bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024‒07‒28
sixty papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Pathological variants in nuclear genes causing mitochondrial complex III deficiency: An update.
  2. Germline regulation of the somatic mitochondrial stress response.
  3. PKR Mediates the Mitochondrial Unfolded Protein Response through Double-Stranded RNA Accumulation under Mitochondrial Stress.
  4. ALS-linked VapB P56S mutation alters neuronal mitochondrial turnover at the synapse.
  5. Cardiolipin remodeling maintains the inner mitochondrial membrane in cells with saturated lipidomes.
  6. Mechanisms and Future Research Perspectives on Mitochondrial Diseases Associated with Isoleucyl-tRNA Synthetase Gene Mutations.
  7. The human mitochondrial translation factor TACO1 alleviates mitoribosome stalling at polyproline stretches.
  8. Complex roles for mitochondrial complexes in microglia.
  9. An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
  10. Ring around the mitochondria.
  11. Mitochondria as Nutritional Targets to Maintain Muscle Health and Physical Function During Ageing.
  12. Spreading depolarization causes reversible neuronal mitochondria fragmentation and swelling in healthy, normally perfused neocortex.
  13. SLC25A48 influences plasma levels of choline and localizes to the inner mitochondrial membrane.
  14. Making a case for mitochondria in hypertrophic cardiomyopathy.
  15. The establishment of a molecular diagnostic platform for mitochondrial diseases: from conventional to next-generation sequencing.
  16. Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
  17. P38α MAPK Coordinates Mitochondrial Adaptation to Caloric Surplus in Skeletal Muscle.
  18. The three-parent baby: Medicolegal, forensic and ethical concerns.
  19. Efficient Elimination of mtDNA from Mammalian Cells with 2',3'-Dideoxycytidine.
  20. Metabolism and HSC fate: what NADPH is made for.
  21. A de novo novel variant in the MT-TD gene is associated with prominent extra-neurologic manifestations.
  22. Mitochondrial inorganic polyphosphate is required to maintain proteostasis within the organelle.
  23. Hyperkinesias in Leigh-like Syndrome with Complex-I Deficiency Due to m.10191T>C in MT-ND3.
  24. Mitochondrial complex-1 as a therapeutic target for cardiac diseases.
  25. Cobra Venom Cytotoxins as a Tool for Probing Mechanisms of Mitochondrial Energetics and Understanding Mitochondrial Membrane Structure.
  26. ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.
  27. Targeting Mitochondrial Dysfunction and Reactive Oxygen Species for Neurodegenerative Disease Treatment.
  28. Molecular mechanisms of genotype-dependent lifespan variation mediated by caloric restriction: insight from wild yeast isolates.
  29. Mitochondrial DNA mosaicism in normal human somatic cells.
  30. Exploring nicotinamide adenine dinucleotide precursors across biosynthesis pathways: Unraveling their role in the ovary.
  31. Extracellular Flux Assay (Seahorse Assay): Diverse Applications in Metabolic Research Across Biological Disciplines.
  32. Prenatal molecular diagnosis of pyruvate dehydrogenase complex deficiency enables rapid initiation of ketogenic diet.
  33. Liver transplantation for mitochondrial DNA depletion syndrome caused by MPV17 deficiency: a case report and literature review.
  34. Towards a universal approach for predicting variant pathogenicity in diverse disease landscapes.
  35. Regulation of Mitochondria-Derived Immune Activation by 'Antiviral' TRIM Proteins.
  36. Resveratrol and Vitamin D: Eclectic Molecules Promoting Mitochondrial Health in Sarcopenia.
  37. Mitochondrial transfer between BMSCs and Müller promotes mitochondrial fusion and suppresses gliosis in degenerative retina.
  38. QAFI: a novel method for quantitative estimation of missense variant impact using protein-specific predictors and ensemble learning.
  39. Utility of genome sequencing in exome-negative pediatric patients with neurodevelopmental phenotypes.
  40. Phospholipid biosynthesis modulates nucleotide metabolism and reductive capacity.
  41. Metabolic plasticity in a Pde6bSTOP/STOP retinitis pigmentosa mouse model following rescue.
  42. Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
  43. Mendelian Randomization Study Reveals a Predicted Relationship between Sensorineural Hearing Loss and Mitochondrial Proteins.
  44. Membrane remodeling by FAM92A1 during brain development regulates neuronal morphology, synaptic function, and cognition.
  45. Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.
  46. Blood proteins predict the risk of many diseases years before onset.
  47. The natural history of dihydrolipoamide dehydrogenase deficiency in Israel.
  48. BOK-engaged mitophagy alleviates neuropathology in Alzheimer's disease.
  49. Rare disease 101: an online resource teaching on over 7000 rare diseases in one short course.
  50. De Novo DNM1L Mutation in a Patient with Encephalopathy, Cardiomyopathy and Fatal Non-Epileptic Paroxysmal Refractory Vomiting.
  51. Evaluation of Neuroinflammatory Contribution to Neurodegeneration in LRRK2 Drosophila Models.
  52. Proteomic signatures improve risk prediction for common and rare diseases.
  53. Acute nicotinamide riboside supplementation increases human cerebral NAD+ levels in vivo.
  54. The Multi-Omic Approach to Newborn Screening: Opportunities and Challenges.
  55. Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.
  56. AI produces gibberish when trained on too much AI-generated data.
  57. Unravelling the origins and forces that shape mtDNA mutations in human cells.
  58. The ISR downstream target ATF4 represses long-term memory in a cell type-specific manner.
  59. Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes.
  60. NMNAT2 is a druggable target to drive neuronal NAD production.
  1. J Inherit Metab Dis. 2024 Jul 25.
    Pathological variants in nuclear genes causing mitochondrial complex III deficiency: An update.
    Kristýna Čunátová, Erika Fernández-Vizarra.
      Mitochondrial disorders are a group of clinically and biochemically heterogeneous genetic diseases within the group of inborn errors of metabolism. Primary mitochondrial diseases are mainly caused by defects in one or several components of the oxidative phosphorylation system (complexes I-V). Within these disorders, those associated with complex III deficiencies are the least common. However, thanks to a deeper knowledge about complex III biogenesis, improved clinical diagnosis and the implementation of next-generation sequencing techniques, the number of pathological variants identified in nuclear genes causing complex III deficiency has expanded significantly. This updated review summarizes the current knowledge concerning the genetic basis of complex III deficiency, and the main clinical features associated with these conditions.
    Keywords:  complex III assembly; complex III deficiency; mitochondrial disease; nuclear gene pathogenic variants; oxidative phosphorylation (OXPHOS)
    DOI:  https://doi.org/10.1002/jimd.12751
  2. Trends Cell Biol. 2024 Jul 20. pii: S0962-8924(24)00142-9. [Epub ahead of print]
    Germline regulation of the somatic mitochondrial stress response.
    Liankui Zhou, Ying Liu.
      Mitochondria are pivotal organelles for cellular energy production and the regulation of stress responses. Recent research has elucidated complex mechanisms through which mitochondrial stress in one tissue can impact distant tissues, thereby promoting overall organismal health. Two recent studies by Shen et al. and Charmpilas et al. have demonstrated that an intact germline serves as a crucial signaling hub for the activation of the somatic mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans.
    Keywords:  UPR(mt); cell-nonautonomous; germline; mitochondria; stress response
    DOI:  https://doi.org/10.1016/j.tcb.2024.07.004
  3. Int J Mol Sci. 2024 Jul 15. pii: 7738. [Epub ahead of print]25(14):
    PKR Mediates the Mitochondrial Unfolded Protein Response through Double-Stranded RNA Accumulation under Mitochondrial Stress.
    Fedho Kusuma, Soyoung Park, Kim Anh Nguyen, Rosalie Elvira, Duckgue Lee, Jaeseok Han.
