomplex in MIC13-SLP2 double KO cells through YME1L depletion reinstates MIC60-subcomplex assembly and cristae morphology. Overall, we propose SLP2 and the MIC10-subcomplex act as a proteolytically controlled 'seeder' complex, facilitating MICOS-MIB complex assembly and maintaining mitochondrial integrity.
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.111467
  17. Sci Rep. 2024 Dec 28. 14(1): 31017
    PCNA and Rnh1 independently participate in the protection of mitochondrial genome against UV-induced mutagenesis in yeast cells.
    Martyna Latoszek, Katarzyna Baginska-Drabiuk, Ewa Sledziewska-Gojska, Aneta Kaniak-Golik.
      In Saccharomyces cerevisiae cells, the bulk of mitochondrial DNA (mtDNA) replication is mediated by the replicative high-fidelity DNA polymerase γ. However, upon UV irradiation low-fidelity translesion polymerases: Polη, Polζ and Rev1, participate in an error-free replicative bypass of UV-induced lesions in mtDNA. We analysed how translesion polymerases could function in mitochondria. We show that, contrary to expectations, yeast PCNA is mitochondrially localized and, upon genotoxic stress, ubiquitinated PCNA can be detected in purified mitochondria. Moreover, the substitution K164R in PCNA leads to an increase of UV-induced point mutations in mtDNA. This UV-dependent effect is highly enhanced in cells in which the Mec1/Rad53/Dun1 checkpoint-dependent deoxynucleotide triphosphate (dNTP) increase in response to DNA damage is blocked and RNase H1 is lacking, suggesting that PCNA plays a role in a replication damage bypass pathway dealing with lesions in multiple ribonucleotides embedded in mtDNA. In addition, our analysis indicates that K164R in PCNA restricts mostly the anti-mutagenic Polη activity on UV-damaged mtDNA, whereas the inhibitory effect on Polζ's activity is only partial. We also show for the first time that in conditions of dNTP depletion yeast Rnh1 neutralizes deleterious effects of ribonucleotides for mtDNA replication, thereby preventing the enhanced instability of rho+ mitochondrial genomes.
    DOI:  https://doi.org/10.1038/s41598-024-82104-4
  18. J Biol Chem. 2024 Dec 21. pii: S0021-9258(24)02626-7. [Epub ahead of print] 108124
    Deafness-associated mitochondrial 12S rRNA mutation reshapes mitochondrial and cellular homeostasis.
    Yunfan He, Zhining Tang, Gao Zhu, Luhang Cai, Chao Chen, Min-Xin Guan.
      Human mitochondrial 12S ribosomal RNA (rRNA) 1555A>G mutation has been associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide. Our previous investigation revealed that the m.1555A>G mutation impaired mitochondrial translation and oxidative phosphorylation (OXPHOS). However, the mechanisms by which mitochondrial dysfunctions induced by m.1555A>G mutation regulate intracellular signaling for mitochondrial and cellular integrity remain poorly understood. Here, we demonstrated that the m.1555A>G mutation downregulated the expression of nuclear-encoded subunits of complexes I and IV but upregulated the expression of assemble factors for OXPHOS complexes, using cybrids derived from one hearing-impaired Chinese subject bearing the m.1555A>G mutation and from one hearing normal control lacking the mutation. These alterations resulted in the aberrant assembly, instability and reduced activities of respiratory chain enzyme complexes I, IV and V, rate of oxygen consumption, and diminished ATP production. Furthermore, the mutant cell lines carrying the m.1555A>G mutation exhibited decreased membrane potential and increased the production of reactive oxygen species. The aberrant assembly and biogenesis of OXPHOS impacted mitochondrial quality controls, including the imbalance of mitochondrial dynamics via increasing fission with abnormal mitochondrial morphology and impaired mitophagy. Strikingly, the cells bearing the m.1555A>G mutation revealed the upregulation of both ubiquitin-dependent and independent mitophagy pathways, evidenced by increasing the levels of Parkin, Pink, BNIP3L and NIX. The m.1555A>G mutation-induced deficiencies ameliorate the cell homeostasis via elevating the autophagy process and upregulating apoptotic pathways. Our findings provide new insights into pathophysiology of mitochondrial deafness arising from reshaping mitochondrial and cellular homeostasis due to 12S rRNA 1555A>G mutation.
    DOI:  https://doi.org/10.1016/j.jbc.2024.108124
  19. Biogerontology. 2024 Dec 27. 26(1): 33
    Aging through the lens of mitochondrial DNA mutations and inheritance paradoxes.
    Jia Chen, Hongyu Li, Runyu Liang, Yongyin Huang, Qiang Tang.
      Mitochondrial DNA encodes essential components of the respiratory chain complexes, serving as the foundation of mitochondrial respiratory function. Mutations in mtDNA primarily impair energy metabolism, exerting far-reaching effects on cellular physiology, particularly in the context of aging. The intrinsic vulnerability of mtDNA is increasingly recognized as a key driver in the initiation of aging and the progression of its related diseases. In the field of aging research, it is critical to unravel the intricate mechanisms underpinning mtDNA mutations in living organisms and to elucidate the pathological consequences they trigger. Interestingly, certain effects, such as oxidative stress and apoptosis, may not universally accelerate aging as traditionally perceived. These phenomena demand deeper investigation and a more nuanced reinterpretation of current findings to address persistent scientific uncertainties. By synthesizing recent insights, this review seeks to clarify how pathogenic mtDNA mutations drive cellular senescence and systemic health deterioration, while also exploring the complex dynamics of mtDNA inheritance that may propagate these mutations. Such a comprehensive understanding could ultimately inform the development of innovative therapeutic strategies to counteract mitochondrial dysfunctions associated with aging.
    Keywords:  Aging; Evolutionary selection; Genetic bottleneck; Mitochondrial DNA mutations; Mother’s curse
    DOI:  https://doi.org/10.1007/s10522-024-10175-x
  20. J Transl Med. 2024 Dec 20. 22(1): 1126
    Mitochondrial quality control: the real dawn of intervertebral disc degeneration?
    Ba Qiu, Xiaoxing Xie, Yanhai Xi.
