bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–06–23
fifty-one papers selected by
Catalina Vasilescu, Helmholz Munich
  1. DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring.
  2. SETD3 is a mechanosensitive enzyme that methylates actin on His-73 to regulate mitochondrial dynamics and function.
  3. Beyond the membrane: Exploring non-viral methods for mitochondrial gene delivery.
  4. Mitochondrial proteases modulate mitochondrial stress signalling and cellular homeostasis in health and disease.
  5. A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1.
  6. The initiation of mitochondrial DNA replication.
  7. Mitochondrial biology: Unique membrane remodeling from the matrix.
  8. Is mitochondrial morphology important for cellular physiology?
  9. Activation of Neurotoxic Astrocytes Due to Mitochondrial Dysfunction Triggered by POLG Mutation.
  10. Exploration of dietary interventions to treat mitochondrial fatty acid disorders in a mouse model.
  11. PDZD8-FKBP8 tethering complex at ER-mitochondria contact sites regulates mitochondrial complexity.
  12. Oxidative protein folding in the intermembrane space of human mitochondria.
  13. MFN2 coordinates mitochondria motility with α-tubulin acetylation and this regulation is disrupted in CMT2A.
  14. RNA: De-silencing to the rescue.
  15. Parkin R274W mutation affects muscle and mitochondrial physiology.
  16. Evaluating the efficacy of vatiquinone in preclinical models of mitochondrial disease.
  17. Mitochondrial therapeutics and mitochondrial transfer for neurodegenerative diseases and aging.
  18. Tissue-specific roles of mitochondrial unfolded protein response during obesity.
  19. Metabolic regulation of misfolded protein import into mitochondria.
  20. An updated compendium and reevaluation of the evidence for nuclear transcription factor occupancy over the mitochondrial genome.
  21. Identifying therapeutic compounds for autosomal dominant optic atrophy (ADOA) through screening in the nematode C. elegans.
  22. Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.
  23. Mitochondrial unfolded protein response (UPRmt): what we know thus far.
  24. Mitochondrial calcium in cardiac ischemia/reperfusion injury and cardioprotection.
  25. Slowing early Parkinson's disease.
  26. Spectrum of rare and common mitochondrial DNA variations from 1029 whole genomes of self-declared healthy individuals from India.
  27. Mitochondria Transplantation: Rescuing Innate Muscle Bioenergetic Impairment in a Model of Aging and Exercise Intolerance.
  28. CKB Promotes Mitochondrial ATP Production by Suppressing Permeability Transition Pore.
  29. Fuse mitochondria to win peer competition.
  30. FDXR variants cause adrenal insufficiency and atypical sexual development.
  31. Exploring the benefits, harms and costs of genomic newborn screening for rare diseases.
  32. Mitochondria and cell death.
  33. Whole genome sequencing for copy number variant detection to improve diagnosis and management of rare diseases.
  34. The Role of Mitochondrial Copy Number in Neurodegenerative Diseases: Present Insights and Future Directions.
  35. Deficient brain GABA metabolism leads to widespread impairments of astrocyte and oligodendrocyte function.
  36. Multiomics analysis reveals serine catabolism as a potential therapeutic target for MELAS.
  37. Unraveling RNA Conformation Dynamics in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episode Syndrome with Solid-State Nanopores.
  38. Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure.
  39. Peripheral blood mononuclear cell respiratory function is associated with progressive glaucomatous vision loss.
  40. Gene therapy restores hearing.
  41. Identification of the central role of RNA polymerase mitochondrial for angiogenesis.
  42. Genome and RNA sequencing were essential to reveal cryptic intronic variants associated to defective ATP6AP1 mRNA processing.
  43. Structural aspects of iron‑sulfur protein biogenesis: An NMR view.
  44. Olfaction regulates peripheral mitophagy and mitochondrial function.
  45. A computational framework to improve cross-platform implementation of transcriptomics signatures.
  46. Genetic Mutations and Mitochondrial Redox Signaling as Modulating Factors in Hypertrophic Cardiomyopathy: A Scoping Review.
  47. An Amino Acid Mixture to Counteract Skeletal Muscle Atrophy: Impact on Mitochondrial Bioenergetics.
  48. A Multimodal Generative AI Copilot for Human Pathology.
  49. Determination of Differential Alternative Splicing Under Stress Conditions.
  50. A Prebiotic Pathway to Nicotinamide Adenine Dinucleotide.
  51. Food perception induces fast fragmentation of hepatic mitochondria.
  1. Nat Commun. 2024 Jun 20. 15(1): 5265
    DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring.
    Adinarayana Marada, Corvin Walter, Tamara Suhm, Sahana Shankar, Arpita Nandy, Tilman Brummer, Ines Dhaouadi, F-Nora Vögtle, Chris Meisinger.
      Mitochondria require an extensive proteome to maintain a variety of metabolic reactions, and changes in cellular demand depend on rapid adaptation of the mitochondrial protein composition. The TOM complex, the organellar entry gate for mitochondrial precursors in the outer membrane, is a target for cytosolic kinases to modulate protein influx. DYRK1A phosphorylation of the carrier import receptor TOM70 at Ser91 enables its efficient docking and thus transfer of precursor proteins to the TOM complex. Here, we probe TOM70 phosphorylation in molecular detail and find that TOM70 is not a CK2 target nor import receptor for MIC19 as previously suggested. Instead, we identify TOM20 as a MIC19 import receptor and show off-target inhibition of the DYRK1A-TOM70 axis with the clinically used CK2 inhibitor CX4945 which activates TOM20-dependent import pathways. Taken together, modulation of DYRK1A signalling adapts the central mitochondrial protein entry gate via synchronization of TOM70- and TOM20-dependent import pathways for metabolic rewiring. Thus, DYRK1A emerges as a cytosolic surveillance kinase to regulate and fine-tune mitochondrial protein biogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-49611-4
  2. J Cell Sci. 2024 Jun 19. pii: jcs.261268. [Epub ahead of print]
    SETD3 is a mechanosensitive enzyme that methylates actin on His-73 to regulate mitochondrial dynamics and function.
    Vaibhav Deshmukh, James F Martin.
      Mitochondria, which act as sensors of metabolic homeostasis and metabolite signaling, form a dynamic intracellular network of continuously changing shape, size, and localization to respond to localized cellular energy demands. Mitochondrial dynamics and function depend on interactions with the F-actin cytoskeleton that are poorly understood. Here, we show that SET domain protein 3 (SETD3), a recently described actin histidine methyltransferase, directly methylates actin Histidine-73 and enhances F-actin polymerization on mitochondria. SETD3 is a mechano-sensitive enzyme which is localized on the outer mitochondrial membrane and promotes actin polymerization around mitochondrias. SETD3 loss of function leads to diminished F-actin around mitochondria and a decrease in mitochondrial branch length, branch number, and mitochondrial movement. Our functional analysis revealed that SETD3 is required for oxidative phosphorylation and mitochondrial complex I assembly, and function. Our data further indicate that SETD3 regulates F-actin formation around mitochondria and is essential for maintaining mitochondrial morphology, movement, and function. Finally, we discovered that SETD3 levels are regulated by ECM stiffness and regulate mitochondrial shape in response to changes in ECM stiffness. These findings provide new insight into the mechanism for F-actin polymerization around mitochondria.
    Keywords:  Cytoskeleton; Mechanotransduction; Mitochondrial dynamics; Post-translational modifications
    DOI:  https://doi.org/10.1242/jcs.261268
  3. Mitochondrion. 2024 Jun 17. pii: S1567-7249(24)00080-1. [Epub ahead of print]78 101922
    Beyond the membrane: Exploring non-viral methods for mitochondrial gene delivery.
    Dilpreet Singh.
      Mitochondrial disorders, stemming from mutations in mitochondrial DNA (mtDNA), present a significant therapeutic challenge due to their complex pathophysiology and broad spectrum of clinical manifestations. Traditional gene therapy approaches, primarily reliant on viral vectors, face obstacles such as potential immunogenicity, insertional mutagenesis, and the specificity of targeting mtDNA. This review delves into non-viral methods for mitochondrial gene delivery, emerging as a promising alternative to overcome these limitations. Focusing on lipid-based nanoparticles, polymer-based vectors, and mitochondrial-targeted peptides, the mechanisms of action, advantages, and current applications in treating mitochondrial diseases was well elucidated. Non-viral vectors offer several benefits, including reduced immunogenicity, enhanced safety profiles, and the flexibility to carry a wide range of genetic material. We examine case studies where these methods have been applied, highlighting their potential in correcting pathogenic mtDNA mutations and mitigating disease phenotypes. Despite their promise, challenges such as delivery efficiency, specificity, and long-term expression stability persist. The review underscores the need for ongoing research to refine these delivery systems carry a wide range of genetic material. We examine case studies where these methods settings. As we advance our understanding of mitochondrial biology and gene delivery technologies, non-viral methods hold the potential to revolutionize the treatment of mitochondrial disorders, offering hope for therapies that can precisely target and correct the underlying genetic defects.
    Keywords:  Gene therapy; Lipid-based nanoparticles; Mitochondrial disorders; Mitochondrial gene delivery; Mitochondrial-targeted peptides; Non-viral vectors; Polymer-based vectors; Precision medicine
    DOI:  https://doi.org/10.1016/j.mito.2024.101922
  4. Biochimie. 2024 Jun 19. pii: S0300-9084(24)00141-X. [Epub ahead of print]
    Mitochondrial proteases modulate mitochondrial stress signalling and cellular homeostasis in health and disease.
    Nicoleta Moisoi.