      Mitochondrial stress, resulting from dysfunction and proteostasis disturbances, triggers the mitochondrial unfolded protein response (UPRMT), which activates gene encoding chaperones and proteases to restore mitochondrial function. Although ATFS-1 mediates mitochondrial stress UPRMT induction in C. elegans, the mechanisms relaying mitochondrial stress signals to the nucleus in mammals remain poorly defined. Here, we explored the role of protein kinase R (PKR), an eIF2α kinase activated by double-stranded RNAs (dsRNAs), in mitochondrial stress signaling. We found that UPRMT does not occur in cells lacking PKR, indicating its crucial role in this process. Mechanistically, we observed that dsRNAs accumulate within mitochondria under stress conditions, along with unprocessed mitochondrial transcripts. Furthermore, we demonstrated that accumulated mitochondrial dsRNAs in mouse embryonic fibroblasts (MEFs) deficient in the Bax/Bak channels are not released into the cytosol and do not induce the UPRMT upon mitochondrial stress, suggesting a potential role of the Bax/Bak channels in mediating the mitochondrial stress response. These discoveries enhance our understanding of how cells maintain mitochondrial integrity, respond to mitochondrial dysfunction, and communicate stress signals to the nucleus through retrograde signaling. This knowledge provides valuable insights into prospective therapeutic targets for diseases associated with mitochondrial stress.
    Keywords:  PKR; UPRMT; integrated stress response; mitochondrial dsRNAs; mitochondrial stress
    DOI:  https://doi.org/10.3390/ijms25147738
  4. J Neurosci. 2024 Jul 25. pii: e0879242024. [Epub ahead of print]
    ALS-linked VapB P56S mutation alters neuronal mitochondrial turnover at the synapse.
    Hiu-Tung C Wong, Angelica E Lang, Chris Stein, Catherine M Drerup.
      Mitochondrial population maintenance in neurons is essential for neuron function and survival. Contact sites between mitochondria and the endoplasmic reticulum (ER) are poised to regulate mitochondrial homeostasis in neurons. These contact sites can function to facilitate transfer of calcium and lipids between the organelles and have been shown to regulate aspects of mitochondrial fission and fusion dynamics. VapB is an ER membrane protein present at a subset of ER-mitochondria contact sites. Mutations in VapB cause neurodegenerative disease. Specifically, a proline-to-serine mutation at amino acid 56 (P56S), correlates with susceptibility to amyotrophic lateral sclerosis (ALS) type 8. Given the relationship between failed mitochondrial health and neurodegenerative disease, we investigated the function of VapB in mitochondrial population maintenance. We demonstrate that transgenic expression of VapBP56S in zebrafish larvae (sex undetermined) increased mitochondrial biogenesis, causing increased mitochondrial population size in the axon terminal. Expression of wild type VapB did not alter biogenesis but, instead, increased mitophagy in the axon terminal. Using genetic manipulations to independently increase mitochondrial biogenesis in zebrafish neurons, we show that biogenesis is normally balanced by mitophagy to maintain a constant mitochondrial population size. VapBP56S transgenics fail to increase mitophagy to compensate for the increase in mitochondrial biogenesis, suggesting an impaired mitophagic response. Finally, using a synthetic ER-mitochondria tether, we show that VapB's function in mitochondrial turnover is likely independent of ER-mitochondrial tethering by contact sites. Our findings demonstrate that VapB can control mitochondrial turnover in the axon terminal, and this function is altered by the P56S ALS-linked mutation.Significance statement Mitochondrial population dysfunction is tightly tied to neurodegenerative diseases, including ALS. Maintenance of the mitochondrial population in neurons requires the birth of new mitochondria and the degradation of damaged organelles. ER-mitochondrial contact site proteins are in a position to regulate both processes in neurons. Our work demonstrates that an ALS-associated mutation in the contact site protein VapB disrupts both processes, identifying VapB as a mediator of regulated mitochondrial turnover to maintain a steady-state mitochondrial population.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0879-24.2024
  5. J Lipid Res. 2024 Jul 20. pii: S0022-2275(24)00106-8. [Epub ahead of print] 100601
    Cardiolipin remodeling maintains the inner mitochondrial membrane in cells with saturated lipidomes.
    Kailash Venkatraman, Itay Budin.
      Cardiolipin (CL) is a unique, four-chain phospholipid synthesized in the inner mitochondrial membrane (IMM). The acyl chain composition of CL is regulated through a remodeling pathway, whose loss causes mitochondrial dysfunction in Barth syndrome (BTHS). Yeast has been used extensively as a model system to characterize CL metabolism, but mutants lacking its two remodeling enzymes, Cld1p and Taz1p, exhibit mild structural and respiratory phenotypes compared to mammalian cells. Here we show the essential role of CL remodeling in the structure and function of the IMM in yeast grown under reduced oxygenation. Microaerobic fermentation, which mimics natural yeast environments, caused the accumulation of saturated fatty acids and, under these conditions, remodeling mutants showed a loss of IMM ultrastructure. We extended this observation to HEK293 cells, where iPLA2 inhibition by Bromoenol lactone resulted in respiratory dysfunction and cristae loss upon mild treatment with exogenous saturated fatty acids. In microaerobic yeast, remodeling mutants accumulated unremodeled, saturated CL, but also displayed reduced total CL levels, highlighting the interplay between saturation and CL biosynthesis and breakdown. We identified the mitochondrial phospholipase A1 Ddl1p as a regulator of CL levels, and those of its precursors phosphatidylglycerol and phosphatidic acid, under these conditions. Loss of DDL1 partially rescued IMM structure in cells unable to initiate CL remodeling and had differing lipidomic effects depending on oxygenation. These results introduce a revised yeast model for investigating CL remodeling and suggest that its structural functions are dependent on the overall lipid environment in the mitochondrion.
    Keywords:  Barth Syndrome; Cardiolipin; Lipid saturation; Mitochondria; Phospholipids
    DOI:  https://doi.org/10.1016/j.jlr.2024.100601
  6. Genes (Basel). 2024 Jul 08. pii: 894. [Epub ahead of print]15(7):
    Mechanisms and Future Research Perspectives on Mitochondrial Diseases Associated with Isoleucyl-tRNA Synthetase Gene Mutations.
    Masaki Watanabe, Nobuya Sasaki.
      Aminoacyl-tRNA synthetases are essential enzymes for the accurate translation of genetic information. IARS1 and IARS2 are isoleucyl-tRNA synthetases functioning in the cytoplasm and mitochondria, respectively, with genetic mutations in these enzymes causing diverse clinical phenotypes in specific organs and tissues. Mutations in IARS1 and IARS2 have recently been linked to mitochondrial diseases. This review aims to explore the relationship between IARS1 and IARS2 and these diseases, providing a comprehensive overview of their association with mitochondrial diseases. Mutations in IARS1 cause weak calf syndrome in cattle and mitochondrial diseases in humans, leading to growth retardation and liver dysfunction. Mutations in IARS2 are associated with Leigh syndrome, craniosynostosis and abnormal genitalia syndrome. Future research is expected to involve genetic analysis of a larger number of patients, identifying new mutations in IARS1 and IARS2, and elucidating their impact on mitochondrial function. Additionally, genetically modified mice and the corresponding phenotypic analysis will serve as powerful tools for understanding the functions of these gene products and unraveling disease mechanisms. This will likely promote the development of new therapies and preventive measures.
    Keywords:  IARS1; IARS2; aminoacyl-tRNA; mitochondrial disease
    DOI:  https://doi.org/10.3390/genes15070894
  7. Nucleic Acids Res. 2024 Jul 22. pii: gkae645. [Epub ahead of print]
    The human mitochondrial translation factor TACO1 alleviates mitoribosome stalling at polyproline stretches.
    Michele Brischigliaro, Annika Krüger, J Conor Moran, Hana Antonicka, Ahram Ahn, Eric A Shoubridge, Joanna Rorbach, Antoni Barrientos.