      Intervertebral disc degeneration is the most common disease in chronic musculoskeletal diseases and the main cause of low back pain, which seriously endangers social health level and increases people's economic burden. Disc degeneration is characterized by NP cell apoptosis, extracellular matrix degradation and disc structure changes. It progresses with age and under the influence of mechanical overload, oxidative stress and genetics. Mitochondria are not only the energy factories of cells, but also participate in a variety of cellular functions such as calcium homeostasis, regulation of cell proliferation, and control of apoptosis. The mitochondrial quality control system involves many mechanisms such as mitochondrial gene regulation, mitochondrial protein import, mitophagy, and mitochondrial dynamics. A large number of studies have confirmed that mitochondrial dysfunction is a key factor in the pathological mechanism of aging and intervertebral disc degeneration, and balancing mitochondrial quality control is extremely important for delaying and treating intervertebral disc degeneration. In this paper, we first demonstrate the molecular mechanism of mitochondrial quality control in detail by describing mitochondrial biogenesis and mitophagy. Then, we describe the ways in which mitochondrial dysfunction leads to disc degeneration, and review in detail the current research on targeting mitochondria for the treatment of disc degeneration, hoping to draw inspiration from the current research to provide innovative perspectives for the treatment of disc degeneration.
    Keywords:  Intervertebral disc degeneration; Mitochondrial dysfunction; Mitochondrial quality control; Mitochondrion
    DOI:  https://doi.org/10.1186/s12967-024-05943-9
  21. Redox Biol. 2024 Dec 22. pii: S2213-2317(24)00452-X. [Epub ahead of print]79 103474
    Mitochondrial ROS modulate presynaptic plasticity in the drosophila neuromuscular junction.
    Irina Stavrovskaya, Bethany Kristi Morin, Stephen Madamba, Cliyahnelle Alexander, Alexis Romano, Samia Alam, Lucas Pavlov, Erna Mitaishvili, Pablo M Peixoto.
      The elevated emission of reactive oxygen species (ROS) from presynaptic mitochondria is well-documented in several inflammatory and neurodegenerative diseases. However, the potential role of mitochondrial ROS in presynaptic function and plasticity remains largely understudied beyond the context of disease. Here, we investigated this potential ROS role in presynaptic function and short-term plasticity by combining optogenetics, whole cell electrophysiological recordings, and live confocal imaging using a well-established protocol for induction and measurement of synaptic potentiation in Drosophila melanogaster neuromuscular junctions (NMJ). Optogenetic induction of ROS emission from presynaptic motorneuron mitochondria expressing mitokiller red (mK) resulted in synaptic potentiation, evidenced by an increase in the frequency of spontaneous mini excitatory junction potentials. Notably, this effect was not observed in flies co-expressing catalase, a cytosolic hydrogen peroxide (H2O2) scavenging enzyme. Moreover, the increase in electrical activity did not coincide with synaptic structural changes. The absence of Wnt1/Wg release from synaptic boutons suggested involvement of alternative or non-canonical signaling pathway(s). However, in existing boutons we observed an increase in the active zone (AZ) marker Brp/Erc1, which serves as docking site for the neurotransmitter vesicle release pool. We propose the involvement of putative redox switches in AZ components as the molecular target of mitochondrial H2O2. These findings establish a novel framework for understanding the signaling role of mROS in presynaptic structural and functional plasticity, providing insights into redox-based mechanisms of neuronal communication.
    Keywords:  Activity-dependent short-term synaptic plasticity; Drosophila; Live imaging; Mitochondrial oxidative signaling; Neuromuscular junction; Optogenetics
    DOI:  https://doi.org/10.1016/j.redox.2024.103474
  22. Free Radic Biol Med. 2024 Dec 18. pii: S0891-5849(24)01147-X. [Epub ahead of print]227 619-628
    Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.
    Yiwei Feng, Zhijian Rao, Xu Tian, Yi Hu, Liantian Yue, Yifan Meng, Qiuling Zhong, Wei Chen, Wenlong Xu, Haoran Li, Yingjia Hu, Rengfei Shi.
      The mitochondrial open reading frame of 12S rRNA-c (MOTS-c) is a biologically active mitochondria-derived peptide. However, the relationship between MOTS-c, skeletal muscle mitochondrial function, and endurance exercise adaptations is unknown. Here, we tested indices such as maximal oxygen uptake and serum MOTS-c levels in marathon runners and sedentary subjects. In addition, we tested aerobic exercise capacity, skeletal muscle mitochondrial respiration rate, and serum MOTS-c levels in mice subjected to long-term endurance training groups and sedentary groups. Our results indicated a close association between serum MOTS-c levels and aerobic exercise capacity. Circulating MOTS-c levels are expected to be an important indicator for predicting aerobic exercise capacity and assessing body fat status, endurance training load, and physical function. More importantly, we found that endurance training may enhance the mitochondrial respiratory function of skeletal muscle by promoting the secretion of MOTS-c and activating the AMPK/PGC-1α pathway.
    Keywords:  Exercise; Mitochondria; Mitochondrial-derived peptides; Skeletal muscle; The mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-C)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.038
  23. Methods Mol Biol. 2025 ;2840 175-183
    Alternating Cellular Functions by Optogenetic Control of Organelles.
    Kangqiang Qiu, Xiuqiong Xu, Kai Zhang, Jiajie Diao.
      Organelles play essential roles in cellular homeostasis and various cellular functions in eukaryotic cells. The current experimental strategy to modulate organelle functions is limited due to the dynamic nature and subcellular distribution of organelles in live cells. Optogenetics utilizes photoactivatable proteins to enable dynamic control of molecular activities through visible light. This modality has been rapidly expanded for the dynamic regulation of organelle functions. This chapter describes a method by optical modulation of the mitochondria-lysosome contacts (MLCs). Detailed procedures of transfection, optogenetic MLCs, mitochondrial morphology, and functional analysis are described. Optogenetic control of organelles in live cells offers an innovative paradigm for cell engineering and synthetic biology.
    Keywords:  Mitochondria-lysosome contacts; Mitochondrial fission; Optogenetics; Regulation of cellular functions; Subcellular manipulation
    DOI:  https://doi.org/10.1007/978-1-0716-4047-0_13
  24. Nucleic Acids Res. 2024 Dec 24. pii: gkae1259. [Epub ahead of print]
    A subcellular selective APEX2-based proximity labeling used for identifying mitochondrial G-quadruplex DNA binding proteins.