      Maintenance of mitochondrial homeostasis requires a plethora of coordinated quality control and adaptations' mechanisms in which mitochondrial proteases play a key role. Their activation or loss of function reverberate beyond local mitochondrial biochemical and metabolic remodelling into coordinated cellular pathways and stress responses that feedback onto the mitochondrial functionality and adaptability. Mitochondrial proteolysis modulates molecular and organellar quality control, metabolic adaptations, lipid homeostasis and regulates transcriptional stress responses. Defective mitochondrial proteolysis results in disease conditions most notably, mitochondrial diseases, neurodegeneration and cancer. Here, it will be discussed how mitochondrial proteases and mitochondria stress signalling impact cellular homeostasis and determine the cellular decision to survive or die, how these processes may impact disease etiopathology, and how modulation of proteolysis may offer novel therapeutic strategies.
    DOI:  https://doi.org/10.1016/j.biochi.2024.06.005
  5. bioRxiv. 2024 Jun 03. pii: 2024.06.03.597144. [Epub ahead of print]
    A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1.
    Joanna Koszela, Anne Rintala-Dempsey, Giulia Salzano, Viveka Pimenta, Outi Kamarainen, Mads Gabrielsen, Aasna L Parui, Gary S Shaw, Helen Walden.
      Mutations in the gene encoding for the E3 ubiquitin ligase Parkin have been linked to early-onset Parkinson's disease. Besides many other cellular roles, Parkin is involved in clearance of damaged mitochondria via mitophagy - a process of particular importance in dopaminergic neurons. Upon mitochondrial damage, Parkin accumulates at the outer mitochondrial membrane and is activated, leading to ubiquitination of many mitochondrial substrates and recruitment of mitophagy effectors. While the activation mechanisms of autoinhibited Parkin have been extensively studied, it remains unknown how Parkin recognises its substrates for ubiquitination, and no substrate interaction site in Parkin has been reported. Here, we identify a conserved region in the flexible linker between the Ubl and RING0 domains of Parkin, which is indispensable for Parkin interaction with the mitochondrial GTPase Miro1. Our results explain the preferential targeting and ubiquitination of Miro1 by Parkin and provide a biochemical explanation for the presence of Parkin at the mitochondrial membrane prior to activation induced by mitochondrial damage. Our findings are important for understanding mitochondrial homeostasis and may inspire new therapeutic avenues for Parkinson's disease.
    DOI:  https://doi.org/10.1101/2024.06.03.597144
  6. Biochem Soc Trans. 2024 Jun 17. pii: BST20230952. [Epub ahead of print]
    The initiation of mitochondrial DNA replication.
    Yi Liu, Haibin Liu, Fan Zhang, Hong Xu.
      Mitochondrial DNA replication is initiated by the transcription of mitochondrial RNA polymerase (mtRNAP), as mitochondria lack a dedicated primase. However, the mechanism determining the switch between continuous transcription and premature termination to generate RNA primers for mitochondrial DNA (mtDNA) replication remains unclear. The pentatricopeptide repeat domain of mtRNAP exhibits exoribonuclease activity, which is required for the initiation of mtDNA replication in Drosophila. In this review, we explain how this exonuclease activity contributes to primer synthesis in strand-coupled mtDNA replication, and discuss how its regulation might co-ordinate mtDNA replication and transcription in both Drosophila and mammals.
    Keywords:  PPR; RNA polymerase; exonucleases; mitochondria; mtDNA; replication
    DOI:  https://doi.org/10.1042/BST20230952
  7. Curr Biol. 2024 Jun 17. pii: S0960-9822(24)00608-0. [Epub ahead of print]34(12): R581-R583
    Mitochondrial biology: Unique membrane remodeling from the matrix.
    Jason A Mears.
      A new study reports the identification of a fission yeast dynamin superfamily protein, Mmc1, that self-assembles on the matrix side of the inner mitochondrial membrane and interacts with subunits of the mitochondrial contact site and cristae organizing system to maintain cristae architecture.
    DOI:  https://doi.org/10.1016/j.cub.2024.05.010
  8. Trends Endocrinol Metab. 2024 Jun 11. pii: S1043-2760(24)00123-1. [Epub ahead of print]
    Is mitochondrial morphology important for cellular physiology?
    Timothy Wai.
      Mitochondria are double membrane-bound organelles the network morphology of which in cells is shaped by opposing events of fusion and fission executed by dynamin-like GTPases. Mutations in these genes can perturb the form and functions of mitochondria in cell and animal models of mitochondrial diseases. An expanding array of chemical, mechanical, and genetic stressors can converge on mitochondrial-shaping proteins and disrupt mitochondrial morphology. In recent years, studies aimed at disentangling the multiple roles of mitochondrial-shaping proteins beyond fission or fusion have provided insights into the homeostatic relevance of mitochondrial morphology. Here, I review the pleiotropy of mitochondrial fusion and fission proteins with the aim of understanding whether mitochondrial morphology is important for cell and tissue physiology.
    Keywords:  fission and fusion; genetic disease; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial morphology
    DOI:  https://doi.org/10.1016/j.tem.2024.05.005
  9. Int J Biol Sci. 2024 ;20(8): 2860-2880
    Activation of Neurotoxic Astrocytes Due to Mitochondrial Dysfunction Triggered by POLG Mutation.
    Kristina Xiao Liang, Anbin Chen, Atefeh Kianian, Cecilie Katrin Kristiansen, Tsering Yangzom, Jessica Furriol, Lena Elise Høyland, Mathias Ziegler, Torbjørn Kråkenes, Charalampos Tzoulis, Evandro Fei Fang, Gareth John Sullivan, Laurence A Bindoff.
      Mitochondrial diseases are associated with neuronal death and mtDNA depletion. Astrocytes respond to injury or stimuli and damage to the central nervous system. Neurodegeneration can cause astrocytes to activate and acquire toxic functions that induce neuronal death. However, astrocyte activation and its impact on neuronal homeostasis in mitochondrial disease remain to be explored. Using patient cells carrying POLG mutations, we generated iPSCs and then differentiated these into astrocytes. POLG astrocytes exhibited mitochondrial dysfunction including loss of mitochondrial membrane potential, energy failure, loss of complex I and IV, disturbed NAD+/NADH metabolism, and mtDNA depletion. Further, POLG derived astrocytes presented an A1-like reactive phenotype with increased proliferation, invasion, upregulation of pathways involved in response to stimulus, immune system process, cell proliferation and cell killing. Under direct and indirect co-culture with neurons, POLG astrocytes manifested a toxic effect leading to the death of neurons. We demonstrate that mitochondrial dysfunction caused by POLG mutations leads not only to intrinsic defects in energy metabolism affecting both neurons and astrocytes, but also to neurotoxic damage driven by astrocytes. These findings reveal a novel role for dysfunctional astrocytes that contribute to the pathogenesis of POLG diseases.
    DOI:  https://doi.org/10.7150/ijbs.93445
  10. J Nutr Biochem. 2024 Jun 13. pii: S0955-2863(24)00125-6. [Epub ahead of print] 109692
    Exploration of dietary interventions to treat mitochondrial fatty acid disorders in a mouse model.
    Kaija J Autio, Hennariikka Koivisto, Werner Schmitz, Anna Puronurmi, Heikki Tanila, Alexander J Kastaniotis.
      Mitochondrial fatty acids synthesis (mtFAS) is a conserved metabolic pathway essential for mitochondrial respiration. The best characterized mtFAS product is the medium-chain fatty acid octanoate (C8) used as a substrate in the synthesis of lipoic acid (LA), a cofactor required by several mitochondrial enzyme complexes. In humans, mutations in the mtFAS component enoyl reductase MECR cause childhood-onset neurodegenerative disorder MEPAN. A complete deletion of Mecr in mice is embryonically lethal, while selective deletion of Mecr in cerebellar Purkinje cells causes neurodegeneration in these cells. A fundamental question in the research of mtFAS deficiency is if the defect is amenable to treatment by supplementation with known mtFAS products. Here we used the Purkinje-cell specific mtFAS deficiency neurodegeneration model mice to study if feeding the mice with a medium-chain triacylglycerol-rich formula supplemented with LA could slow down or prevent the neurodegeneration in Purkinje cell-specific Mecr KO mice. Feeding started at the age of 4 weeks and continued until the age of 9 months. The neurological status on the mice was assessed at the age of 3, 6 and 9 months with behavioral tests and the state of the Purkinje cell deterioration in the cerebellum was studied histologically. We showed that feeding the mice with medium chain triacylglycerols and LA affected fatty acid profiles in the cerebellum and plasma but did not prevent the development of neurodegeneration in these mice. Our results indicate that dietary supplementation with medium chain fatty acids and LA alone is not an efficient way to treat mtFAS disorders.
    Keywords:  Mitochondrial fatty acid synthesis; lipoic acid; medium chain fatty acid; mouse model; neurodegeneration
    DOI:  https://doi.org/10.1016/j.jnutbio.2024.109692
  11. bioRxiv. 2024 Jun 03. pii: 2023.08.22.554218. [Epub ahead of print]
    PDZD8-FKBP8 tethering complex at ER-mitochondria contact sites regulates mitochondrial complexity.
    Koki Nakamura, Saeko Aoyama-Ishiwatari, Takahiro Nagao, Mohammadreza Paaran, Christopher J Obara, Yui Sakurai-Saito, Jake Johnston, Yudan Du, Shogo Suga, Masafumi Tsuboi, Makoto Nakakido, Kouhei Tsumoto, Yusuke Kishi, Yukiko Gotoh, Chulhwan Kwak, Hyun-Woo Rhee, Jeong Kon Seo, Hidetaka Kosako, Clint Potter, Bridget Carragher, Jennifer Lippincott-Schwartz, Franck Polleux, Yusuke Hirabayashi.