      The prokaryotic translation elongation factor P (EF-P) and the eukaryotic/archaeal counterparts eIF5A/aIF5A are proteins that serve a crucial role in mitigating ribosomal stalling during the translation of specific sequences, notably those containing consecutive proline residues (1,2). Although mitochondrial DNA-encoded proteins synthesized by mitochondrial ribosomes also contain polyproline stretches, an EF-P/eIF5A mitochondrial counterpart remains unidentified. Here, we show that the missing factor is TACO1, a protein causative of a juvenile form of neurodegenerative Leigh's syndrome associated with cytochrome c oxidase deficiency, until now believed to be a translational activator of COX1 mRNA. By using a combination of metabolic labeling, puromycin release and mitoribosome profiling experiments, we show that TACO1 is required for the rapid synthesis of the polyproline-rich COX1 and COX3 cytochrome c oxidase subunits, while its requirement is negligible for other mitochondrial DNA-encoded proteins. In agreement with a role in translation efficiency regulation, we show that TACO1 cooperates with the N-terminal extension of the large ribosomal subunit bL27m to provide stability to the peptidyl-transferase center during elongation. This study illuminates the translation elongation dynamics within human mitochondria, a TACO1-mediated biological mechanism in place to mitigate mitoribosome stalling at polyproline stretches during protein synthesis, and the pathological implications of its malfunction.
    DOI:  https://doi.org/10.1093/nar/gkae645
  8. Nat Metab. 2024 Jul 24.
    Complex roles for mitochondrial complexes in microglia.
    Rosa C Paolicelli, Stefano Pluchino.
      
    DOI:  https://doi.org/10.1038/s42255-024-01095-8
  9. Nat Aging. 2024 Jul 23.
    An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
    Zehan Song, Sang Hee Park, Wei-Chieh Mu, Yufan Feng, Chih-Ling Wang, Yifei Wang, Marine Barthez, Ayane Maruichi, Jiayue Guo, Fanghan Yang, Anita Wong Lin, Kartoosh Heydari, Claudia C S Chini, Eduardo N Chini, Cholsoon Jang, Danica Chen.
      How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD+-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD+ metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca2+ influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging.
    DOI:  https://doi.org/10.1038/s43587-024-00670-8
  10. Sci Signal. 2024 Jul 23. 17(846): eadr8314
    Ring around the mitochondria.
    Wei Wong.
      Hexokinase 1 forms constricting rings around mitochondria that prevent fission induced by energy stress.
    DOI:  https://doi.org/10.1126/scisignal.adr8314
  11. Sports Med. 2024 Jul 26.
    Mitochondria as Nutritional Targets to Maintain Muscle Health and Physical Function During Ageing.
    Sophie C Broome, Jamie Whitfield, Leonidas G Karagounis, John A Hawley.
      The age-related loss of skeletal muscle mass and physical function leads to a loss of independence and an increased reliance on health-care. Mitochondria are crucial in the aetiology of sarcopenia and have been identified as key targets for interventions that can attenuate declines in physical capacity. Exercise training is a primary intervention that reduces many of the deleterious effects of ageing in skeletal muscle quality and function. However, habitual levels of physical activity decline with age, making it necessary to implement adjunct treatments to maintain skeletal muscle mitochondrial health and physical function. This review provides an overview of the effects of ageing and exercise training on human skeletal muscle mitochondria and considers several supplements that have plausible mechanistic underpinning to improve physical function in ageing through their interactions with mitochondria. Several supplements, including MitoQ, urolithin A, omega-3 polyunsaturated fatty acids (n3-PUFAs), and a combination of glycine and N-acetylcysteine (GlyNAC) can improve physical function in older individuals through a variety of inter-dependent mechanisms including increases in mitochondrial biogenesis and energetics, decreases in mitochondrial reactive oxygen species emission and oxidative damage, and improvements in mitochondrial quality control. While there is evidence that some nicotinamide adenine dinucleotide precursors can improve physical function in older individuals, such an outcome seems unrelated to and independent of changes in skeletal muscle mitochondrial function. Future research should investigate the safety and efficacy of compounds that can improve skeletal muscle health in preclinical models through mechanisms involving mitochondria, such as mitochondrial-derived peptides and mitochondrial uncouplers, with a view to extending the human health-span.
    DOI:  https://doi.org/10.1007/s40279-024-02072-7
  12. J Cereb Blood Flow Metab. 2024 Jul 25. 271678X241257887
    Spreading depolarization causes reversible neuronal mitochondria fragmentation and swelling in healthy, normally perfused neocortex.
    Jeremy Sword, Ioulia V Fomitcheva, Sergei A Kirov.
      Mitochondrial function is tightly linked to morphology, and fragmentation of dendritic mitochondria during noxious conditions suggests loss of function. In the normoxic cortex, spreading depolarization (SD) is a phenomenon underlying migraine aura. It is unknown whether mitochondria structure is affected by normoxic SD. In vivo two-photon imaging followed by quantitative serial section electron microscopy (ssEM) was used to monitor dendritic mitochondria in the normoxic cortex of urethane-anesthetized mature male and female mice during and after SD initiated by focal KCl microinjection. Structural dynamics of dendrites and their mitochondria were visualized by transfecting excitatory, glutamatergic neurons of the somatosensory cortex with bicistronic AAV, which induced tdTomoto labeling in neuronal cytoplasm and mitochondria labeling with roGFP. Normoxic SD triggered rapidly reversible fragmentation of dendritic mitochondria alongside dendritic beading; however, mitochondria took significantly longer to recover. Several rounds of SD resulted in transient mitochondrial fragmentation and dendritic beading without accumulating injury, as both recovered. SsEM corroborated normoxic SD-elicited dendritic and mitochondrial swelling and transformation of the filamentous mitochondrial network into shorter, swollen tubular, and globular structures. Our results revealed normoxic SD-induced disruption of the dendritic mitochondrial structure that might impact mitochondrial bioenergetics during migraine with aura.
    Keywords:  Spreading depolarization; cerebral edema; dendrite; migraine; mitochondria
    DOI:  https://doi.org/10.1177/0271678X241257887
  13. Mol Genet Metab. 2024 Jun 20. pii: S1096-7192(24)00402-5. [Epub ahead of print]143(1-2): 108518
    SLC25A48 influences plasma levels of choline and localizes to the inner mitochondrial membrane.
    David J Bernard, Faith Pangilinan, Caitlin Mendina, Tara Desporte, Stephen M Wincovitch, Darren J Walsh, Richard K Porter, Anne M Molloy, Barry Shane, Lawrence C Brody.
      Choline contributes to the biogenesis of methyl groups, neurotransmitters, and cell membranes. Our genome-wide association study (GWAS) of circulating choline in 2228 college students found that alleles in SLC25A48 (rs6596270) influence choline concentrations in men (p = 9.6 × 10-8), but not women. Previously, the subcellular location and function of SLC25A48 were unknown. Using super-resolution immunofluorescence microscopy, we localized SLC25A48 to the inner mitochondrial membrane. Our results suggest that SLC25A48 transports choline across the inner mitochondrial membrane.
    Keywords:  Betaine; Choline; Inner mitochondrial membrane transport; Mitochondria; One carbon metabolism; SLC25A48
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108518
  14. Future Cardiol. 2024 Mar 11. 20(4): 179-182
    Making a case for mitochondria in hypertrophic cardiomyopathy.
    Pankaj Prasun, Utkarsh Kohli.
      Hypertrophic cardiomyopathy (HCM) is a well-known manifestation of inherited mitochondrial disease. Still, currently available gene panels do not include mitochondrial genome sequencing. Mitochondrial dysfunction plays a very important role in the pathogenesis of HCM, whether tested positive or negative by the currently available gene panels for HCM. Mitochondrial DNA variations may act as modifiers of disease manifestation in genotype-positive individuals. In genotype-negative individuals, it may be the primary driver of pathogenesis. A recent study has demonstrated that mitochondrial dysfunction is correlated with septal hypertrophy in genotype-negative HCM, which can be amenable to mitochondria-targeted therapy. It is important to consider mitochondrial genome sequencing as part of the genetic evaluation of HCM.