    Xu Wang, Geng Qin, Jie Yang, Chuanqi Zhao, Jinsong Ren, Xiaogang Qu.
      G-quadruplexes (G4s), as an important type of non-canonical nucleic acid structure, have received much attention because of their regulations of various biological processes in cells. Identifying G4s-protein interactions is essential for understanding G4s-related biology. However, current strategies for exploring G4 binding proteins (G4BPs) include pull-down assays in cell lysates or photoaffinity labeling, which are lack of sufficient spatial specificity at the subcellular level. Herein, we develop a subcellular selective APEX2-based proximity labeling strategy to investigate the interactome of mitochondrial DNA (mtDNA) G4s in living cells. By this method, we have identified several mtDNA G4BPs. Among them, a previously unrecognized mtDNA G4BP, DHX30 has been selected as an example to explore its important biofunctions. DHX30 localizes both in cytoplasm and mitochondria and can resolve mtDNA G4s. Further studies have demonstrated that DHX30 unfolds mtDNA G4 in living cells, which results in a decrease in glycolysis activity of tumor cells. Besides, RHPS4, a known mtDNA G4 stabilizer, will reverse this inhibition effect. Benefiting from the high spatiotemporal resolution and the ability of genetically encoded systems to perform the labeling with exquisite specificity within living cells, our approach can realize the identification of subcellular localized G4BPs. Our work provides a novel strategy to map protein interactions of specific nucleic acid features in subcellular compartments of living cells.
    DOI:  https://doi.org/10.1093/nar/gkae1259
  25. Adv Sci (Weinh). 2024 Dec 23. e2404620
    Nuclear Control of Mitochondrial Homeostasis and Venetoclax Efficacy in AML via COX4I1.
    Leisi Zhang, Honghai Zhang, Ting-Yu Wang, Mingli Li, Anthony K N Chan, Hyunjun Kang, Lai C Foong, Qiao Liu, Sheela Pangeni Pokharel, Nicole M Mattson, Priyanka Singh, Zeinab Elsayed, Benjamin Kuang, Xueer Wang, Steven T Rosen, Jianjun Chen, Lu Yang, Tsui-Fen Chou, Rui Su, Chun-Wei David Chen.
      Cell signaling pathways are enriched for biological processes crucial for cellular communication, response to external stimuli, and metabolism. Here, a cell signaling-focused CRISPR screen identified cytochrome c oxidase subunit 4 isoform 1 (COX4I1) as a novel vulnerability in acute myeloid leukemia (AML). Depletion of COX4I1 hindered leukemia cell proliferation and impacted in vivo AML progression. Mechanistically, loss of COX4I1 induced mitochondrial stress and ferroptosis, disrupting mitochondrial ultrastructure and oxidative phosphorylation. CRISPR gene tiling scans, coupled with mitochondrial proteomics, dissected critical regions within COX4I1 essential for leukemia cell survival, providing detailed insights into the mitochondrial Complex IV assembly network. Furthermore, COX4I1 depletion or pharmacological inhibition of Complex IV (using chlorpromazine) synergized with venetoclax, providing a promising avenue for improved leukemia therapy. This study highlights COX4I1, a nuclear encoded mitochondrial protein, as a critical mitochondrial checkpoint, offering insights into its functional significance and potential clinical implications in AML.
    Keywords:  COX4I1; chlorpromazine; leukemia; mitochondria; venetoclax
    DOI:  https://doi.org/10.1002/advs.202404620
  26. J Invest Dermatol. 2024 Dec 24. pii: S0022-202X(24)03026-4. [Epub ahead of print]
    Mitochondrial deletion4977 abundance in melanoma-adjacent skin.
    Katie J Lee, Yung-Ching Kao, Darren J Smit, Brigid Betz-Stablein, Nancy Huang, Samuel Kahler, H Peter Soyer, Mitchell S Stark.
      
    Keywords:  melanoma; mitochondria; photodamage; skin; somatic genomics
    DOI:  https://doi.org/10.1016/j.jid.2024.11.009
  27. Cell Prolif. 2024 Dec 26. e13796
    Mitonuclear Communication in Stem Cell Function.
    Baozhou Peng, Yaning Wang, Hongbo Zhang.
      Mitochondria perform multiple functions within the cell, including the production of ATP and a great deal of metabolic intermediates, while also contributing to the cellular stress response. The majority of mitochondrial proteins are encoded by nuclear genomes, highlighting the importance of mitonuclear communication for sustaining mitochondrial homeostasis and functional. As a crucial part of the intracellular signalling network, mitochondria can impact stem cell fate determinations. Considering the essential function of stem cells in tissue maintenance, regeneration and aging, it is important to understand how mitochondria influence stem cell fate. This review explores the significant roles of mitonuclear communication and mitochondrial proteostasis, highlighting their influence on stem cells. We also examine how mitonuclear interactions contribute to cellular homeostasis, stem cell therapies, and the potential for extending lifespan.
    Keywords:  aging; fate determination; metabolism; mitochondria; mitochondrial stress; mitonuclear communication; stem cell
    DOI:  https://doi.org/10.1111/cpr.13796
  28. bioRxiv. 2024 Dec 12. pii: 2024.12.09.627454. [Epub ahead of print]
    Mitochondrial DNA mutations in human oocytes undergo frequency-dependent selection but do not increase with age.
    Barbara Arbeithuber, Kate Anthony, Bonnie Higgins, Peter Oppelt, Omar Shebl, Irene Tiemann-Boege, Francesca Chiaromonte, Thomas Ebner, Kateryna D Makova.
      Mitochondria, cellular powerhouses, harbor DNA (mtDNA) inherited from the mothers. MtDNA mutations can cause diseases, yet whether they increase with age in human germline cells-oocytes-remains understudied. Here, using highly accurate duplex sequencing of full-length mtDNA, we detected de novo mutations in single oocytes, blood, and saliva in women between 20 and 42 years of age. We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies (≥1%) were less prevalent in coding than non-coding regions, whereas mutations with low allele frequencies (<1%) were more uniformly distributed along mtDNA, suggesting frequency-dependent purifying selection. In somatic tissues, mutations caused elevated amino acid changes in protein-coding regions, suggesting positive or destructive selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations having functional consequences and with aging. These findings are particularly timely as humans tend to reproduce later in life.