      Mitochondria-ER membrane contact sites (MERCS) represent a fundamental ultrastructural feature underlying unique biochemistry and physiology in eukaryotic cells. The ER protein PDZD8 is required for the formation of MERCS in many cell types, however, its tethering partner on the outer mitochondrial membrane (OMM) is currently unknown. Here we identified the OMM protein FKBP8 as the tethering partner of PDZD8 using a combination of unbiased proximity proteomics, CRISPR-Cas9 endogenous protein tagging, Cryo-Electron Microscopy (Cryo-EM) tomography, and correlative light-EM (CLEM). Single molecule tracking revealed highly dynamic diffusion properties of PDZD8 along the ER membrane with significant pauses and capture at MERCS. Overexpression of FKBP8 was sufficient to narrow the ER-OMM distance, whereas independent versus combined deletions of these two proteins demonstrated their interdependence for MERCS formation. Furthermore, PDZD8 enhances mitochondrial complexity in a FKBP8-dependent manner. Our results identify a novel ER-mitochondria tethering complex that regulates mitochondrial morphology in mammalian cells.
    DOI:  https://doi.org/10.1101/2023.08.22.554218
  12. FEBS Open Bio. 2024 Jun 12.
    Oxidative protein folding in the intermembrane space of human mitochondria.
    Christine Zarges, Jan Riemer.
      The mitochondrial intermembrane space hosts a machinery for oxidative protein folding, the mitochondrial disulfide relay. This machinery imports a large number of soluble proteins into the compartment, where they are retained through oxidative folding. Additionally, the disulfide relay enhances the stability of many proteins by forming disulfide bonds. In this review, we describe the mitochondrial disulfide relay in human cells, its components, and their coordinated collaboration in mechanistic detail. We also discuss the human pathologies associated with defects in this machinery and its protein substrates, providing a comprehensive overview of its biological importance and implications for health.
    Keywords:  ALR; IMS; MIA40; mitochondria; oxidative protein folding; protein import
    DOI:  https://doi.org/10.1002/2211-5463.13839
  13. iScience. 2024 Jun 21. 27(6): 109994
    MFN2 coordinates mitochondria motility with α-tubulin acetylation and this regulation is disrupted in CMT2A.
    Atul Kumar, Delfina Larrea, Maria Elena Pero, Paola Infante, Marilisa Conenna, Grace J Shin, Vincent Van Elias, Wesley B Grueber, Lucia Di Marcotullio, Estela Area-Gomez, Francesca Bartolini.
      Mitofusin-2 (MFN2), a large GTPase residing in the mitochondrial outer membrane and mutated in Charcot-Marie-Tooth type 2 disease (CMT2A), is a regulator of mitochondrial fusion and tethering with the ER. The role of MFN2 in mitochondrial transport has however remained elusive. Like MFN2, acetylated microtubules play key roles in mitochondria dynamics. Nevertheless, it is unknown if the α-tubulin acetylation cycle functionally interacts with MFN2. Here, we show that mitochondrial contacts with microtubules are sites of α-tubulin acetylation, which occurs through MFN2-mediated recruitment of α-tubulin acetyltransferase 1 (ATAT1). This activity is critical for MFN2-dependent regulation of mitochondria transport, and axonal degeneration caused by CMT2A MFN2 associated R94W and T105M mutations may depend on the inability to release ATAT1 at sites of mitochondrial contacts with microtubules. Our findings reveal a function for mitochondria in α-tubulin acetylation and suggest that disruption of this activity plays a role in the onset of MFN2-dependent CMT2A.
    Keywords:  Cell biology; Lipidomics; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109994
  14. Curr Biol. 2024 Jun 17. pii: S0960-9822(24)00609-2. [Epub ahead of print]34(12): R573-R575
    RNA: De-silencing to the rescue.
    James P Held, Maulik R Patel.
      The fate of transcribed RNA dictates cellular function. A new study finds that mutations in specific RNA processing machinery genes result in de-silencing of a transcript encoding a subunit of the mitochondrial electron transport chain and rescue of a mitochondrial respiratory complex I defect.
    DOI:  https://doi.org/10.1016/j.cub.2024.05.011
  15. Biochim Biophys Acta Mol Basis Dis. 2024 Jun 13. pii: S0925-4439(24)00295-3. [Epub ahead of print]1870(7): 167302
    Parkin R274W mutation affects muscle and mitochondrial physiology.
    Martina Sevegnani, Adriano Lama, Francesco Girardi, Michael W Hess, Maria Paulina Castelo, Irene Pichler, Stefano Biressi, Giovanni Piccoli.
      Recessive mutations in the Parkin gene (PRKN) are the most common cause of young-onset inherited parkinsonism. Parkin is a multifunctional E3 ubiquitin ligase that plays a variety of roles in the cell including the degradation of proteins and the maintenance of mitochondrial homeostasis, integrity, and biogenesis. In 2001, the R275W mutation in the PRKN gene was identified in two unrelated families with a multigenerational history of postural tremor, dystonia and parkinsonism. Drosophila models of Parkin R275W showed selective and progressive degeneration of dopaminergic neuronal clusters, mitochondrial abnormalities, and prominent climbing defects. In the Prkn mouse orthologue, the amino acid R274 corresponds to human R275. Here we described an age-related motor impairment and a muscle phenotype in R274W +/+ mice. In vitro, Parkin R274W mutation correlates with abnormal myoblast differentiation, mitochondrial defects, and alteration in mitochondrial mRNA and protein levels. Our data suggest that the Parkin R274W mutation may impact mitochondrial physiology and eventually myoblast proliferation and differentiation.
    Keywords:  Atrophy; PARIS; Parkin
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167302
  16. Res Sq. 2024 Jun 03. pii: rs.3.rs-4202689. [Epub ahead of print]
    Evaluating the efficacy of vatiquinone in preclinical models of mitochondrial disease.
    Ernst-Bernhard Kayser, Yihan Chen, Michael Mulholland, Vivian Truong, Katerina James, Allison Hanaford, Simon Johnson.
      Background Genetic mitochondrial diseases are a major challenge in modern medicine, impacting around 1:4,000 individuals. Leigh syndrome is the most common pediatric presentation of mitochondrial disease. There are currently no effective clinical treatments for mitochondrial disease. In humans, patients are often treated with antioxidants, vitamins, and strategies targeting energetics. The vitamin-E related compound vatiquinone (EPI-743, α-tocotrienol quinone) has been the subject of at least 19 clinical trials in the US since 2012, but the effects of vatiquinone on an animal model of mitochondrial disease have not yet been reported. Here, assessed the impact of vatiquinone on disease progression and in two animal models of mitochondrial disease. Methods The efficacy of vatiquinone in vitro was assessed using human fibroblasts treated with the general mitochondrial oxidative stress inducer paraquat, the GPX4 inhibitor RSL3, or the glutathione synthase inhibitor BSO in combination with excess iron. The therapeutic potential of vatiquinone in vivo was assessed using tamoxifen-induced mouse model for GPX4 deficiency and the Ndufs4 knockout mouse model of Leigh syndrome. In both models, animals were treated daily with vatiquinone or vehicle and relevant disease endpoints were assessed. Results Vatiquinone robustly prevented death in cultured cells induced by RSL3 or BSO/iron, but had no effect on paraquat induced cell death. Vatiquinone had no impact on disease onset, progression, or survival in either the tamoxifen-inducible GPX4 deficient model or the Ndufs4 (-/-) mouse model, though the drug may have reduced seizure risk. Conclusions Vatiquinone provided no benefit to survival in two mouse models of disease, but may prevent seizures in the Ndufs4 (-/-) model. Our findings are consistent with recent press statements regarding clinical trial results and have implications for drug trial design and reporting in patients with rare diseases.
    DOI:  https://doi.org/10.21203/rs.3.rs-4202689/v1
  17. Neural Regen Res. 2025 Mar 01. 20(3): 794-796
    Mitochondrial therapeutics and mitochondrial transfer for neurodegenerative diseases and aging.
    Neville Ng, Michelle Newbery, Nicole Miles, Lezanne Ooi.
      
    DOI:  https://doi.org/10.4103/NRR.NRR-D-23-02106
  18. Obes Rev. 2024 Jun 16. e13791
    Tissue-specific roles of mitochondrial unfolded protein response during obesity.
    Fernanda S Carneiro, Carlos K Katashima, Joshua D Dodge, Dennys E Cintra, José Rodrigo Pauli, Adelino S R Da Silva, Eduardo R Ropelle.
      Obesity is a worldwide multifactorial disease caused by an imbalance in energy metabolism, increasing adiposity, weight gain, and promoting related diseases such as diabetes, cardiovascular diseases, neurodegeneration, and cancer. Recent findings have reported that metabolic stress related to obesity induces a mitochondrial stress response called mitochondrial unfolded protein response (UPRmt), a quality control pathway that occurs in a nuclear DNA-mitochondria crosstalk, causing transduction of chaperones and proteases under stress conditions. The duality of UPRmt signaling, with both beneficial and detrimental effects, acts in different contexts depending on the tissue, cell type, and physiological states, affecting the mitochondrial function and efficiency and the metabolism homeostasis during obesity, which remains not fully clarified. Therefore, this review discusses the most recent findings regarding UPRmt signaling during obesity, bringing an overview of UPRmt across different metabolic tissues.
    Keywords:  metabolism; mitochondria; mitochondrial unfolded protein response; obesity
    DOI:  https://doi.org/10.1111/obr.13791
  19. Elife. 2024 Jun 20. pii: RP87518. [Epub ahead of print]12
    Metabolic regulation of misfolded protein import into mitochondria.
    Yuhao Wang, Linhao Ruan, Jin Zhu, Xi Zhang, Alexander Chih-Chieh Chang, Alexis Tomaszewski, Rong Li.
      Mitochondria are the cellular energy hub and central target of metabolic regulation. Mitochondria also facilitate proteostasis through pathways such as the 'mitochondria as guardian in cytosol' (MAGIC) whereby cytosolic misfolded proteins (MPs) are imported into and degraded inside mitochondria. In this study, a genome-wide screen in Saccharomyces cerevisiae uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of MPs into mitochondria while promoting mitochondrial biogenesis under glucose starvation. We show that this inhibition requires a downstream transcription factor regulating mitochondrial gene expression and is likely to be conferred through substrate competition and mitochondrial import channel selectivity. We further show that Snf1/AMPK activation protects mitochondrial fitness in yeast and human cells under stress induced by MPs such as those associated with neurodegenerative diseases.