    Keywords:  cardiomyopathy; gene panel; hypertrophic cardiomyopathy; mitochondria; mitochondrial DNA
    DOI:  https://doi.org/10.1080/14796678.2024.2360355
  15. Biomed J. 2024 Jul 22. pii: S2319-4170(24)00073-8. [Epub ahead of print] 100770
    The establishment of a molecular diagnostic platform for mitochondrial diseases: from conventional to next-generation sequencing.
    Ni-Chin Tsai, Chai-Wai Liou, Yin-Hua Cheng, Hao-Ting Lien, Tzu-Ling Lin, Tsu-Kung Lin, Min-Yu Lan, Pi-Lien Hung, Tzu-Jou Wang, Chen-Hao Lee, Yi-Chih Liang, Kuo-Chung Lan.
      BACKGROUND: The aim of this study was to create a molecular diagnostic platform and establish a diagnostic pipeline for patients highly suspected of mitochondrial disorders. The effectiveness of three methods, namely, traditional restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR), Sanger sequencing for hotspot detection and whole mitochondrial DNA (mtDNA), and third-generation (Nanopore) whole mtDNA sequencing, will be compared in diagnosing patients with suspected primary mitochondrial diseases (PMDs). The strengths and limitations of different methods are also discussed.MATERIAL AND METHODS: A single-center prospective cohort study was conducted to validate the diagnostic pipeline for suspected mitochondrial diseases. In the first stage, a PCR-based method with five sets of primers was used to screen for eight hotspots (m.3243A>G, m.3460G>A, m.8344A>G, m.8993T>G, m.9185T>C, m.11778G>A, m.13513G>A, and m.4977deletion) using either RFLP or direct Sanger sequencing. Sanger sequencing was also used to confirm the RFLP-positive samples. In the second stage, for samples with negative screening results for the eight hotspots, mitochondrial whole-genome sequencing was performed using Sanger sequencing or third-generation nanopore sequencing.
    RESULTS: Between June 2020 and May 2023, 30 patients from ages 0 to 63 with clinically suspected mitochondrial disease were enrolled. The positive yield for the diagnosis of PMDs was 8/30=26.7%, and the sensitivity of the heteroplasmy level for the RFLP-based method was approximately 5%. The remaining 22 patients who tested negative at the first stage were tested using Sanger sequencing or the third-generation sequencing Nanopore, and all tested negative for pathological mtDNA mutations. Compared to the Sanger sequencing method, the results of RFLP-PCR were compromised by the limitations of incomplete RFLP enzyme digestion. For whole-genome sequencing of mtDNA, Sanger sequencing, instead of nanopore sequencing, is preferred at our institution because of its cost-effectiveness.
    CONCLUSIONS: In our highly selective cohort, most tested positive in the first stage of the 8 hot spots screen. Sanger sequencing is a conventional and accurate method for mitochondrial disease screening, at least for the most common hot spots in the region. The results revealed that Sanger sequencing is an accurate method with the benefit of being more cost-effective. This integral platform of molecular diagnosis bears the advantages of being relatively low cost and having a shorter reporting time, facilitating crucial identification of patients with clinical evidence of such disorders. This diagnostic flowchart has also been translated into routine clinical use in the tertiary hospital.
    Keywords:  Mitochondrial DNA amplification; mitochondrial disease; molecular diagnostic platform; whole mitochondrial DNA sequencing
    DOI:  https://doi.org/10.1016/j.bj.2024.100770
  16. Mol Cell. 2024 Jul 25. pii: S1097-2765(24)00542-2. [Epub ahead of print]84(14): 2593-2595
    Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
    Antigoni Diokmetzidou, Luca Scorrano.
      In this issue of Molecular Cell, Pilic et al.1 show that hexokinase, the first enzyme of glycolysis, forms perimitochondrial rings that prevent mitochondrial fragmentation when ATP levels drop.
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.035
  17. Int J Mol Sci. 2024 Jul 16. pii: 7789. [Epub ahead of print]25(14):
    P38α MAPK Coordinates Mitochondrial Adaptation to Caloric Surplus in Skeletal Muscle.
    Liron Waingerten-Kedem, Sharon Aviram, Achinoam Blau, Tony Hayek, Eyal Bengal.
      Excessive calorie intake leads to mitochondrial overload and triggers metabolic inflexibility and insulin resistance. In this study, we examined how attenuated p38α activity affects glucose and fat metabolism in the skeletal muscles of mice on a high-fat diet (HFD). Mice exhibiting diminished p38α activity (referred to as p38αAF) gained more weight and displayed elevated serum insulin levels, as well as a compromised response in the insulin tolerance test, compared to the control mice. Additionally, their skeletal muscle tissue manifested impaired insulin signaling, leading to resistance in insulin-mediated glucose uptake. Examination of muscle metabolites in p38αAF mice revealed lower levels of glycolytic intermediates and decreased levels of acyl-carnitine metabolites, suggesting reduced glycolysis and β-oxidation compared to the controls. Additionally, muscles of p38αAF mice exhibited severe abnormalities in their mitochondria. Analysis of myotubes derived from p38αAF mice revealed reduced mitochondrial respiratory capacity relative to the myotubes of the control mice. Furthermore, these myotubes showed decreased expression of Acetyl CoA Carboxylase 2 (ACC2), leading to increased fatty acid oxidation and diminished inhibitory phosphorylation of pyruvate dehydrogenase (PDH), which resulted in elevated mitochondrial pyruvate oxidation. The expected consequence of reduced mitochondrial respiratory function and uncontrolled nutrient oxidation observed in p38αAF myotubes mitochondrial overload and metabolic inflexibility. This scenario explains the increased likelihood of insulin resistance development in the muscles of p38αAF mice compared to the control mice on a high-fat diet. In summary, within skeletal muscles, p38α assumes a crucial role in orchestrating the mitochondrial adaptation to caloric surplus by promoting mitochondrial biogenesis and regulating the selective oxidation of nutrients, thereby preventing mitochondrial overload, metabolic inflexibility, and insulin resistance.
    Keywords:  high-fat diet; insulin resistance; metabolomics; mitochondrial metabolism; p38α MAPK; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms25147789
  18. Med Sci Law. 2024 Jul 26. 258024241266566
    The three-parent baby: Medicolegal, forensic and ethical concerns.
    Nandini Chitara, Kewal Krishan, Tanuj Kanchan.
      In the recent past, human genetics and in vitro fertilization (IVF) have undergone various advances to combat with several congenital and developmental disorders. These advances are a boon for the families and patients who were restricted from having a child due to one or the other reasons. One such reason is the mitochondrial DNA (mtDNA) mutations, which are definitely transmitted from the mother to the child due to uniparental/maternal inheritance of mitochondria. Depending upon the range of the mutation (mutation loads) present, the mtDNA mutation leads to various devitalizing to fatal disorders, all of which are incurable. Scientists and researchers developed a technique known as mitochondrial donation technique or mitochondrial replacement therapy (MRT) to combat with the mtDNA mutations. The technique relies on the replacement of faulty mitochondria in the mother's egg with the normal wild-type from a donor female resulting in a "three-parent baby." On the other side, forensic scientists and anthropologists continuously explore the mtDNA in various medicolegal cases and in uncoupling the mystery of human origin and migration respectively. In this regard, we explored the genetic, forensic and ethical aspects of a "three-parent baby." The present communication also attempts to highlight the importance and limitations of the MRT technique/three-parent baby in a medicolegal context.
    Keywords:  Mitochondrial DNA mutations; congenital disorder; medicolegal and forensic aspects; mitochondrial donation technique; three-parent baby
    DOI:  https://doi.org/10.1177/00258024241266566
  19. DNA (Basel). 2024 Sep;4(3): 201-211
    Efficient Elimination of mtDNA from Mammalian Cells with 2',3'-Dideoxycytidine.
    Natalya Kozhukhar, Mikhail F Alexeyev.