    DOI:  https://doi.org/10.1101/2024.12.09.627454
  29. JIMD Rep. 2025 Jan;66(1): e12459
    Mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicing.
    Undiagnosed Diseases Network
      Trifunctional protein deficiency (TFP) is a disorder of fatty acid beta-oxidation associated with metabolic, cardiac, and liver dysfunction in severe forms. We present two siblings diagnosed by newborn screening and confirmed by biochemical testing at birth. Their clinical course was complicated by recurrent rhabdomyolysis, retinopathy, and hypoparathyroidism. Both siblings were also diagnosed with focal segmental glomerulosclerosis (FSGS) and bone marrow failure and ultimately died of hypoxemic respiratory failure. Initial sequencing of the TFP-associated genes HADHA and HADHB showed only a paternally inherited variant in HADHB, NM_000183.3:c.1059del (p.Gly354AspfsTer10). Subsequent evaluation by the Undiagnosed Diseases Network with genome and transcriptome sequencing revealed a rare maternally inherited 17 base pair deletion in HADHB, NM_000183.3:c.1390-515_1390-499del, located in the final intron and resulting in a pseudoexon that harbors a premature termination codon. Both sisters were compound heterozygous for this and the paternal premature termination codon. No other variants were detected that were potentially causative for the FSGS and bone marrow failure on genome sequencing. A review of the literature at that time revealed several case reports of the uncommon clinical findings of FSGS, bone marrow failure, and pulmonary involvement in patients with TFP, confirming this clinical diagnosis as the complete explanation for these siblings.
    Keywords:  RNAseq; Undiagnosed Diseases Network; intronic variant; nephrotic syndrome; trifunctional protein deficiency
    DOI:  https://doi.org/10.1002/jmd2.12459
  30. Metabolites. 2024 Dec 18. pii: 711. [Epub ahead of print]14(12):
    The Mitochondrial Blueprint: Unlocking Secondary Metabolite Production.
    Yang Li, Yujia Zhang, Xinyu He, Ziyi Guo, Ning Yang, Guohui Bai, Juanjuan Zhao, Delin Xu.
      Mitochondrial metabolism plays a pivotal role in regulating the synthesis of secondary metabolites, which are crucial for the survival and adaptation of organisms. These metabolites are synthesized during specific growth stages or in response to environmental stress, reflecting the organism's ability to adapt to changing conditions. Mitochondria, while primarily known for their role in energy production, directly regulate secondary metabolite biosynthesis by providing essential precursor molecules, energy, and reducing equivalents necessary for metabolic reactions. Furthermore, they indirectly influence secondary metabolism through intricate signaling pathways, including reactive oxygen species (ROS), metabolites, and redox signaling, which modulate various metabolic processes. This review explores recent advances in understanding the molecular mechanisms governing mitochondrial metabolism and their regulatory roles in secondary metabolite biosynthesis, which highlights the involvement of transcription factors, small RNAs, and post-translational mitochondrial modifications in shaping these processes. By integrating current insights, it aims to inspire future research into mitochondrial regulatory mechanisms in Arabidopsis thaliana, Solanum tuberosum, Nicotiana tabacum, and others that may enhance their secondary metabolite production. A deeper understanding of the roles of mitochondria in secondary metabolism could contribute to the development of new approaches in biotechnology applications.
    Keywords:  biosynthesis; mitochondria; regulation mechanism; secondary metabolites; signaling pathway
    DOI:  https://doi.org/10.3390/metabo14120711
  31. Cell Stem Cell. 2024 Dec 12. pii: S1934-5909(24)00413-2. [Epub ahead of print]
    Different effects of fatty acid oxidation on hematopoietic stem cells based on age and diet.
    Salma Merchant, Animesh Paul, Amanda Reyes, Daniel Cassidy, Ashley Leach, Dohun Kim, Sarah Muh, Gerik Grabowski, Gerta Hoxhaj, Zhiyu Zhao, Sean J Morrison.
      Fatty acid oxidation is of uncertain importance in most stem cells. We show by 14C-palmitate tracing and metabolomic analysis that hematopoietic stem/progenitor cells (HSPCs) engage in long-chain fatty acid oxidation that depends upon carnitine palmitoyltransferase 1a (CPT1a) and hydroxyacyl-CoA dehydrogenase (HADHA) enzymes. CPT1a or HADHA deficiency had little or no effect on HSPCs or hematopoiesis in young adult mice. Young HSPCs had the plasticity to oxidize other substrates, including glutamine, and compensated for loss of fatty acid oxidation by decreasing pyruvate dehydrogenase phosphorylation, which should increase function. This metabolic plasticity declined as mice aged, when CPT1a or HADHA deficiency altered hematopoiesis and impaired hematopoietic stem cell (HSC) function upon serial transplantation. A high-fat diet increased fatty acid oxidation and reduced HSC function. This was rescued by CPT1a or HADHA deficiency, demonstrating that increased fatty acid oxidation can undermine HSC function. Long-chain fatty acid oxidation is thus dispensable in young HSCs but necessary during aging and deleterious with a high-fat diet.
    Keywords:  aging; fatty acid; hematopoiesis; high-fat diet; metabolic plasticity; metabolism; mitochondria; β-oxidation
    DOI:  https://doi.org/10.1016/j.stem.2024.11.014
  32. Neurotherapeutics. 2024 Dec 26. pii: S1878-7479(24)00200-9. [Epub ahead of print] e00513
    Nuclear respiratory factor-1 (NRF1) induction drives mitochondrial biogenesis and attenuates amyloid beta-induced mitochondrial dysfunction and neurotoxicity.
    Matteo Massaro, Gherardo Baudo, Hyunho Lee, Haoran Liu, Elvin Blanco.