    Keywords:  AMPK; MAGIC; S. cerevisiae; cell biology; human; metabolism; misfolded protein; mitochondria; protein import; proteostasis
    DOI:  https://doi.org/10.7554/eLife.87518
  20. bioRxiv. 2024 Jun 06. pii: 2024.06.04.597442. [Epub ahead of print]
    An updated compendium and reevaluation of the evidence for nuclear transcription factor occupancy over the mitochondrial genome.
    Georgi K Marinov, Vivekanandan Ramalingam, William J Greenleaf, Anshul Kundaje.
      In most eukaryotes, mitochondrial organelles contain their own genome, usually circular, which is the remnant of the genome of the ancestral bacterial endosymbiont that gave rise to modern mitochondria. Mitochondrial genomes are dramatically reduced in their gene content due to the process of endosymbiotic gene transfer to the nucleus; as a result most mitochondrial proteins are encoded in the nucleus and imported into mitochondria. This includes the components of the dedicated mitochondrial transcription and replication systems and regulatory factors, which are entirely distinct from the information processing systems in the nucleus. However, since the 1990s several nuclear transcription factors have been reported to act in mitochondria, and previously we identified 8 human and 3 mouse transcription factors (TFs) with strong localized enrichment over the mitochondrial genome using ChIP-seq (Chromatin Immunoprecipitation) datasets from the second phase of the ENCODE (Encyclopedia of DNA Elements) Project Consortium. Here, we analyze the greatly expanded in the intervening decade ENCODE compendium of TF ChIP-seq datasets (a total of 6,153 ChIP experiments for 942 proteins, of which 763 are sequence-specific TFs) combined with interpretative deep learning models of TF occupancy to create a comprehensive compendium of nuclear TFs that show evidence of association with the mitochondrial genome. We find some evidence for chrM occupancy for 50 nuclear TFs and two other proteins, with bZIP TFs emerging as most likely to be playing a role in mitochondria. However, we also observe that in cases where the same TF has been assayed with multiple antibodies and ChIP protocols, evidence for its chrM occupancy is not always reproducible. In the light of these findings, we discuss the evidential criteria for establishing chrM occupancy and reevaluate the overall compendium of putative mitochondrial-acting nuclear TFs.
    DOI:  https://doi.org/10.1101/2024.06.04.597442
  21. Methods Cell Biol. 2024 ;pii: S0091-679X(24)00141-9. [Epub ahead of print]188 89-108
    Identifying therapeutic compounds for autosomal dominant optic atrophy (ADOA) through screening in the nematode C. elegans.
    Fivos Borbolis, Konstantinos Palikaras.
      Autosomal Dominant Optic Atrophy (ADOA) is a rare neurodegenerative condition, characterized by the bilateral loss of vision due to the degeneration of retinal ganglion cells. Its primary cause is linked to mutations in OPA1 gene, which ultimately affect mitochondrial structure and function. The current lack of successful treatments for ADOA emphasizes the need to investigate the mechanisms driving disease pathogenesis and exploit the potential of animal models for preclinical trials. Among such models, Caenorhabditis elegans stands out as a powerful tool, due its simplicity, its genetic tractability, and its relevance to human biology. Despite the lack of a visual system, the presence of mutated OPA1 in the nematode recapitulates ADOA pathology, by stimulating key pathogenic features of the human condition that can be studied in a fast and relatively non-laborious manner. Here, we provide a detailed guide on how to assess the therapeutic efficacy of chemical compounds, in either small or large scale, by evaluating three crucial phenotypes of humanized ADOA model nematodes, that express pathogenic human OPA1 in their GABAergic motor neurons: axonal mitochondria number, neuronal cell death and defecation cycle time. The described methods can deepen our understanding of ADOA pathogenesis and offer a practical framework for developing novel treatment schemes, providing hope for improved therapeutic outcomes and a better quality of life for individuals affected by this currently incurable condition.
    Keywords:  ADOA; C. elegans; Disease models; Drug screening; Mitochondria; Neurodegeneration; OPA1
    DOI:  https://doi.org/10.1016/bs.mcb.2024.04.004
  22. Dev Cell. 2024 May 20. pii: S1534-5807(24)00295-8. [Epub ahead of print]
    Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.
    George Kelly, Tetsushi Kataura, Johan Panek, Gailing Ma, Hanna Salmonowicz, Ashley Davis, Hannah Kendall, Charlotte Brookes, Daniel Moscoh Ayine-Tora, Peter Banks, Glyn Nelson, Laura Dobby, Patricia R Pitrez, Laura Booth, Lydia Costello, Gavin D Richardson, Penny Lovat, Stefan Przyborski, Lino Ferreira, Laura Greaves, Karolina Szczepanowska, Thomas von Zglinicki, Satomi Miwa, Max Brown, Michael Flagler, John E Oblong, Charles C Bascom, Bernadette Carroll, Jóhannes Reynisson, Viktor I Korolchuk.
      Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor (SAR). Importantly, this pathway was suppressed upon the induction of cellular senescence and in naturally aged cells, leading to a robust shutdown of mitophagy. Inhibition of mitophagy in proliferating cells was sufficient to trigger the senescence program, while reactivation of mitophagy was necessary for the anti-senescence effects of NAD precursors or rapamycin. Furthermore, reactivation of mitophagy by a p62-targeting small molecule rescued markers of cellular aging, which establishes mitochondrial quality control as a promising target for anti-aging interventions.
    Keywords:  PINK1; Parkin; aging; autophagy; mitophagy; nicotinamide; nicotinamide riboside; p62; rapamycin; redox; senescence
    DOI:  https://doi.org/10.1016/j.devcel.2024.04.020
  23. Front Cell Dev Biol. 2024 ;12 1405393
    Mitochondrial unfolded protein response (UPRmt): what we know thus far.
    Angie K Torres, Veronika Fleischhart, Nibaldo C Inestrosa.
      Mitochondria are key organelles for the optimal function of the cell. Among their many functions, they maintain protein homeostasis through their own proteostatic machinery, which involves proteases and chaperones that regulate protein import and folding inside mitochondria. In the early 2000s, the mitochondrial unfolded protein response (UPRmt) was first described in mammalian cells. This stress response is activated by the accumulation of unfolded/misfolded proteins within the mitochondrial matrix, which results in the transmission of a signal to the nucleus to increase the expression of proteases and chaperones to address the abnormal mitochondrial protein load. After its discovery, this retrograde signaling pathway has also been described in other organisms of different complexities, suggesting that it is a conserved stress response. Although there are some specific differences among organisms, the mechanism of this stress response is mostly similar and involves the transmission of a signal from mitochondria to the nucleus that induces chromatin remodeling to allow the binding of specific transcription factors to the promoters of chaperones and proteases. In the last decade, proteins and signaling pathways that could be involved in the regulation of the UPRmt, including the Wnt signaling pathway, have been described. This minireview aims to summarize what is known about the mechanism of the UPRmt and its regulation, specifically in mammals and C. elegans.
    Keywords:  Caenorhabditis elegans; UPRmt; misfolded protein; mitochondria; stress; wnt signaling
    DOI:  https://doi.org/10.3389/fcell.2024.1405393
  24. Basic Res Cardiol. 2024 Jun 19.
    Mitochondrial calcium in cardiac ischemia/reperfusion injury and cardioprotection.
    Edoardo Bertero, Tudor-Alexandru Popoiu, Christoph Maack.
      Mitochondrial calcium (Ca2+) signals play a central role in cardiac homeostasis and disease. In the healthy heart, mitochondrial Ca2+ levels modulate the rate of oxidative metabolism to match the rate of adenosine triphosphate consumption in the cytosol. During ischemia/reperfusion (I/R) injury, pathologically high levels of Ca2+ in the mitochondrial matrix trigger the opening of the mitochondrial permeability transition pore, which releases solutes and small proteins from the matrix, causing mitochondrial swelling and ultimately leading to cell death. Pharmacological and genetic approaches to tune mitochondrial Ca2+ handling by regulating the activity of the main Ca2+ influx and efflux pathways, i.e., the mitochondrial Ca2+ uniporter and sodium/Ca2+ exchanger, represent promising therapeutic strategies to protect the heart from I/R injury.
    Keywords:  Calcium handling; Cardiac myocytes; Ischemia/reperfusion injury; Mitochondria; Myocardial infarction; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s00395-024-01060-2
  25. Nat Aging. 2024 Jun;4(6): 748
    Slowing early Parkinson's disease.
    George Andrew S Inglis.
      
    DOI:  https://doi.org/10.1038/s43587-024-00660-w
  26. Comput Biol Chem. 2024 Jun 10. pii: S1476-9271(24)00106-3. [Epub ahead of print]112 108118
    Spectrum of rare and common mitochondrial DNA variations from 1029 whole genomes of self-declared healthy individuals from India.
    Vishu Gupta, Bani Jolly, Rahul C Bhoyar, Mohit Kumar Divakar, Abhinav Jain, Anushree Mishra, Vigneshwar Senthivel, Mohamed Imran, Vinod Scaria, Sridhar Sivasubbu.
      Mitochondrial disorders are a class of heterogeneous disorders caused by genetic variations in the mitochondrial genome (mtDNA) as well as the nuclear genome. The spectrum of mtDNA variants remains unexplored in the Indian population. In the present study, we have cataloged 2689 high confidence single nucleotide variants, small insertions and deletions in mtDNA in 1029 healthy Indian individuals. We found a major proportion (76.5 %) of the variants being rare (AF<=0.005) in the studied population. Intriguingly, we found two 'confirmed' pathogenic variants (m.1555 A>G and m.14484 T>C) with a frequency of ∼1 in 250 individuals in our dataset. The high carrier frequency underscores the need for screening of the mtDNA pathogenic mutations in newborns in India. Interestingly, our analysis also revealed 202 variants in our dataset which have been 'reported' in disease cases as per the MITOMAP database. Additionally, we found the frequency of haplogroup M (52.2 %) to be the highest among all the 18 top-level haplogroups found in our dataset. In comparison to the global population datasets, 20 unique mtDNA variants are found in the Indian population. We hope the whole genome sequencing based compendium of mtDNA variants along with their allele frequencies and heteroplasmy levels in the Indian population will drive additional genome scale studies for mtDNA. Furthermore, the identification of clinically relevant variants in our dataset will aid in better clinical interpretation of the variants in mitochondrial disorders.