      Mammalian cell lines devoid of mitochondrial DNA (mtDNA) are indispensable in studies aimed at elucidating the contribution of mtDNA to various cellular processes or interactions between nuclear and mitochondrial genomes. However, the repertoire of tools for generating such cells (also known as rho-0 or ρ0 cells) remains limited, and approaches remain time- and labor-intensive, ultimately limiting their availability. Ethidium bromide (EtBr), which is most commonly used to induce mtDNA loss in mammalian cells, is cytostatic and mutagenic as it affects both nuclear and mitochondrial genomes. Therefore, there is growing interest in new tools for generating ρ0 cell lines. Here, we examined the utility of 2',3'-dideoxycytidine (ddC, zalcitabine) alone or in combination with EtBr for generating ρ0 cell lines of mouse and human origin as well as inducing the ρ0 state in mouse/human somatic cell hybrids. We report that ddC is superior to EtBr in both immortalized mouse fibroblasts and human 143B cells. Also, unlike EtBr, ddC exhibits no cytostatic effects at the highest concentration tested (200 μM), making it more suitable for general use. We conclude that ddC is a promising new tool for generating mammalian ρ0 cell lines.
    Keywords:  A549; HT1080; HeLa; ddC; mtDNA depletion; rho-0 cells
    DOI:  https://doi.org/10.3390/dna4030013
  20. Trends Cell Biol. 2024 Jul 24. pii: S0962-8924(24)00141-7. [Epub ahead of print]
    Metabolism and HSC fate: what NADPH is made for.
    Claudia Morganti, Massimo Bonora, Keisuke Ito.
      Mitochondrial metabolism plays a central role in the regulation of hematopoietic stem cell (HSC) biology. Mitochondrial fatty acid oxidation (FAO) is pivotal in controlling HSC self-renewal and differentiation. Herein, we discuss recent evidence suggesting that NADPH generated in the mitochondria can influence the fate of HSCs. Although NADPH has multiple functions, HSCs show high levels of NADPH that are preferentially used for cholesterol biosynthesis. Endogenous cholesterol supports the biogenesis of extracellular vesicles (EVs), which are essential for maintaining HSC properties. We also highlight the significance of EVs in hematopoiesis through autocrine signaling. Elucidating the mitochondrial NADPH-cholesterol axis as part of the metabolic requirements of healthy HSCs will facilitate the development of new therapies for hematological disorders.
    Keywords:  FAO; HSC self-renewal; cholesterol; exosome; hematopoiesis; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.tcb.2024.07.003
  21. Clin Genet. 2024 Jul 26.
    A de novo novel variant in the MT-TD gene is associated with prominent extra-neurologic manifestations.
    Liuyu Sun, Yali Ren, Yinan Ma, Ying Zhu, Ye Wu, Suxia Wang, Lin Nie, Huijie Xiao, Yuwu Jiang, Fang Wang.
      Defects in the mitochondrial tRNA genes cause a group of highly clinically and genetically heterogeneous disorders, which poses a challenge for clinical identification and genetic diagnosis. Here, we present a pre-school boy with a novel MT-TD variant m.7560T>C at the heteroplasmy level of 76.53% in blood, 93.34% in urine sediments, and absent in the healthy mother's blood and urine. Besides convulsions, brain magnetic resonance imaging abnormalities and high plasma lactate, the boy presented with the prominent extra-neurologic phenotype including steroid-resistant nephrotic syndrome associated with focal segmental glomerulosclerosis characterized by abnormal mitochondria in podocytes, cortical blindness, and pancreatitis. To our knowledge, this is the unique case with MT-TD m.7560T>C-related multi-organ impairments, which expands the phenotypic and mutational spectrum of primary mitochondrial diseases.
    Keywords:  cortical blindness; glomerulopathy; mitochondrially encoded tRNA‐Asp; pancreatitis
    DOI:  https://doi.org/10.1111/cge.14594
  22. Front Cell Dev Biol. 2024 ;12 1423208
    Mitochondrial inorganic polyphosphate is required to maintain proteostasis within the organelle.
    Renata T Da Costa, Pedro Urquiza, Matheus M Perez, YunGuang Du, Mei Li Khong, Haiyan Zheng, Mariona Guitart-Mampel, Pia A Elustondo, Ernest R Scoma, Vedangi Hambardikar, Beatrix Ueberheide, Julian A Tanner, Alejandro Cohen, Evgeny V Pavlov, Cole M Haynes, Maria E Solesio.
      The existing literature points towards the presence of robust mitochondrial mechanisms aimed at mitigating protein dyshomeostasis within the organelle. However, the precise molecular composition of these mechanisms remains unclear. Our data show that inorganic polyphosphate (polyP), a polymer well-conserved throughout evolution, is a component of these mechanisms. In mammals, mitochondria exhibit a significant abundance of polyP, and both our research and that of others have already highlighted its potent regulatory effect on bioenergetics. Given the intimate connection between energy metabolism and protein homeostasis, the involvement of polyP in proteostasis has also been demonstrated in several organisms. For example, polyP is a bacterial primordial chaperone, and its role in amyloidogenesis has already been established. Here, using mammalian models, our study reveals that the depletion of mitochondrial polyP leads to increased protein aggregation within the organelle, following stress exposure. Furthermore, mitochondrial polyP is able to bind to proteins, and these proteins differ under control and stress conditions. The depletion of mitochondrial polyP significantly affects the proteome under both control and stress conditions, while also exerting regulatory control over gene expression. Our findings suggest that mitochondrial polyP is a previously unrecognized, and potent component of mitochondrial proteostasis.
    Keywords:  mitochondria; mitochondrial inorganic polyphosphate; polyP; protein homeostasis; proteostasis
    DOI:  https://doi.org/10.3389/fcell.2024.1423208
  23. Ann Afr Med. 2024 Jul 01. 23(3): 512-513
    Hyperkinesias in Leigh-like Syndrome with Complex-I Deficiency Due to m.10191T>C in MT-ND3.
    Shaundra M Newstead, Josef Finsterer.
      Hyperkinesias in a patient with complex-I deficiency due to the variant m.10191T>C in MT-ND3 have not been previously reported. The patient is a 32 years-old female with multisystem mitochondrial disease due to variant m.10191T>C in MT-ND3, who has been experiencing episodic, spontaneous or induced abnormal movements since age 23. The abnormal movements started as right hemi-athetosis, bilateral dystonia of the legs, or unilateral dystonia of the right arm and leg. They often progressed to severe ballism, involving the trunk, and limbs. The arms were more dystonic than the legs. In conclusion, complex-I deficiency due to the variant m.10191T>C in MT-ND3 may manifest as multisystem disease including hyperkinesias. Neurologists should be aware of hyperkinesias as a manifestation of complex-I deficiency.
    DOI:  https://doi.org/10.4103/aam.aam_32_23
  24. Mol Cell Biochem. 2024 Jul 20.
    Mitochondrial complex-1 as a therapeutic target for cardiac diseases.
    Neeraj Kumar Rai, Harikrishnan Venugopal, Rithika Rajesh, Pranavi Ancha, Sundararajan Venkatesh.
      Mitochondrial dysfunction is critical for the development and progression of cardiovascular diseases (CVDs). Complex-1 (CI) is an essential component of the mitochondrial electron transport chain that participates in oxidative phosphorylation and energy production. CI is the largest multisubunit complex (~ 1 Mda) and comprises 45 protein subunits encoded by seven mt-DNA genes and 38 nuclear genes. These subunits function as the enzyme nicotinamide adenine dinucleotide  hydrogen (NADH): ubiquinone oxidoreductase. CI dysregulation has been implicated in various CVDs, including heart failure, ischemic heart disease, pressure overload, hypertrophy, and cardiomyopathy. Several studies demonstrated that impaired CI function contributes to increased oxidative stress, altered calcium homeostasis, and mitochondrial DNA damage in cardiac cells, leading to cardiomyocyte dysfunction and apoptosis. CI dysfunction has been associated with endothelial dysfunction, inflammation, and vascular remodeling, critical processes in developing atherosclerosis and hypertension. Although CI is crucial in physiological and pathological conditions, no potential therapeutics targeting CI are available to treat CVDs. We believe that a lack of understanding of CI's precise mechanisms and contributions to CVDs limits the development of therapeutic strategies. In this review, we comprehensively analyze the role of CI in cardiovascular health and disease to shed light on its potential therapeutic target role in CVDs.