      Mitochondrial dysfunction is an important driver of neurodegeneration and synaptic abnormalities in Alzheimer's disease (AD). Amyloid beta (Aβ) in mitochondria leads to increased reactive oxygen species (ROS) production, resulting in a vicious cycle of oxidative stress in coordination with a defective electron transport chain (ETC), decreasing ATP production. AD neurons exhibit impaired mitochondrial dynamics, evidenced by fusion and fission imbalances, increased fragmentation, and deficient mitochondrial biogenesis, contributing to fewer mitochondria in brains of AD patients. Nuclear respiratory factor-1 (NRF1) is a regulator of mitochondrial biogenesis through its activation of mitochondrial transcription factor A (TFAM). Our hypothesis posited that NRF1 induction in neuronal cells exposed to amyloid β1-42 (Aβ1-42) would increase de novo mitochondrial synthesis and improve mitochondrial function, restoring neuronal survival. Following NRF1 messenger RNA (mRNA) transfection of Aβ1-42-treated SH-SY5Y cells, a marked increase in mitochondrial mass was observed. Metabolic programming toward enhanced oxidative phosphorylation resulted in increased ATP production. Oxidative stress in the form of mitochondrial ROS accumulation was reduced and mitochondrial membrane potential preserved. Mitochondrial homeostasis was maintained, evidenced by balanced fusion and fission processes. Ultimately, improvement of mitochondrial function was associated with significant decreases in Aβ1-42-induced neuronal death and neurite disruption. Our findings highlight the potential of NRF1 upregulation to counteract Aβ1-42-associated mitochondrial dysfunction and neurodegenerative cell processes, opening avenues for innovative therapeutic approaches aimed at safeguarding mitochondrial health in AD neurons.
    Keywords:  Alzheimer's disease; Amyloid beta; Mitochondrial biogenesis; Mitochondrial dysfunction; Nuclear respiratory factor-1 (NRF1)
    DOI:  https://doi.org/10.1016/j.neurot.2024.e00513
  33. Cell Rep. 2024 Dec 21. pii: S2211-1247(24)01445-1. [Epub ahead of print]44(1): 115094
    The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses.
    Chan Hoon Jung, Yoon Jee Lee, Eun Hye Cho, Gee Eun Lee, Sung Tae Kim, Ki Sa Sung, Daeho Kim, Dong Hyun Kim, Yeon Sung Son, Jin-Hyun Ahn, Dohyun Han, Yong Tae Kwon.
      The human body reacts to tissue damage by generating damage-associated molecular patterns (DAMPs) that activate sterile immune responses. To date, little is known about how DAMPs are removed to avoid excessive immune responses. Here, we show that proteasomal dysfunction induces the release of mitochondrial DNA (mtDNA) as a DAMP that activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway and is subsequently degraded through the N-degron pathway. In the resolution phase of sterile immune responses, DNA-dependent protein kinase (DNA-PK) senses cytosolic mtDNA and activates N-terminal (Nt-) arginylation by ATE1 R-transferases. The substrates of Nt-arginylation include the molecular chaperone BiP/GRP78 retrotranslocated from the endoplasmic reticulum (ER). R-BiP, the Nt-arginylated species of BiP, is associated with cytosolic mtDNA to accelerate its targeting to autophagic membranes for lysosomal degradation. Thus, cytosolic mtDNA activates the N-degron pathway to facilitate its own degradation and form a negative feedback loop, by which the cell can turn off sterile immune responses at the right time.
    Keywords:  ATE1; CP: Immunology; DNA-PK; KU70; R-BiP; autophagy; mitochondrial DNA; proteasomal dysfunction; sterile immune response; the N-degron pathway; type I interferon
    DOI:  https://doi.org/10.1016/j.celrep.2024.115094
  34. Nucleic Acids Res. 2024 Dec 27. pii: gkae1261. [Epub ahead of print]
    The Vsr-like protein FASTKD4 regulates the stability and polyadenylation of the MT-ND3 mRNA.
    Xuan Yang, Maike Stentenbach, Laetitia A Hughes, Stefan J Siira, Kelvin Lau, Michael Hothorn, Jean-Claude Martinou, Oliver Rackham, Aleksandra Filipovska.
      Expression of the compact mitochondrial genome is regulated by nuclear encoded, mitochondrially localized RNA-binding proteins (RBPs). RBPs regulate the lifecycles of mitochondrial RNAs from transcription to degradation by mediating RNA processing, maturation, stability and translation. The Fas-activated serine/threonine kinase (FASTK) family of RBPs has been shown to regulate and fine-tune discrete aspects of mitochondrial gene expression. Although the roles of specific targets of FASTK proteins have been elucidated, the molecular mechanisms of FASTK proteins in mitochondrial RNA metabolism remain unclear. Therefore, we resolved the structure of FASTKD4 at atomic level that includes the RAP domain and the two FAST motifs, creating a positively charged cavity resembling that of the very short patch repair endonuclease. Our biochemical studies show that FASTKD4 binds the canonical poly(A) tail of MT-ND3 enabling its maturation and translation. The in vitro role of FASTKD4 is consistent with its loss in cells that results in decreased MT-ND3 polyadenylation, which destabilizes this messenger RNA in mitochondria.
    DOI:  https://doi.org/10.1093/nar/gkae1261
  35. Biomaterials. 2024 Dec 15. pii: S0142-9612(24)00559-3. [Epub ahead of print]316 123023
    Mitochondria-targeting materials and therapies for regenerative engineering.
    Hongying Fu, Jingrong Cheng, Le Hu, Boon Chin Heng, Xuehui Zhang, Xuliang Deng, Yang Liu.
      The hemostatic, inflammatory, proliferative, and remodeling phases of healing require precise spatiotemporal coordination and orchestration of numerous biological processes. As the primary energy generators in the cell, mitochondria play multifunctional roles in regulating metabolism, stress reactions, immunity, and cell density during the process of tissue regeneration. Mitochondrial dynamics involves numerous crucial processes, fusion, fission, autophagy, and translocation, which are all necessary for preserving mitochondrial function, distributing energy throughout cells, and facilitating cellular signaling. Tissue regeneration is specifically associated with mitochondrial dynamics due to perturbations of Ca2+, H2O2 and ROS levels, which can result in mitochondrial malfunction. Increasing evidence from multiple models suggests that clinical interventions or medicinal drugs targeting mitochondrial dynamics could be a promising approach. This review highlights significant advances in the understanding of mitochondrial dynamics in tissue regeneration, with specific attention on mitochondria-targeting biomaterials that accelerate multiple tissues' regeneration by regulating mitochondrial metabolism. The innovations in nanomaterials and nanosystems enhance mitochondrial-targeting therapies are critically examined with the prospects of modulating mitochondrial dynamics for new therapies in regenerative engineering.