    Keywords:  Allele frequencies; Haplogroups; Heteroplasmy; Indian population; Mitochondrial DNA; Mitochondrial Disorders
    DOI:  https://doi.org/10.1016/j.compbiolchem.2024.108118
  27. J Strength Cond Res. 2024 Jul 01. 38(7): 1189-1199
    Mitochondria Transplantation: Rescuing Innate Muscle Bioenergetic Impairment in a Model of Aging and Exercise Intolerance.
    Tasnim Arroum, Gerald A Hish, Kyle J Burghardt, Mohamed Ghamloush, Belal Bazzi, Abdallah Mrech, Paul T Morse, Steven L Britton, Lauren G Koch, James D McCully, Maik Hüttemann, Moh H Malek.
       ABSTRACT: Arroum, T, Hish, GA, Burghardt, KJ, Ghamloush, M, Bazzi, B, Mrech, A, Morse, PT, Britton, SL, Koch, LG, McCully, JD, Hüttemann, M, and Malek, MH. Mitochondria transplantation: Rescuing innate muscle bioenergetic impairment in a model of aging and exercise intolerance. J Strength Cond Res 38(7): 1189-1199, 2024-Mitochondria, through oxidative phosphorylation, are crucial for energy production. Disease, genetic impairment, or deconditioning can harm muscle mitochondria, affecting energy production. Endurance training enhances mitochondrial function but assumes mobility. Individuals with limited mobility lack effective treatments for mitochondrial dysfunction because of disease or aging. Mitochondrial transplantation replaces native mitochondria that have been damaged with viable, respiration-competent mitochondria. Here, we used a rodent model selectively bred for low-capacity running (LCR), which exhibits innate mitochondrial dysfunction in the hind limb muscles. Hence, the purpose of this study was to use a distinct breed of rats (i.e., LCR) that display hereditary skeletal muscle mitochondrial dysfunction to evaluate the consequences of mitochondrial transplantation. We hypothesized that the transplantation of mitochondria would effectively alleviate mitochondrial dysfunction in the hind limb muscles of rats when compared with placebo injections. In addition, we hypothesized that rats receiving the mitochondrial transplantation would experience an improvement in their functional capacity, as evaluated through incremental treadmill testing. Twelve aged LCR male rats (18 months old) were randomized into 2 groups (placebo or mitochondrial transplantation). One LCR rat of the same age and sex was used as the donor to isolate mitochondria from the hindlimb muscles. Isolated mitochondria were injected into both hindlimb muscles (quadriceps femoris, tibialis anterior (TA), and gastrocnemius complex) of a subset LCR (n = 6; LCR-M) rats. The remaining LCR (n = 5; LCR-P) subset received a placebo injection containing only the vehicle without the isolated mitochondria. Four weeks after mitochondrial transplantation, rodents were euthanized and hindlimb muscles harvested. The results indicated a significant (p < 0.05) increase in mitochondrial markers for glycolytic (plantaris and TA) and mixed (quadricep femoris) muscles, but not oxidative muscle (soleus). Moreover, we found significant (p < 0.05) epigenetic changes (i.e., hypomethylation) at the global and site-specific levels for a key mitochondrial regulator (transcription factor A mitochondrial) between the placebo and mitochondrial transplantation groups. To our knowledge, this is the first study to examine the efficacy of mitochondrial transplantation in a rodent model of aging with congenital skeletal muscle dysfunction.
    DOI:  https://doi.org/10.1519/JSC.0000000000004793
  28. Adv Sci (Weinh). 2024 Jun 19. e2403093
    CKB Promotes Mitochondrial ATP Production by Suppressing Permeability Transition Pore.
    Le He, Jianghua Lin, Shaojuan Lu, Hao Li, Jie Chen, Xinyi Wu, Qixin Yan, Hailiang Liu, Hui Li, Yufeng Shi.
      Creatine kinases are essential for maintaining cellular energy balance by facilitating the reversible transfer of a phosphoryl group from ATP to creatine, however, their role in mitochondrial ATP production remains unknown. This study shows creatine kinases, including CKMT1A, CKMT1B, and CKB, are highly expressed in cells relying on the mitochondrial F1F0 ATP synthase for survival. Interestingly, silencing CKB, but not CKMT1A or CKMT1B, leads to a loss of sensitivity to the inhibition of F1F0 ATP synthase in these cells. Mechanistically, CKB promotes mitochondrial ATP but reduces glycolytic ATP production by suppressing mitochondrial calcium (mCa2+) levels, thereby preventing the activation of mitochondrial permeability transition pore (mPTP) and ensuring efficient mitochondrial ATP generation. Further, CKB achieves this regulation by suppressing mCa2+ levels through the inhibition of AKT activity. Notably, the CKB-AKT signaling axis boosts mitochondrial ATP production in cancer cells growing in a mouse tumor model. Moreover, this study also uncovers a decline in CKB expression in peripheral blood mononuclear cells with aging, accompanied by an increase in AKT signaling in these cells. These findings thus shed light on a novel signaling pathway involving CKB that directly regulates mitochondrial ATP production, potentially playing a role in both pathological and physiological conditions.
    Keywords:  AKT; F1F0 ATP synthase; aging; cancer; creatine kinase brain‐type (CKB); mitochondrial permeability transition pore (mPTP)
    DOI:  https://doi.org/10.1002/advs.202403093
  29. Neuron. 2024 Jun 19. pii: S0896-6273(24)00331-3. [Epub ahead of print]112(12): 1897-1899
    Fuse mitochondria to win peer competition.
    Lang Wang, Yan Gu.
      In this issue of Neuron, Kochan et al.1 report that enhanced mitochondrial fusion is essential for the heightened synaptic plasticity in adult-born neurons during the critical period, thus supporting their competition with neurons of similar age for survival.
    DOI:  https://doi.org/10.1016/j.neuron.2024.05.005
  30. JCI Insight. 2024 Jun 11. pii: e179071. [Epub ahead of print]
    FDXR variants cause adrenal insufficiency and atypical sexual development.
    Emanuele Pignatti, Jesse Slone, María Ángeles Gómez Cano, Teresa Margaret Campbell, Jimmy Vu, Kay-Sara Sauter, Amit V Pandey, Francisco Martínez-Azorín, Marina Alonso-Riaño, Derek E Neilson, Nicola Longo, Therina du Toit, Clarissa D Voegel, Taosheng Huang, Christa E Flück.
      Genetic defects affecting steroid biosynthesis cause cortisol deficiency and differences of sex development; among them recessive mutations in the steroidogenic enzymes CYP11A1 and CYP11B, whose function is supported by reducing equivalents donated by ferredoxin reductase (FDXR) and ferredoxin. So far, mutations in the mitochondrial flavoprotein FDXR have been associated with a progressive neuropathic mitochondriopathy named FDXR-Related Mitochondriopathy (FRM), but cortisol insufficiency has not been documented. However, FRM patients often experience worsening or demise following stress associated with infections. We investigated two female FRM patients carrying the novel homozygous FDXR mutation p.G437R with ambiguous genitalia at birth and sudden death in the first year of life; they presented with cortisol deficiency and androgen excess compatible with 11-hydroxylase deficiency. In addition, steroidogenic FDXR-variant cell lines reprogrammed from three FRM patients' fibroblasts displayed deficient mineralocorticoid and glucocorticoid production. Finally, Fdxr-mutant mice allelic to the severe p.R386W human variant, showed reduced progesterone and corticosterone production. Therefore, our comprehensive studies show that human FDXR variants may cause compensated, but possibly life-threatening adrenocortical insufficiency in stress by affecting adrenal glucocorticoid and mineralocorticoid synthesis through direct enzyme inhibition, most likely in combination with disturbed mitochondrial redox balance.
    Keywords:  Endocrinology; Genetic diseases; Genetics; Mitochondria; Molecular genetics
    DOI:  https://doi.org/10.1172/jci.insight.179071
  31. Nat Med. 2024 Jun 19.
    Exploring the benefits, harms and costs of genomic newborn screening for rare diseases.
    Emma L Baple, Richard H Scott, Siddharth Banka, James Buchanan, Louise Fish, Sarah Wynn, Dominic Wilkinson, Sian Ellard, Daniel G MacArthur, Zornitza Stark.
      
    DOI:  https://doi.org/10.1038/s41591-024-03055-x
  32. Nat Cell Biol. 2024 Jun 20.
    Mitochondria and cell death.
    Hannah L Glover, Annabell Schreiner, Grant Dewson, Stephen W G Tait.
      Mitochondria are cellular factories for energy production, calcium homeostasis and iron metabolism, but they also have an unequivocal and central role in intrinsic apoptosis through the release of cytochrome c. While the subsequent activation of proteolytic caspases ensures that cell death proceeds in the absence of collateral inflammation, other phlogistic cell death pathways have been implicated in using, or engaging, mitochondria. Here we discuss the emerging complexities of intrinsic apoptosis controlled by the BCL-2 family of proteins. We highlight the emerging theory that non-lethal mitochondrial apoptotic signalling has diverse biological roles that impact cancer, innate immunity and ageing. Finally, we delineate the role of mitochondria in other forms of cell death, such as pyroptosis, ferroptosis and necroptosis, and discuss mitochondria as central hubs for the intersection and coordination of cell death signalling pathways, underscoring their potential for therapeutic manipulation.