    Keywords:  Cardiac diseases; Complex I; Heart failure; Mitochondrial dysfunction; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s11010-024-05074-1
  25. Toxins (Basel). 2024 Jun 25. pii: 287. [Epub ahead of print]16(7):
    Cobra Venom Cytotoxins as a Tool for Probing Mechanisms of Mitochondrial Energetics and Understanding Mitochondrial Membrane Structure.
    Edward S Gasanoff, Ruben K Dagda.
      In this paper, we provide an overview of mitochondrial bioenergetics and specific conditions that lead to the formation of non-bilayer structures in mitochondria. Secondly, we provide a brief overview on the structure/function of cytotoxins and how snake venom cytotoxins have contributed to increasing our understanding of ATP synthesis via oxidative phosphorylation in mitochondria, to reconcile some controversial aspects of the chemiosmotic theory. Specifically, we provide an emphasis on the biochemical contribution of delocalized and localized proton movement, involving direct transport of protons though the Fo unit of ATP synthase or via the hydrophobic environment at the center of the inner mitochondrial membrane (proton circuit) on oxidative phosphorylation, and how this influences the rate of ATP synthesis. Importantly, we provide new insights on the molecular mechanisms through which cobra venom cytotoxins affect mitochondrial ATP synthesis, mitochondrial structure, and dynamics. Finally, we provide a perspective for the use of cytotoxins as novel pharmacological tools to study membrane bioenergetics and mitochondrial biology, how they can be used in translational research, and their potential therapeutic applications.
    Keywords:  ATP synthase; bioenergetics; cobra venom cytotoxins; cytotoxins; neurodegeneration; non-bilayer lipid phase; updated working model of the chemiosmotic theory
    DOI:  https://doi.org/10.3390/toxins16070287
  26. Nat Commun. 2024 Jul 21. 15(1): 6143
    ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.
    Mailis Liiv, Annika Vaarmann, Dzhamilja Safiulina, Vinay Choubey, Ruby Gupta, Malle Kuum, Lucia Janickova, Zuzana Hodurova, Michal Cagalinec, Akbar Zeb, Miriam A Hickey, Yi-Long Huang, Nana Gogichaishvili, Merle Mandel, Mario Plaas, Eero Vasar, Jens Loncke, Tim Vervliet, Ting-Fen Tsai, Geert Bultynck, Vladimir Veksler, Allen Kaasik.
      Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP3R-mediated Ca2+ transfer from ER to mitochondria and decreased mitochondrial Ca2+ uptake. In turn, reduced mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal health.
    DOI:  https://doi.org/10.1038/s41467-024-50502-x
  27. Int J Mol Sci. 2024 Jul 21. pii: 7952. [Epub ahead of print]25(14):
    Targeting Mitochondrial Dysfunction and Reactive Oxygen Species for Neurodegenerative Disease Treatment.
    Eui-Hwan Choi, Mi-Hye Kim, Sun-Ji Park.
      Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases, and they affect millions of people worldwide, particularly older individuals. Therefore, there is a clear need to develop novel drug targets for the treatment of age-related neurodegenerative diseases. Emerging evidence suggests that mitochondrial dysfunction and reactive oxygen species (ROS) generation play central roles in the onset and progression of neurodegenerative diseases. Mitochondria are key regulators of respiratory function, cellular energy adenosine triphosphate production, and the maintenance of cellular redox homeostasis, which are essential for cell survival. Mitochondrial morphology and function are tightly regulated by maintaining a balance among mitochondrial fission, fusion, biogenesis, and mitophagy. In this review, we provide an overview of the main functions of mitochondria, with a focus on recent progress highlighting the critical role of ROS-induced oxidative stress, dysregulated mitochondrial dynamics, mitochondrial apoptosis, mitochondria-associated inflammation, and impaired mitochondrial function in the pathogenesis of age-related neurodegenerative diseases, such as AD and PD. We also discuss the potential of mitochondrial fusion and biogenesis enhancers, mitochondrial fission inhibitors, and mitochondria-targeted antioxidants as novel drugs for the treatment of these diseases.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; mitochondrial dysfunction; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms25147952
  28. Front Aging. 2024 ;5 1408160
    Molecular mechanisms of genotype-dependent lifespan variation mediated by caloric restriction: insight from wild yeast isolates.
    Samantha McLean, Mitchell Lee, Weiqiang Liu, Rohil Hameed, Vikas Anil Gujjala, Xuming Zhou, Matt Kaeberlein, Alaattin Kaya.
      Caloric restriction (CR) is known to extend lifespan across different species and holds great promise for preventing human age-onset pathologies. However, two major challenges exist. First, despite extensive research, the mechanisms of lifespan extension in response to CR remain elusive. Second, genetic differences causing variations in response to CR and genetic factors contributing to variability of CR response on lifespan are largely unknown. Here, we took advantage of natural genetic variation across 46 diploid wild yeast isolates of Saccharomyces species and the lifespan variation under CR conditions to uncover the molecular factors associated with CR response types. We identified genes and metabolic pathways differentially regulated in CR-responsive versus non-responsive strains. Our analysis revealed that altered mitochondrial function and activation of GCN4-mediated environmental stress response are inevitably linked to lifespan variation in response to CR and a unique mitochondrial metabolite might be utilized as a predictive marker for CR response rate. In sum, our data suggests that the effects of CR on longevity may not be universal, even among the closely related species or strains of a single species. Since mitochondrial-mediated signaling pathways are evolutionarily conserved, the dissection of related genetic pathways will be relevant to understanding the mechanism by which CR elicits its longevity effect.
    Keywords:  caloric restriction; genotype variation; lifespan; metabolism; yeast
    DOI:  https://doi.org/10.3389/fragi.2024.1408160
  29. Nat Genet. 2024 Jul 22.
    Mitochondrial DNA mosaicism in normal human somatic cells.
    Jisong An, Chang Hyun Nam, Ryul Kim, Yunah Lee, Hyein Won, Seongyeol Park, Won Hee Lee, Hansol Park, Christopher J Yoon, Yohan An, Jie-Hyun Kim, Jong Kwan Jun, Jeong Mo Bae, Eui-Cheol Shin, Bun Kim, Yong Jun Cha, Hyun Woo Kwon, Ji Won Oh, Jee Yoon Park, Min Jung Kim, Young Seok Ju.
      Somatic cells accumulate genomic alterations with age; however, our understanding of mitochondrial DNA (mtDNA) mosaicism remains limited. Here we investigated the genomes of 2,096 clones derived from three cell types across 31 donors, identifying 6,451 mtDNA variants with heteroplasmy levels of ≳0.3%. While the majority of these variants were unique to individual clones, suggesting stochastic acquisition with age, 409 variants (6%) were shared across multiple embryonic lineages, indicating their origin from heteroplasmy in fertilized eggs. The mutational spectrum exhibited replication-strand bias, implicating mtDNA replication as a major mutational process. We evaluated the mtDNA mutation rate (5.0 × 10-8 per base pair) and a turnover frequency of 10-20 per year, which are fundamental components shaping the landscape of mtDNA mosaicism over a lifetime. The expansion of mtDNA-truncating mutations toward homoplasmy was substantially suppressed. Our findings provide comprehensive insights into the origins, dynamics and functional consequences of mtDNA mosaicism in human somatic cells.
    DOI:  https://doi.org/10.1038/s41588-024-01838-z
  30. FASEB J. 2024 Jul 31. 38(14): e23804
    Exploring nicotinamide adenine dinucleotide precursors across biosynthesis pathways: Unraveling their role in the ovary.
    Caifang Ren, Shuang Zhang, Yanyan Chen, Kaiping Deng, Meiqian Kuang, Zihao Gong, Ke Zhang, Panqi Wang, Pan Huang, Zhengrong Zhou, Aihua Gong.