    Keywords:  Mitochondria-targeting materials; Mitochondrial dynamics; Mitochondrial transfer; Regenerative engineering
    DOI:  https://doi.org/10.1016/j.biomaterials.2024.123023
  36. Cancer Metab. 2024 Dec 23. 12(1): 39
    Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma.
    Fatimah J Al Khazal, Sanjana Mahadev Bhat, Yuxiang Zhu, Cristina M de Araujo Correia, Sherry X Zhou, Brandon A Wilbanks, Clifford D Folmes, Gary C Sieck, Judith Favier, L James Maher.
      Heterozygosity for loss-of-function alleles of the genes encoding the four subunits of succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD), as well as the SDHAF2 assembly factor predispose affected individuals to pheochromocytoma and paraganglioma (PPGL), two rare neuroendocrine tumors that arise from neural crest-derived paraganglia. Tumorigenesis results from loss of the remaining functional SDHx gene copy, leading to a cell with no functional SDH and a defective tricarboxylic acid (TCA) cycle. It is believed that the subsequent accumulation of succinate competitively inhibits multiple dioxygenase enzymes that normally suppress hypoxic signaling and demethylate histones and DNA, ultimately leading to increased expression of genes involved in angiogenesis and cell proliferation. Why SDH loss is selectively tumorigenic in neuroendocrine cells remains poorly understood. In the absence of SDH-loss tumor-derived cell models, the cellular burden of SDH loss and succinate accumulation have been investigated through conditional knockouts of SDH subunits in pre-existing murine or human cell lines with varying degrees of clinical relevance. Here we characterize two available murine SDH-loss cell lines, immortalized adrenally-derived premature chromaffin cells vs. immortalized fibroblasts, at a level of detail beyond that currently reported in the literature and with the intention of laying the foundation for future investigations into adaptive pathways and vulnerabilities in SDH-loss cells. We report different mechanistic and phenotypic manifestations of SDH subunit loss in the presented cellular contexts. These findings highlight similarities and differences in the cellular response to SDH loss between the two cell models. We show that adrenally-derived cells display more severe morphological cellular and mitochondrial alterations, yet are unique in preserving residual Complex I function, perhaps allowing them to better tolerate SDH loss, thus making them a closer model to SDH-loss PPGL relative to fibroblasts.(281 words).
    Keywords:  Complex I; Hypoxia; Paraganglioma; Pheochromocytoma; Succinate dehydrogenase; Tricarboxylic acid cycle
    DOI:  https://doi.org/10.1186/s40170-024-00369-9
  37. Genomics Proteomics Bioinformatics. 2024 Dec 26. pii: qzae092. [Epub ahead of print]
    Single Cell Sequencing Traces Mitochondrial Transfers.
    Mengying Wu, Weilin Pu, Zhenglong Gu.
      
    DOI:  https://doi.org/10.1093/gpbjnl/qzae092
  38. J Biol Chem. 2024 Dec 23. pii: S0021-9258(24)02619-X. [Epub ahead of print] 108117
    Disruption of deoxyribonucleotide triphosphate biosynthesis leads to RAS proto-oncogene activation and perturbation of mitochondrial metabolism.
    Rodolphe Suspène, Kyle A Raymond, Pablo Guardado-Calvo, Julien Dairou, Frédéric Bonhomme, Christine Bonenfant, Serge Guyetant, Thierry Lecomte, Jean-Christophe Pagès, Jean-Pierre Vartanian.
      Perturbation of the deoxyribonucleotide triphosphate (dNTP) pool is recognized for contributing to the mutagenic processes involved in oncogenesis. The RAS gene family encodes well characterized oncoproteins whose structure and function are among the most frequently altered in several cancers. In this work, we show that fluctuation of the dNTP pool induces CG->TA mutations across the whole genome, including RAS gene at codons for glycine 12 and 13, known hotspots in cancers. Cell culture addition of the ribonucleotide reductase inhibitor thymidine increases the mutation frequency in nuclear DNA and leads to disruption of mitochondrial metabolism. Interestingly, this effect is counteracted by the addition of deoxycytidine. Finally, screening for the loss of hydrogen bonds detecting CG->TA transition in RAS gene of 135 patients with colorectal cancer confirmed the clinical relevance of this process. All together, these data demonstrate that fluctuation of intracellular dNTP pool alters the nuclear DNA and mitochondrial metabolism.
    Keywords:  DNA; RAS gene; cancer; mitochondria; mutation; nucleotide
    DOI:  https://doi.org/10.1016/j.jbc.2024.108117
  39. Elife. 2024 Dec 23. pii: RP97180. [Epub ahead of print]13
    Base editing of Ptbp1 in neurons alleviates symptoms in a mouse model of Parkinson's disease.
    Desiree Böck, Maria Wilhelm, Jonas Mumenthaler, Daniel Fabio Carpanese, Peter I Kulcsár, Simon d'Aquin, Alessio Cremonesi, Anahita Rassi, Johannes Häberle, Tommaso Patriarchi, Gerald Schwank.
      Parkinson's disease (PD) is a multifactorial disease caused by irreversible progressive loss of dopaminergic neurons (DANs). Recent studies have reported the successful conversion of astrocytes into DANs by repressing polypyrimidine tract binding protein 1 (PTBP1), which led to the rescue of motor symptoms in a chemically-induced mouse model of PD. However, follow-up studies have questioned the validity of this astrocyte-to-DAN conversion model. Here, we devised an adenine base editing strategy to downregulate PTBP1 in astrocytes and neurons in a chemically-induced PD mouse model. While PTBP1 downregulation in astrocytes had no effect, PTBP1 downregulation in neurons of the striatum resulted in the expression of the DAN marker tyrosine hydroxylase (TH) in non-dividing neurons, which was associated with an increase in striatal dopamine concentrations and a rescue of forelimb akinesia and spontaneous rotations. Phenotypic analysis using multiplexed iterative immunofluorescence imaging further revealed that most of these TH-positive cells co-expressed the dopaminergic marker DAT and the pan-neuronal marker NEUN, with the majority of these triple-positive cells being classified as mature GABAergic neurons. Additional research is needed to fully elucidate the molecular mechanisms underlying the expression of the observed markers and understand how the formation of these cells contributes to the rescue of spontaneous motor behaviors. Nevertheless, our findings support a model where downregulation of neuronal, but not astrocytic, PTBP1 can mitigate symptoms in PD mice.