    DOI:  https://doi.org/10.1038/s41556-024-01429-4
  33. Dev Med Child Neurol. 2024 Jun 19.
    Whole genome sequencing for copy number variant detection to improve diagnosis and management of rare diseases.
      
    DOI:  https://doi.org/10.1111/dmcn.16008
  34. Int J Mol Sci. 2024 May 31. pii: 6062. [Epub ahead of print]25(11):
    The Role of Mitochondrial Copy Number in Neurodegenerative Diseases: Present Insights and Future Directions.
    Annamaria Cerantonio, Luigi Citrigno, Beatrice Maria Greco, Selene De Benedittis, Giuseppe Passarino, Raffaele Maletta, Antonio Qualtieri, Alberto Montesanto, Patrizia Spadafora, Francesca Cavalcanti.
      Neurodegenerative diseases are progressive disorders that affect the central nervous system (CNS) and represent the major cause of premature death in the elderly. One of the possible determinants of neurodegeneration is the change in mitochondrial function and content. Altered levels of mitochondrial DNA copy number (mtDNA-CN) in biological fluids have been reported during both the early stages and progression of the diseases. In patients affected by neurodegenerative diseases, changes in mtDNA-CN levels appear to correlate with mitochondrial dysfunction, cognitive decline, disease progression, and ultimately therapeutic interventions. In this review, we report the main results published up to April 2024, regarding the evaluation of mtDNA-CN levels in blood samples from patients affected by Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). The aim is to show a probable link between mtDNA-CN changes and neurodegenerative disorders. Understanding the causes underlying this association could provide useful information on the molecular mechanisms involved in neurodegeneration and offer the development of new diagnostic approaches and therapeutic interventions.
    Keywords:  mitochondrial DNA copy number; mitochondrial function; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/ijms25116062
  35. Glia. 2024 Jun 20.
    Deficient brain GABA metabolism leads to widespread impairments of astrocyte and oligodendrocyte function.
    Jens V Andersen, Oana C Marian, Filippa L Qvist, Emil W Westi, Blanca I Aldana, Arne Schousboe, Anthony S Don, Niels H Skotte, Petrine Wellendorph.
      The neurometabolic disorder succinic semialdehyde dehydrogenase (SSADH) deficiency leads to great neurochemical imbalances and severe neurological manifestations. The cause of the disease is loss of function of the enzyme SSADH, leading to impaired metabolism of the principal inhibitory neurotransmitter GABA. Despite the known identity of the enzymatic deficit, the underlying pathology of SSADH deficiency remains unclear. To uncover new mechanisms of the disease, we performed an untargeted integrative analysis of cerebral protein expression, functional metabolism, and lipid composition in a genetic mouse model of SSADH deficiency (ALDH5A1 knockout mice). Our proteomic analysis revealed a clear regional vulnerability, as protein alterations primarily manifested in the hippocampus and cerebral cortex of the ALDH5A1 knockout mice. These regions displayed aberrant expression of proteins linked to amino acid homeostasis, mitochondria, glial function, and myelination. Stable isotope tracing in acutely isolated brain slices demonstrated an overall maintained oxidative metabolism of glucose, but a selective decrease in astrocyte metabolic activity in the cerebral cortex of ALDH5A1 knockout mice. In contrast, an elevated capacity of oxidative glutamine metabolism was observed in the ALDH5A1 knockout brain, which may serve as a neuronal compensation of impaired astrocyte glutamine provision. In addition to reduced expression of critical oligodendrocyte proteins, a severe depletion of myelin-enriched sphingolipids was found in the brains of ALDH5A1 knockout mice, suggesting degeneration of myelin. Altogether, our study highlights that impaired astrocyte and oligodendrocyte function is intimately linked to SSADH deficiency pathology, suggesting that selective targeting of glial cells may hold therapeutic potential in this disease.
    Keywords:  SSADH deficiency; brain energy metabolism; glia; glutamate/GABA‐glutamine cycle; myelin
    DOI:  https://doi.org/10.1002/glia.24585
  36. FASEB J. 2024 Jun 30. 38(12): e23742
    Multiomics analysis reveals serine catabolism as a potential therapeutic target for MELAS.
    Tongling Liufu, Xutong Zhao, Meng Yu, Zhiying Xie, Lingchao Meng, He Lv, Wei Zhang, Yun Yuan, Guogang Xing, Jianwen Deng, Zhaoxia Wang.
      Mitochondrial disease is a devastating genetic disorder, with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and m.3243A>G being the most common phenotype and genotype, respectively. The treatment for MELAS patients is still less effective. Here, we performed transcriptomic and proteomic analysis in muscle tissue of MELAS patients, and discovered that the expression of molecules involved in serine catabolism were significantly upregulated, and serine hydroxymethyltransferase 2 (SHMT2) increased significantly in both the mRNA and protein levels. The SHMT2 protein level was also increased in myoblasts with m.3243A>G mutation, which was transdifferentiated from patients derived fibroblasts, accompanying with the decreased nicotinamide adenine dinucleotide (NAD+)/reduced NAD+ (NADH) ratio and cell viability. After treating with SHMT2 inhibitor (SHIN1), the NAD+/NADH ratio and cell viability in MELAS myoblasts increased significantly. Taken together, our study indicates that enhanced serine catabolism plays an important role in the pathogenesis of MELAS and that SHIN1 can be a potential small molecule for the treatment of this disease.
    Keywords:  M.3243 A>G; MELAS; NADH; SHIN1; SHMT2; multiomics
    DOI:  https://doi.org/10.1096/fj.202302286RRR
  37. ACS Nano. 2024 Jun 21.
    Unraveling RNA Conformation Dynamics in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episode Syndrome with Solid-State Nanopores.
    Srilahari Namani, Kyril Kavetsky, Chih-Yuan Lin, Sunita Maharjan, Howard B Gamper, Nan-Sheng Li, Joseph A Piccirilli, Ya-Ming Hou, Marija Drndic.
      This study investigates transfer ribonucleic acid (tRNA) conformational dynamics in the context of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) using solid-state silicon nitride (SiN) nanopore technology. SiN nanopores in thin membranes with specific dimensions exhibit high signal resolution, enabling real-time and single-molecule electronic detection of tRNA conformational changes. We focus on human mitochondrial tRNALeu(UAA) (mt-Leu(UAA)) that decodes Leu codons UUA/UUG (UUR) during protein synthesis on the mt-ribosome. The single A14G substitution in mt-Leu(UAA) is the major cause of MELAS disease. Measurements of current blockades and dwell times reveal distinct conformational dynamics of the wild-type (WT) and the A14G variant of mt-Leu(UAA) in response to the conserved post-transcriptional m1G9 methylation. While the m1G9-modified WT transcript adopts a more stable structure relative to the unmodified transcript, the m1G9-modified MELAS transcript adopts a less stable structure relative to the unmodified transcript. Notably, these differential features were observed at 0.4 M KCl, but not at 3 M KCl, highlighting the importance of experimental settings that are closer to physiological conditions. This work demonstrates the feasibility of the nanopore platform to discern tRNA molecules that differ by a single-nucleotide substitution or by a single methylation event, providing an important step forward to explore changes in the conformational dynamics of other RNA molecules in human diseases.
    Keywords:  MELAS; m1G9 methylation; mitochondrial tRNA; nanopore; silicon nitride; tRNA conformation
    DOI:  https://doi.org/10.1021/acsnano.4c04625
  38. bioRxiv. 2024 Jun 09. pii: 2024.06.06.597841. [Epub ahead of print]
    Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure.
    Rachel C Weiss, Kelly D Pyles, Kevin Cho, Michelle Brennan, Jonathan S Fisher, Gary J Patti, Kyle S McCommis.
       Background: Heart failure involves metabolic alterations including increased glycolysis despite unchanged or decreased glucose oxidation. The mitochondrial pyruvate carrier (MPC) regulates pyruvate entry into the mitochondrial matrix, and cardiac deletion of the MPC in mice causes heart failure. How MPC deletion results in heart failure is unknown.
    Methods: We performed targeted metabolomics and isotope tracing in wildtype (fl/fl) and cardiac-specific Mpc2-/- (CS-Mpc2-/-) hearts after in vivo injection of U- 13 C-glucose. Cardiac glycogen was assessed biochemically and by transmission electron microscopy. Cardiac uptake of 2-deoxyglucose was measured and western blotting performed to analyze insulin signaling and enzymatic regulators of glycogen synthesis and degradation. Isotope tracing and glycogen analysis was also performed in hearts from mice fed either low-fat diet or a ketogenic diet previously shown to reverse the CS-Mpc2-/- heart failure. Cardiac glycogen was also assessed in mice infused with angiotensin-II that were fed low-fat or ketogenic diet.
    Results: Failing CS-Mpc2-/- hearts contained normal levels of ATP and phosphocreatine, yet these hearts displayed increased enrichment from U- 13 C-glucose and increased glycolytic metabolite pool sizes. 13 C enrichment and pool size was also increased for the glycogen intermediate UDP-glucose, as well as increased enrichment of the glycogen pool. Glycogen levels were increased ∼6-fold in the failing CS-Mpc2-/- hearts, and glycogen granules were easily detected by electron microscopy. This increased glycogen synthesis occurred despite enhanced inhibitory phosphorylation of glycogen synthase and reduced expression of glycogenin-1. In young, non-failing CS-Mpc2-/- hearts, increased glycolytic 13 C enrichment occurred, but glycogen levels remained low and unchanged compared to fl/fl hearts. Feeding a ketogenic diet to CS-Mpc2-/- mice reversed the heart failure and normalized the cardiac glycogen and glycolytic metabolite accumulation. Cardiac glycogen levels were also elevated in mice infused with angiotensin-II, and both the cardiac hypertrophy and glycogen levels were improved by ketogenic diet.