      Natural Nicotinamide Adenine Dinucleotide (NAD+) precursors have attracted much attention due to their positive effects in promoting ovarian health. However, their target tissue, synthesis efficiency, advantages, and disadvantages are still unclear. This review summarizes the distribution of NAD+ at the tissue, cellular and subcellular levels, discusses its biosynthetic pathways and the latest findings in ovary, include: (1) NAD+ plays distinct roles both intracellularly and extracellularly, adapting its distribution in response to requirements. (2) Different precursors differs in target tissues, synthetic efficiency, biological utilization, and adverse effects. Importantly: tryptophan is primarily utilized in the liver and kidneys, posing metabolic risks in excess; nicotinamide (NAM) is indispensable for maintaining NAD+ levels; nicotinic acid (NA) constructs a crucial bridge between intestinal microbiota and the host with diverse functions; nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) increase NAD+ systemically and can be influenced by delivery route, tissue specificity, and transport efficiency. (3) The biosynthetic pathways of NAD+ are intricately intertwined. They provide multiple sources and techniques for NAD+ synthesis, thereby reducing the dependence on a single molecule to maintain cellular NAD+ levels. However, an excess of a specific precursor potentially influencing other pathways. In addition, Protein expression analysis suggest that ovarian tissues may preferentially utilize NAM and NMN. These findings summarize the specific roles and potential of NAD+ precursors in enhancing ovarian health. Future research should delve into the molecular mechanisms and intervention strategies of different precursors, aiming to achieve personalized prevention or treatment of ovarian diseases, and reveal their clinical application value.
    Keywords:  NAD+; NAM; NMN; ovary; tryptophan
    DOI:  https://doi.org/10.1096/fj.202400453R
  31. Mol Cells. 2024 Jul 18. pii: S1016-8478(24)00120-1. [Epub ahead of print] 100095
    Extracellular Flux Assay (Seahorse Assay): Diverse Applications in Metabolic Research Across Biological Disciplines.
    Inhwan Yoo, Ihyeon Ahn, Jihyeon Lee, Namgyu Lee.
      Metabolic networks are fundamental to cellular processes, driving energy production, biosynthesis, redox regulation, and cellular signaling. Recent advancements in metabolic research tools have provided unprecedented insights into cellular metabolism. Among these tools, the extracellular flux analyzer stands out for its real-time measurement of key metabolic parameters: glycolysis, mitochondrial respiration, and fatty acid oxidation (FAO), leading to its widespread use. This review provides a comprehensive summary of the basic principles and workflow of the extracellular flux assay (the Seahorse assay) and its diverse applications. We highlight the assay's versatility across various biological models, including cancer cells, immunocytes, C. elegans, tissues, isolated mitochondria, and 3D structures like organoids, and summarize key considerations for using extracellular flux assay in these models. Additionally, we discuss the limitations of the Seahorse assay and propose future directions for its development. This review aims to enhance the understanding of extracellular flux assay and its significance in biological studies.
    Keywords:  ETC; Extracellular Flux Assay; Glycolysis; Metabolism; Mitochondria; Seahorse assay
    DOI:  https://doi.org/10.1016/j.mocell.2024.100095
  32. Am J Med Genet A. 2024 Jul 26. e63825
    Prenatal molecular diagnosis of pyruvate dehydrogenase complex deficiency enables rapid initiation of ketogenic diet.
    Aaron B Bowen, Otto Rapalino, Camilo Jaimes, Eva-Maria Ratai, Yingyi Zhong, Elizabeth A Thiele, Amy Kritzer, Rebecca D Ganetzky, Nina B Gold, Melissa A Walker.
      Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial disorder of carbohydrate oxidation characterized by lactic acidosis and central nervous system involvement. Knowledge of the affected metabolic pathways and clinical observations suggest that early initiation of the ketogenic diet may ameliorate the metabolic and neurologic course of the disease. We present a case in which first trimester ultrasound identified structural brain abnormalities prompting a prenatal molecular diagnosis of PDCD. Ketogenic diet, thiamine, and N-acetylcysteine were initiated in the perinatal period with good response, including sustained developmental progress. This case highlights the importance of a robust neurometabolic differential diagnosis for prenatally diagnosed structural anomalies and the use of prenatal molecular testing to facilitate rapid, genetically tailored intervention.
    Keywords:  MR spectroscopy; ketogenic diet; mitochondrial disease; prenatal genetic testing; prenatal neuroimaging; pyruvate dehydrogenase complex deficiency
    DOI:  https://doi.org/10.1002/ajmg.a.63825
  33. Front Surg. 2024 ;11 1348806
    Liver transplantation for mitochondrial DNA depletion syndrome caused by MPV17 deficiency: a case report and literature review.
    Liu-Yuan Wei, Xiu-Qi Chen, Li Huang, Qing-Wen Shan, Qing Tang.
      Objective: To study the effectiveness of liver transplantation (LT) in treating mitochondrial DNA depletion syndrome (MDS) caused by the MPV17 gene variant.Case presentation: A boy aged 2.8 years presented with edema of the lower limbs and abdomen, which persisted for over 10 days and was of unknown origin; this was accompanied by abnormal liver function, intractable hypoglycemia, and hyperlactatemia. During the second week of onset, he developed acute-on-chronic liver failure and was diagnosed with MDS due to homozygous variant c.293C>T in the MPV17 gene. Subsequently, he underwent LT from a cadaveric donor. At follow-up after 15 months, his liver function was found to be normal, without any symptoms. Additionally, a literature review was performed that included MDS patients with the MPV17 variant who underwent LT. The results demonstrated that the survival rates for MDS patients who underwent LT were 69.5%, 38.6%, 38.6%, and 38.6% at 1-year, 5-year, 10-year, and 20-year intervals, respectively. Sub-group analyses revealed the survival rate of MDS patients with isolated liver disease (83.33%, 5/6) was higher than that of hepatocerebral MDS patients (44.44%, 8/18). Fifteen variants were identified in the MPV17 gene, and patients with the c.293C>T (p.P98l) variant exhibited the highest survival rate.
    Conclusion: Hepatocerebral MDS patients without neurological symptoms may benefit from LT.
    Keywords:  MPV17 gene; chidren; liver transplant; mitochondrial DNA depletion syndrome; mitochondrial disease
    DOI:  https://doi.org/10.3389/fsurg.2024.1348806
  34. J Genet Genomics. 2024 Jul 21. pii: S1673-8527(24)00193-0. [Epub ahead of print]
    Towards a universal approach for predicting variant pathogenicity in diverse disease landscapes.
    Xiang Chen, Xiaomin Yu.
      
    Keywords:  Disease-Specific Models; Genetic Variants; Machine Learning; Pathogenicity Prediction; gnomAD Database
    DOI:  https://doi.org/10.1016/j.jgg.2024.07.015
  35. Viruses. 2024 Jul 19. pii: 1161. [Epub ahead of print]16(7):
    Regulation of Mitochondria-Derived Immune Activation by 'Antiviral' TRIM Proteins.
    Seeun Oh, Michael A Mandell.
      Mitochondria are key orchestrators of antiviral responses that serve as platforms for the assembly and activation of innate immune-signaling complexes. In response to viral infection, mitochondria can be triggered to release immune-stimulatory molecules that can boost interferon production. These same molecules can be released by damaged mitochondria to induce pathogenic, antiviral-like immune responses in the absence of infection. This review explores how members of the tripartite motif-containing (TRIM) protein family, which are recognized for their roles in antiviral defense, regulate mitochondria-based innate immune activation. In antiviral defense, TRIMs are essential components of immune signal transduction pathways and function as directly acting viral restriction factors. TRIMs carry out conceptually similar activities when controlling immune activation related to mitochondria. First, they modulate immune-signaling pathways that can be activated by mitochondrial molecules. Second, they co-ordinate the direct removal of mitochondria and associated immune-activating factors through mitophagy. These insights broaden the scope of TRIM actions in innate immunity and may implicate TRIMs in diseases associated with mitochondria-derived inflammation.