    Keywords:  6-OHDA; CRISPR-cas; Ptbp1; base editing; gene therapy; mouse; neuroscience; parkinson's disease; regenerative medicine; stem cells
    DOI:  https://doi.org/10.7554/eLife.97180
  40. Aging Cell. 2024 Dec 25. e14446
    Nuclear respiratory factor-1 (NRF1) induction as a powerful strategy to deter mitochondrial dysfunction and senescence in mesenchymal stem cells.
    Hyunho Lee, Matteo Massaro, Nourhan Abdelfattah, Gherardo Baudo, Haoran Liu, Kyuson Yun, Elvin Blanco.
      Mesenchymal stem cells (MSCs) are promising candidates for regenerative therapies due to their self-renewal and differentiation capabilities. Pathological microenvironments expose MSCs to senescence-inducing factors such as reactive oxygen species (ROS), resulting in MSC functional decline and loss of stemness. Oxidative stress leads to mitochondrial dysfunction, a hallmark of senescence, and is prevalent in aging tissues characterized by elevated ROS levels. We hypothesized that overexpression of nuclear respiratory factor-1 (NRF1), a driver of mitochondrial biogenesis, could metabolically potentiate MSCs and prevent MSC senescence. Single-cell RNA sequencing (scRNA-Seq) revealed that MSCs transfected with NRF1 messenger RNA (mRNA) exhibited upregulated expression of genes associated with oxidative phosphorylation (OXPHOS), decreased glycolytic markers, and suppression of senescence-related pathways. To test whether NRF1 induction could mitigate stress-induced premature senescence, we exposed MSCs to hydrogen peroxide (H2O2) and validated our findings in a replicative senescence model. NRF1 mRNA transfection significantly increased mitochondrial mass and improved aberrant mitochondrial processes associated with senescence, including reduced mitochondrial and intracellular total ROS production. Mitochondrial health and dynamics were preserved, and respiratory function was restored, as evidenced by enhanced OXPHOS, reduced glycolysis, and increased ATP production. Notably, NRF1 overexpression led to decreased senescence-associated β-galactosidase (SA-β-gal) activity and reduced expression of senescence markers p53, p21, and p16. Our findings demonstrate that NRF1 induction attenuates MSC senescence by enhancing mitochondrial function, suggesting potential translational applications for MSC-based therapies and senescence-targeted interventions.
    Keywords:  mesenchymal stem cells; mitochondrial biogenesis; mitochondrial dysfunction; nuclear respiratory factor‐1 (NRF1); oxidative stress; senescence
    DOI:  https://doi.org/10.1111/acel.14446
  41. Eur J Med Chem. 2024 Dec 11. pii: S0223-5234(24)01032-8. [Epub ahead of print]283 117150
    Advancing mitochondrial therapeutics: Synthesis and pharmacological evaluation of pyrazole-based inhibitors targeting the mitochondrial pyruvate carrier.
    Lingaiah Maram, Jessica M Michael, Henry Politte, Vaishnavi S Srirama, Aymen Hadji, Mohammad Habibi, Meredith O Kelly, Rita T Brookheart, Brian N Finck, Lamees Hegazy, Kyle S McCommis, Bahaa Elgendy.
      Inhibition of mitochondrial pyruvate transport via the mitochondrial pyruvate carrier (MPC) has shown beneficial effects in treating metabolic diseases, certain cancers, various forms of neurodegeneration, and hair loss. These benefits arise either from the direct inhibition of mitochondrial pyruvate metabolism or from the metabolic rewiring when pyruvate entry is inhibited. However, current MPC inhibitors are either nonspecific or possess poor pharmacokinetic properties. To address this, approximately 50 pyrazole-based MPC inhibitors were synthesized to explore the structure-activity relationship for MPC inhibition, evaluated through inhibition of mitochondrial pyruvate respiration. These inhibitors were designed with increased steric hindrance around electron-deficient double bonds, allowing for refined structural modifications that reduce their potential to act as Michael acceptors. Additionally, the new MPC inhibitors directly inhibited stellate cell activation, indicating their potential as therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). Unlike the thiazolidinedione class of MPC inhibitors, these compounds did not activate the nuclear receptor PPARγ. Molecular modeling was conducted to explore interactions between these novel inhibitors and the MPC complex. We have identified the chemical determinants critical for MPC inhibition and successfully developed novel inhibitors that are potent, specific and possess excellent physicochemical properties, high solubility, and outstanding metabolic stability in human liver microsomes.
    DOI:  https://doi.org/10.1016/j.ejmech.2024.117150
  42. Exp Neurol. 2024 Dec 20. pii: S0014-4886(24)00449-7. [Epub ahead of print]385 115123
    Ndufs4 inactivation in glutamatergic neurons reveals swallow-breathing discoordination in a mouse model of Leigh syndrome.
    Alyssa Huff, Luiz Marcelo Oliveira, Marlusa Karlen-Amarante, Favour Ebiala, Jan Marino Ramirez, Franck Kalume.
      Swallowing, both nutritive and non-nutritive, is highly dysfunctional in children with Leigh Syndrome (LS) and contributes to the need for both gastrostomy and tracheostomy tube placement. Without these interventions aspiration of food, liquid, and mucus occur resulting in repeated bouts of respiratory infection. No study has investigated whether mouse models of LS, a neurometabolic disorder, exhibit dysfunctions in neuromuscular activity of swallow and breathing integration. We used a genetic mouse model of LS in which the NDUFS4 gene is knocked out (KO) specifically in Vglut2 or Gad2 neurons. We found increased variability of the swallow motor pattern, disruption in breathing regeneration post swallow, and water-induced apneas only in Vglut2 KO mice. These physiological changes likely contribute to weight loss and premature death seen in this mouse model. Following chronic hypoxia (CH) exposure, there was no difference in swallow motor pattern, breathing regeneration, weight, and life expectancy in the Vglut2-Ndufs4-KO CH mice compared to control CH, indicating a phenotypic rescue or prevention. These findings show that like patients with LS, Ndufs4 mouse models of LS exhibit swallow impairments as well as swallow-breathing discoordination alongside the other phenotypic traits described in previous studies. Understanding this aspect of LS will open roads for the development of future more efficacious therapeutic intervention for this illness.