    Conclusions: Our results indicate that loss of MPC in the heart causes glycogen accumulation and heart failure, while a ketogenic diet can reverse both the glycogen accumulation and heart failure. We conclude that maintaining mitochondrial pyruvate import and metabolism is critical for the heart, unless cardiac pyruvate metabolism is reduced by consumption of a ketogenic diet.
    DOI:  https://doi.org/10.1101/2024.06.06.597841
  39. Nat Med. 2024 Jun 17.
    Peripheral blood mononuclear cell respiratory function is associated with progressive glaucomatous vision loss.
    Bledi Petriti, Alessandro Rabiolo, Kai-Yin Chau, Pete A Williams, Giovanni Montesano, Gerassimos Lascaratos, David F Garway-Heath.
      Intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma and all licensed treatments lower IOP. However, many patients continue to lose vision despite IOP-lowering treatment. Identifying biomarkers for progressive vision loss would have considerable clinical utility. We demonstrate that lower peripheral blood mononuclear cell (PBMC) oxygen consumption rate (OCR) is strongly associated with faster visual field (VF) progression in patients treated by lowering IOP (P < 0.001, 229 eyes of 139 participants), explaining 13% of variance in the rate of progression. In a separate reference cohort of untreated patients with glaucoma (213 eyes of 213 participants), IOP explained 16% of VF progression variance. OCR is lower in patients with glaucoma (n = 168) than in controls (n = 50; P < 0.001) and is lower in patients with low baseline IOP (n = 99) than those with high baseline IOP (n = 69; P < 0.01). PBMC nicotinamide adenine dinucleotide (NAD) levels are lower in patients with glaucoma (n = 29) compared to controls (n = 25; P < 0.001) and strongly associated with OCR (P < 0.001). Our results support PBMC OCR and NAD levels as new biomarkers for progressive glaucoma.
    DOI:  https://doi.org/10.1038/s41591-024-03068-6
  40. Nat Biotechnol. 2024 Jun;42(6): 829
    Gene therapy restores hearing.
      
    DOI:  https://doi.org/10.1038/s41587-024-02292-2
  41. Cell Commun Signal. 2024 Jun 21. 22(1): 343
    Identification of the central role of RNA polymerase mitochondrial for angiogenesis.
    Meng-Jia Huan, Ping-Ping Fu, Xia Chen, Zhao-Xia Wang, Zhou-Rui Ma, Shi-Zhong Cai, Qin Jiang, Qian Wang.
      Mitochondria are central to endothelial cell activation and angiogenesis, with the RNA polymerase mitochondrial (POLRMT) serving as a key protein in regulating mitochondrial transcription and oxidative phosphorylation. In our study, we examined the impact of POLRMT on angiogenesis and found that its silencing or knockout (KO) in human umbilical vein endothelial cells (HUVECs) and other endothelial cells resulted in robust anti-angiogenic effects, impeding cell proliferation, migration, and capillary tube formation. Depletion of POLRMT led to impaired mitochondrial function, characterized by mitochondrial depolarization, oxidative stress, lipid oxidation, DNA damage, and reduced ATP production, along with significant apoptosis activation. Conversely, overexpressing POLRMT promoted angiogenic activity in the endothelial cells. In vivo experiments demonstrated that endothelial knockdown of POLRMT, by intravitreous injection of endothelial specific POLRMT shRNA adeno-associated virus, inhibited retinal angiogenesis. In addition, inhibiting POLRMT with a first-in-class inhibitor IMT1 exerted significant anti-angiogenic impact in vitro and in vivo. Significantly elevated expression of POLRMT was observed in the retinal tissues of streptozotocin-induced diabetic retinopathy (DR) mice. POLRMT endothelial knockdown inhibited pathological retinal angiogenesis and mitigated retinal ganglion cell (RGC) degeneration in DR mice. At last, POLRMT expression exhibited a substantial increase in the retinal proliferative membrane tissues of human DR patients. These findings collectively establish the indispensable role of POLRMT in angiogenesis, both in vitro and in vivo.
    DOI:  https://doi.org/10.1186/s12964-024-01712-9
  42. Mol Genet Metab. 2024 Jun 06. pii: S1096-7192(24)00395-0. [Epub ahead of print]142(3): 108511
    Genome and RNA sequencing were essential to reveal cryptic intronic variants associated to defective ATP6AP1 mRNA processing.
    Blai Morales-Romero, Gerard Muñoz-Pujol, Rafael Artuch, Angels García-Cazorla, Mar O'Callaghan, Jolanta Sykut-Cegielska, Jaume Campistol, Pedro Juan Moreno-Lozano, Machteld M Oud, Ron A Wevers, Dirk J Lefeber, Anna Esteve-Codina, Vicente A Yepez, Julien Gagneur, Saskia B Wortmann, Holger Prokisch, Antonia Ribes, Judit García-Villoria, Frederic Tort.
      The diagnosis of Mendelian disorders has notably advanced with integration of whole exome and genome sequencing (WES and WGS) in clinical practice. However, challenges in variant interpretation and uncovered variants by WES still leave a substantial percentage of patients undiagnosed. In this context, integrating RNA sequencing (RNA-seq) improves diagnostic workflows, particularly for WES inconclusive cases. Additionally, functional studies are often necessary to elucidate the impact of prioritized variants on gene expression and protein function. Our study focused on three unrelated male patients (P1-P3) with ATP6AP1-CDG (congenital disorder of glycosylation), presenting with intellectual disability and varying degrees of hepatopathy, glycosylation defects, and an initially inconclusive diagnosis through WES. Subsequent RNA-seq was pivotal in identifying the underlying genetic causes in P1 and P2, detecting ATP6AP1 underexpression and aberrant splicing. Molecular studies in fibroblasts confirmed these findings and identified the rare intronic variants c.289-233C > T and c.289-289G > A in P1 and P2, respectively. Trio-WGS also revealed the variant c.289-289G > A in P3, which was a de novo change in both patients. Functional assays expressing the mutant alleles in HAP1 cells demonstrated the pathogenic impact of these variants by reproducing the splicing alterations observed in patients. Our study underscores the role of RNA-seq and WGS in enhancing diagnostic rates for genetic diseases such as CDG, providing new insights into ATP6AP1-CDG molecular bases by identifying the first two deep intronic variants in this X-linked gene. Additionally, our study highlights the need to integrate RNA-seq and WGS, followed by functional validation, in routine diagnostics for a comprehensive evaluation of patients with an unidentified molecular etiology.
    Keywords:  ATP6AP1-CDG; Congenital disorders of glycosylation; Intronic variant; RNA-seq; Whole exome sequencing; Whole genome sequencing
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108511
  43. Biochim Biophys Acta Mol Cell Res. 2024 Jun 18. pii: S0167-4889(24)00129-0. [Epub ahead of print] 119786
    Structural aspects of iron‑sulfur protein biogenesis: An NMR view.
    Leonardo Querci, Mario Piccioli, Simone Ciofi-Baffoni, Lucia Banci.
      Over the last decade, structural aspects involving iron‑sulfur (Fe/S) protein biogenesis have played an increasingly important role in understanding the high mechanistic complexity of mitochondrial and cytosolic machineries maturing Fe/S proteins. In this respect, solution NMR has had a significant impact because of its ability to monitor transient protein-protein interactions, which are abundant in the networks of pathways leading to Fe/S cluster biosynthesis and transfer, as well as thanks to the developments of paramagnetic NMR in both terms of new methodologies and accurate data interpretation. Here, we review the use of solution NMR in characterizing the structural aspects of human Fe/S proteins and their interactions in the framework of Fe/S protein biogenesis. We will first present a summary of the recent advances that have been achieved by paramagnetic NMR and then we will focus our attention on the role of solution NMR in the field of human Fe/S protein biogenesis.
    Keywords:  CIA machinery; Ferredoxin; Glutaredoxin; ISC assembly machinery; Mitochondria; NMR; Paramagnetism; iron‑sulfur cluster
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119786
  44. Sci Adv. 2024 Jun 21. 10(25): eadn0014
    Olfaction regulates peripheral mitophagy and mitochondrial function.
    Julian G Dishart, Corinne L Pender, Koning Shen, Hanlin Zhang, Megan Ly, Madison B Webb, Andrew Dillin.
      The central nervous system coordinates peripheral cellular stress responses, including the unfolded protein response of the mitochondria (UPRMT); however, the contexts for which this regulatory capability evolved are unknown. UPRMT is up-regulated upon pathogenic infection and in metabolic flux, and the olfactory nervous system has been shown to regulate pathogen resistance and peripheral metabolic activity. Therefore, we asked whether the olfactory nervous system in Caenorhabditis elegans controls the UPRMT cell nonautonomously. We found that silencing a single inhibitory olfactory neuron pair, AWC, led to robust induction of UPRMT and reduction of oxidative phosphorylation dependent on serotonin signaling and parkin-mediated mitophagy. Further, AWC ablation confers resistance to the pathogenic bacteria Pseudomonas aeruginosa partially dependent on the UPRMT transcription factor atfs-1 and fully dependent on mitophagy machinery. These data illustrate a role for the olfactory nervous system in regulating whole-organism mitochondrial dynamics, perhaps in preparation for postprandial metabolic stress or pathogenic infection.
    DOI:  https://doi.org/10.1126/sciadv.adn0014
  45. EBioMedicine. 2024 Jun 19. pii: S2352-3964(24)00239-1. [Epub ahead of print]105 105204
    A computational framework to improve cross-platform implementation of transcriptomics signatures.
    Louis Kreitmann, Giselle D'Souza, Luca Miglietta, Ortensia Vito, Heather R Jackson, Dominic Habgood-Coote, Michael Levin, Alison Holmes, Myrsini Kaforou, Jesus Rodriguez-Manzano.
      The emergence of next-generation sequencing technologies and computational advances have expanded our understanding of gene expression regulation (i.e., the transcriptome). This has also led to an increased interest in using transcriptomic biomarkers to improve disease diagnosis and stratification, to assess prognosis and predict the response to treatment. Significant progress in identifying transcriptomic signatures for various clinical needs has been made, with large discovery studies accounting for challenges such as patient variability, unwanted batch effects, and data complexities; however, obstacles related to the technical aspects of cross-platform implementation still hinder the successful integration of transcriptomic technologies into standard diagnostic workflows. In this article, we discuss the challenges associated with integrating transcriptomic signatures derived using high-throughput technologies (such as RNA-sequencing) into clinical diagnostic tools using nucleic acid amplification (NAA) techniques. The novelty of the proposed approach lies in our aim to embed constraints related to cross-platform implementation in the process of signature discovery. These constraints could include technical limitations of amplification platform and chemistry, the maximal number of targets imposed by the chosen multiplexing strategy, and the genomic context of identified RNA biomarkers. Finally, we propose to build a computational framework that would integrate these constraints in combination with existing statistical and machine learning models used for signature identification. We envision that this could accelerate the integration of RNA signatures discovered by high-throughput technologies into NAA-based approaches suitable for clinical applications.
    Keywords:  Diagnostics; Host-response; Molecular test; Multiplex PCR; Nucleic acid amplification techniques; PCR-based technologies; RNA sequencing; Transcriptomic signatures
    DOI:  https://doi.org/10.1016/j.ebiom.2024.105204
  46. Int J Mol Sci. 2024 May 28. pii: 5855. [Epub ahead of print]25(11):
    Genetic Mutations and Mitochondrial Redox Signaling as Modulating Factors in Hypertrophic Cardiomyopathy: A Scoping Review.
    Antonio da Silva Menezes Junior, Ana Luísa Guedes de França-E-Silva, Henrique Lima de Oliveira, Khissya Beatryz Alves de Lima, Iane de Oliveira Pires Porto, Thays Millena Alves Pedroso, Daniela de Melo E Silva, Aguinaldo F Freitas.
      Hypertrophic cardiomyopathy (HCM) is a heart condition characterized by cellular and metabolic dysfunction, with mitochondrial dysfunction playing a crucial role. Although the direct relationship between genetic mutations and mitochondrial dysfunction remains unclear, targeting mitochondrial dysfunction presents promising opportunities for treatment, as there are currently no effective treatments available for HCM. This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews guidelines. Searches were conducted in databases such as PubMed, Embase, and Scopus up to September 2023 using "MESH terms". Bibliographic references from pertinent articles were also included. Hypertrophic cardiomyopathy (HCM) is influenced by ionic homeostasis, cardiac tissue remodeling, metabolic balance, genetic mutations, reactive oxygen species regulation, and mitochondrial dysfunction. The latter is a common factor regardless of the cause and is linked to intracellular calcium handling, energetic and oxidative stress, and HCM-induced hypertrophy. Hypertrophic cardiomyopathy treatments focus on symptom management and complication prevention. Targeted therapeutic approaches, such as improving mitochondrial bioenergetics, are being explored. This includes coenzyme Q and elamipretide therapies and metabolic strategies like therapeutic ketosis. Understanding the biomolecular, genetic, and mitochondrial mechanisms underlying HCM is crucial for developing new therapeutic modalities.
    Keywords:  hypertrophic cardiomyopathy; metabolism; mitochondrial dysfunction; mitochondrial redox signaling
    DOI:  https://doi.org/10.3390/ijms25115855
  47. Int J Mol Sci. 2024 May 31. pii: 6056. [Epub ahead of print]25(11):
    An Amino Acid Mixture to Counteract Skeletal Muscle Atrophy: Impact on Mitochondrial Bioenergetics.
    Francesco Bellanti, Aurelio Lo Buglio, Giuseppe Pannone, Maria Carmela Pedicillo, Ilenia Sara De Stefano, Angela Pignataro, Cristiano Capurso, Gianluigi Vendemiale.
      Skeletal muscle atrophy (SMA) is caused by a rise in muscle breakdown and a decline in protein synthesis, with a consequent loss of mass and function. This study characterized the effect of an amino acid mixture (AA) in models of SMA, focusing on mitochondria. C57/Bl6 mice underwent immobilization of one hindlimb (I) or cardiotoxin-induced muscle injury (C) and were compared with controls (CTRL). Mice were then administered AA in drinking water for 10 days and compared to a placebo group. With respect to CTRL, I and C reduced running time and distance, along with grip strength; however, the reduction was prevented by AA. Tibialis anterior (TA) muscles were used for histology and mitochondria isolation. I and C resulted in TA atrophy, characterized by a reduction in both wet weight and TA/body weight ratio and smaller myofibers than those of CTRL. Interestingly, these alterations were lightly observed in mice treated with AA. The mitochondrial yield from the TA of I and C mice was lower than that of CTRL but not in AA-treated mice. AA also preserved mitochondrial bioenergetics in TA muscle from I and C mice. To conclude, this study demonstrates that AA prevents loss of muscle mass and function in SMA by protecting mitochondria.
    Keywords:  amino acids; cardiotoxin; immobilization; sarcopenia
    DOI:  https://doi.org/10.3390/ijms25116056
  48. Nature. 2024 Jun 12.
    A Multimodal Generative AI Copilot for Human Pathology.
    Ming Y Lu, Bowen Chen, Drew F K Williamson, Richard J Chen, Melissa Zhao, Aaron K Chow, Kenji Ikemura, Ahrong Kim, Dimitra Pouli, Ankush Patel, Amr Soliman, Chengkuan Chen, Tong Ding, Judy J Wang, Georg Gerber, Ivy Liang, Long Phi Le, Anil V Parwani, Luca L Weishaupt, Faisal Mahmood.
      The field of computational pathology[1,2] has witnessed remarkable progress in the development of both task-specific predictive models and task-agnostic self-supervised vision encoders[3,4]. However, despite the explosive growth of generative artificial intelligence (AI), there has been limited study on building general purpose, multimodal AI assistants and copilots[5] tailored to pathology. Here we present PathChat, a vision-language generalist AI assistant for human pathology. We build PathChat by adapting a foundational vision encoder for pathology, combining it with a pretrained large language model and finetuning the whole system on over 456,000 diverse visual language instructions consisting of 999,202 question-answer turns. We compare PathChat against several multimodal vision language AI assistants and GPT4V, which powers the commercially available multimodal general purpose AI assistant ChatGPT-4[7]. PathChat achieved state-of-the-art performance on multiple-choice diagnostic questions from cases of diverse tissue origins and disease models. Furthermore, using open-ended questions and human expert evaluation, we found that overall PathChat produced more accurate and pathologist-preferable responses to diverse queries related to pathology. As an interactive and general vision-language AI Copilot that can flexibly handle both visual and natural language inputs, PathChat can potentially find impactful applications in pathology education, research, and human-in-the-loop clinical decision making.
    DOI:  https://doi.org/10.1038/s41586-024-07618-3
  49. Methods Mol Biol. 2024 ;2832 67-79
    Determination of Differential Alternative Splicing Under Stress Conditions.
    Paola Punzo, Riccardo Suede Cigliano, Riccardo Aversano, Stefania Grillo, Giorgia Batelli.
      Alternative splicing (AS) is an important mechanism contributing to stress-induced regulation of gene expression and proteome diversity. Massive sequencing technologies allow the identification of transcripts generated via stress-responsive AS, potentially important for adaptation to stress conditions. Several bioinformatics tools have been developed to identify differentially expressed alternative splicing events/transcripts from RNA-sequencing results. This chapter describes a detailed protocol for differential alternative splicing analysis using the rMATS tool. In addition, we provide guidelines for validation of the detected splice variants by qRT-PCR based on the obtained output files.
    Keywords:  Bioinformatics; Oligonucleotide design; Pre-mRNA splicing; RNA-sequencing; qRT-PCR validation; rMATS
    DOI:  https://doi.org/10.1007/978-1-0716-3973-3_5
  50. Chemistry. 2024 Jun 17. e202402055
    A Prebiotic Pathway to Nicotinamide Adenine Dinucleotide.
    Maximilian Bechtel, Nathalie Kurrle, Oliver Trapp.
      Enzymes play a fundamental role in cellular metabolism. A wide range of enzymes require the presence of complementary coenzymes and cofactors to function properly. While coenzymes are believed to have been part of the last universal ancestor (LUCA) or have been present even earlier, the syntheses of crucial coenzymes like the redox-active coenzymes flavin adenine dinucleotide (FAD) or nicotinamide adenine dinucleotide (NAD+) remain challenging. Here, we present a pathway to NAD+ under prebiotic conditions starting with ammonia, cyanoacetaldehyde, prop-2-ynal and sugar-forming precursors, yielding in situ the nicotinamide riboside. Regioselective phosphorylation and water stable light activated adenosine monophosphate derivatives allow for topographically and irradiation-controlled formation of NAD+. Our findings indicate that NAD+, a coenzyme vital to life, can be formed non-enzymatically from simple organic feedstock molecules via photocatalytic activation under prebiotically plausible early Earth conditions in a continuous process under aqueous conditions.
    Keywords:  coenzyme; nucleotide; phosphorylation; prebiotic chemistry; ribose
    DOI:  https://doi.org/10.1002/chem.202402055
  51. Trends Endocrinol Metab. 2024 Jun 18. pii: S1043-2760(24)00162-0. [Epub ahead of print]
    Food perception induces fast fragmentation of hepatic mitochondria.
    Arnaud Chevrollier, Jérome Boursier, Valérie Desquiret-Dumas.
      Henschke et al. have recently shown that sensory food perception in mice integrated at the hypothalamus would be sufficient to suppress hepatic glucose production in a rapid mechanism involving a newly described AKT-dependent kinase pathway that engages mitochondrial fission dynamics. Exploiting this pathway could guide strategies to treat type 2 diabetes.
    Keywords:  AKT kinase; diabetes mellitus; fission; liver mitochondria
    DOI:  https://doi.org/10.1016/j.tem.2024.06.002
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