    Keywords:  Airway protection; Dysphagia; Hypoxia; Mitochondrial disease
    DOI:  https://doi.org/10.1016/j.expneurol.2024.115123
  43. Nanomedicine (Lond). 2024 Dec 20. 1-14
    Non-viral gene therapy for Leber's congenital amaurosis: progress and possibilities.
    Latifat Abdulsalam, James Mordecai, Irshad Ahmad.
      Leber's congenital amaurosis (LCA) represents a set of rare and pervasive hereditary conditions of the retina that cause severe vision loss starting in early childhood. Targeted treatment intervention has become possible thanks to recent advances in understanding LCA genetic basis. While viral vectors have shown efficacy in gene delivery, they present challenges related to safety, low cargo capacity, and the potential for random genomic integration. Non-viral gene therapy is a safer and more flexible alternative to treating the underlying genetic mutation causing LCA. Non-viral gene delivery methods, such as inorganic nanoparticles, polymer-based delivery systems, and lipid-based nanoparticles, bypass the risks of immunogenicity and genomic integration, potentially offering a more versatile and personalized treatment for patients. This review explores the genetic background of LCA, emphasizing the mutations involved, and explores diverse non-viral gene delivery methods being developed. It also highlights recent studies on non-viral gene therapy for LCA in animal models and clinical trials. It presents future perspectives for gene therapy, including integrating emerging technologies like CRISPR-Cas9, interdisciplinary collaborations, personalized medicine, and ethical considerations.
    Keywords:  DNA nanoparticle; Leber’s congenital amaurosis; degeneration; gene therapy; genetics; non-viral vectors; ocular gene therapy
    DOI:  https://doi.org/10.1080/17435889.2024.2443387
  44. Nat Chem Biol. 2025 Jan;21(1): 6-15
    Thoughts for the future.
    Lona M Alkhalaf, Cheryl Arrowsmith, Emily P Balskus, Giovanna Bergamini, Rashna Bhandari, Christopher J Chang, Peng Chen, Xing Chen, Alessio Ciulli, Julia A Cricco, Benjamin G Davis, Martina Delbianco, Natalia Dudareva, Erin Dueber, Fleur Ferguson, Priscila Oliveira de Giuseppe, Itaru Hamachi, Ming Chen Hammond, Stavroula K Hatzios, Won Do Heo, Jon Paul Janet, Siddhesh S Kamat, Stefan Knapp, Yamuna Krishnan, Kathrin Lang, Luca Laraia, Reuben B Leveson-Gower, Xiang David Li, David R Liu, Mo-Fang Liu, Nir London, Nilkamal Mahanta, Cristina Mayor-Ruiz, Tom Muir, Mário Tyago Murakami, Hyun-Woo Rhee, Matt Robers, Alex Satz, Brenda A Schulman, Ben Shen, Brian Shoichet, Erick Strauss, Tsutomu Suzuki, Pratyush Tiwary, Herbert Waldmann, Thomas R Ward, Amy Weeks, Eranthie Weerapana, Georg Winter.
      
    DOI:  https://doi.org/10.1038/s41589-024-01802-2
  45. Sci Rep. 2024 Dec 28. 14(1): 30767
    Targeting mitochondrial RNAs enhances the efficacy of the DNA-demethylating agents.
    Stephanie Tan, Sujin Kim, Yoosik Kim.
      Hypomethylating agents (HMAs) such as azacytidine and decitabine are FDA-approved chemotherapy drugs for hematologic malignancy. By inhibiting DNA methyltransferases, HMAs reactivate tumor suppressor genes (TSGs) and endogenous double-stranded RNAs (dsRNAs) that limit tumor growth and trigger apoptosis via viral mimicry. Yet, HMAs show limited effects in many solid tumors despite the strong induction of TSGs and dsRNAs. Here we show that targeting mitochondrial RNAs (mtRNAs) can enhance the HMA-mediated cell death in lung adenocarcinoma cells. We find that HMA treatment accompanies increased mtRNA levels and subsequent enhancement of metabolic activity, resulting in higher ATP production. Compromising the mitochondrial function by downregulating mature mtRNA expression increased cell death by HMAs. We further perform a CRISPR screening on mtRNA processing factors and find that mtRNA polymerase (POLRMT) and ElaC Ribonuclease Z 2 (ELAC2) depleted cells show increased sensitivity to HMAs by suppressing decitabine-triggered enhancement of ATP production. Moreover, we show that a small molecular inhibitor of POLRMT compromises the metabolic activity and synergistically enhances the cytotoxicity of HMAs. Our study unveils the insensitivity to HMAs through the elevation of mtRNAs and suggests mtRNA regulatory factors as potential synergistic targets to improve the therapeutic benefit of HMAs.
    Keywords:  Decitabine; Drug response; Hypomethylating agents; Mitochondrial RNA; RNA processing
    DOI:  https://doi.org/10.1038/s41598-024-80834-z
  46. Mol Ther Methods Clin Dev. 2024 Dec 12. 32(4): 101386
    Optimizing regulatory frameworks for gene therapies in rare diseases: Challenges and solutions.
    Diane Berry, Kate Donigan, Lisa Kahlman, James Long, Christina Markus, Caitlin K McCombs.
      The advent of genetic medicines and advanced diagnostics has revolutionized the treatment landscape for rare diseases and, with over 10,000 identified conditions affecting millions globally, has the potential to improve many lives. Despite this progress, only 5% of rare diseases have FDA-approved therapies, highlighting a significant unmet need. This article examines the critical need for optimizing the regulatory environment to support the development and approval of gene therapies for rare and ultrarare diseases, which often face unique challenges due to their complexity in the midst of a rapidly evolving field. Key issues discussed include the mismatch between traditional regulatory paradigms and the nature of gene therapies, the need for innovative clinical trial designs, and the importance of flexible manufacturing processes. The article proposes targeted reforms to align regulatory frameworks with the needs of patients with rare diseases and the pace of science, emphasizing the value of a holistic evidence approach, platform technologies, and iterative manufacturing evaluations. By addressing these challenges, we can accelerate the development of life-changing therapies in order to realize the opportunity to provide treatments to patients with rare genetic disorders in their lifetime.
    DOI:  https://doi.org/10.1016/j.omtm.2024.101386
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