    Keywords:  MAVS; MDA5; RIG-I; STING; TBK1; TRIM; antiviral defense; autophagy; cGAS; inflammation; interferon; mitochondria; mitophagy; restriction factor; tripartite motif
    DOI:  https://doi.org/10.3390/v16071161
  36. Int J Mol Sci. 2024 Jul 09. pii: 7503. [Epub ahead of print]25(14):
    Resveratrol and Vitamin D: Eclectic Molecules Promoting Mitochondrial Health in Sarcopenia.
    Cristina Russo, Maria Stella Valle, Floriana D'Angeli, Sofia Surdo, Lucia Malaguarnera.
      Sarcopenia refers to the progressive loss and atrophy of skeletal muscle function, often associated with aging or secondary to conditions involving systemic inflammation, oxidative stress, and mitochondrial dysfunction. Recent evidence indicates that skeletal muscle function is not only influenced by physical, environmental, and genetic factors but is also significantly impacted by nutritional deficiencies. Natural compounds with antioxidant properties, such as resveratrol and vitamin D, have shown promise in preventing mitochondrial dysfunction in skeletal muscle cells. These antioxidants can slow down muscle atrophy by regulating mitochondrial functions and neuromuscular junctions. This review provides an overview of the molecular mechanisms leading to skeletal muscle atrophy and summarizes recent advances in using resveratrol and vitamin D supplementation for its prevention and treatment. Understanding these molecular mechanisms and implementing combined interventions can optimize treatment outcomes, ensure muscle function recovery, and improve the quality of life for patients.
    Keywords:  mitochondria; muscle dysfunction; muscle homeostasis; oxidative stress; resveratrol; vitamin D
    DOI:  https://doi.org/10.3390/ijms25147503
  37. iScience. 2024 Jul 19. 27(7): 110309
    Mitochondrial transfer between BMSCs and Müller promotes mitochondrial fusion and suppresses gliosis in degenerative retina.
    Xiaona Huang, Luodan A, Hui Gao, Juncai He, Lingling Ge, Zhe Cha, Hong Gong, Xi Lin, Huiting Li, Yongping Tang, Dan Jiang, Xiaotang Fan, Haiwei Xu.
      Mitochondrial dysfunction and Müller cells gliosis are significant pathological characteristics of retinal degeneration (RD) and causing blinding. Stem cell therapy is a promising treatment for RD, the recently accepted therapeutic mechanism is cell fusion induced materials transfer. However, whether materials including mitochondrial transfer between grafted stem cells and recipient's cells contribute to suppressing gliosis and mechanism are unclear. In present study, we demonstrated that bone marrow mesenchymal stem cells (BMSCs) transferred mitochondria to Müller cells by cell fusion and tunneling nanotubes. BMSCs-derived mitochondria (BMSCs-mito) were integrated into mitochondrial network of Müller cells, improving mitochondrial function, reducing oxidative stress and gliosis, which protected visual function partially in the degenerative rat retina. RNA sequencing analysis revealed that BMSCs-mito increased mitochondrial DNA (mtDNA) content and facilitated mitochondrial fusion in damaged Müller cells. It suggests that mitochondrial transfer from BMSCs remodels Müller cells metabolism and suppresses gliosis; thus, delaying the degenerative progression of RD.
    Keywords:  cell biology; sensory neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2024.110309
  38. Hum Genet. 2024 Jul 24.
    QAFI: a novel method for quantitative estimation of missense variant impact using protein-specific predictors and ensemble learning.
    Selen Ozkan, Natàlia Padilla, Xavier de la Cruz.
      Next-generation sequencing (NGS) has revolutionized genetic diagnostics, yet its application in precision medicine remains incomplete, despite significant advances in computational tools for variant annotation. Many variants remain unannotated, and existing tools often fail to accurately predict the range of impacts that variants have on protein function. This limitation restricts their utility in relevant applications such as predicting disease severity and onset age. In response to these challenges, a new generation of computational models is emerging, aimed at producing quantitative predictions of genetic variant impacts. However, the field is still in its early stages, and several issues need to be addressed, including improved performance and better interpretability. This study introduces QAFI, a novel methodology that integrates protein-specific regression models within an ensemble learning framework, utilizing conservation-based and structure-related features derived from AlphaFold models. Our findings indicate that QAFI significantly enhances the accuracy of quantitative predictions across various proteins. The approach has been rigorously validated through its application in the CAGI6 contest, focusing on ARSA protein variants, and further tested on a comprehensive set of clinically labeled variants, demonstrating its generalizability and robust predictive power. The straightforward nature of our models may also contribute to better interpretability of the results.
    DOI:  https://doi.org/10.1007/s00439-024-02692-z
  39. Am J Med Genet A. 2024 Jul 19. e63817
    Utility of genome sequencing in exome-negative pediatric patients with neurodevelopmental phenotypes.
    Tomoki T Nomakuchi, Eden Y Teferedegn, Dong Li, Kayla J Muirhead, Holly Dubbs, Jacqueline Leonard, Colleen Muraresku, Emily Sergio, Kaley Arnold, Amy Pizzino, Cara M Skraban, Elaine H Zackai, Kai Wang, Rebecca D Ganetzky, Adeline L Vanderver, Rebecca C Ahrens-Nicklas, Elizabeth J K Bhoj.
      Exome sequencing (ES) has emerged as an essential tool in the evaluation of neurodevelopmental disorders (NDD) of unknown etiology. Genome sequencing (GS) offers advantages over ES due to improved detection of structural, copy number, repeat number and non-coding variants. However, GS is less commonly utilized due to higher cost and more intense analysis. Here, we present nine cases of pediatric NDD that were molecularly diagnosed with GS between 2017 and 2022, following non-diagnostic ES. All individuals presented with global developmental delay or regression. Other features present in our cohort included epilepsy, white matter abnormalities, brain malformation and dysmorphic features. Two cases were diagnosed on GS due to newly described gene-disease relationship or variant reclassification (MAPK8IP3, CHD3). Additional features missed on ES that were later detected on GS were: intermediate-size deletions in three cases who underwent ES that were not validated for CNV detection, pathogenic variants within the non-protein coding genes SNORD118 and RNU7-1, pathogenic variant within the promoter region of GJB1, and a coding pathogenic variant within BCAP31 which was not sufficiently covered on ES. GS following non-diagnostic ES led to the identification of pathogenic variants in this cohort of nine cases, four of which would not have been identified by reanalysis alone.
    Keywords:  exome sequencing; genome sequencing; neurodevelopmental disability; neurodevelopmental disorders
    DOI:  https://doi.org/10.1002/ajmg.a.63817
  40. Nat Chem Biol. 2024 Jul 26.
    Phospholipid biosynthesis modulates nucleotide metabolism and reductive capacity.
    Yibing Zhu, Xiaomeng Tong, Jingyuan Xue, Hong Qiu, Dan Zhang, Dao-Qiong Zheng, Zong-Cai Tu, Cunqi Ye.
      Phospholipid and nucleotide syntheses are fundamental metabolic processes in eukaryotic organisms, with their dysregulation implicated in various disease states. Despite their importance, the interplay between these pathways remains poorly understood. Using genetic and metabolic analyses in Saccharomyces cerevisiae, we elucidate how cytidine triphosphate usage in the Kennedy pathway for phospholipid synthesis influences nucleotide metabolism and redox balance. We find that deficiencies in the Kennedy pathway limit nucleotide salvage, prompting compensatory activation of de novo nucleotide synthesis and the pentose phosphate pathway. This metabolic shift enhances the production of antioxidants such as NADPH and glutathione. Moreover, we observe that the Kennedy pathway for phospholipid synthesis is inhibited during replicative aging, indicating its role in antioxidative defense as an adaptive mechanism in aged cells. Our findings highlight the critical role of phospholipid synthesis pathway choice in the integrative regulation of nucleotide metabolism, redox balance and membrane properties for cellular defense.
    DOI:  https://doi.org/10.1038/s41589-024-01689-z
  41. Mol Metab. 2024 Jul 19. pii: S2212-8778(24)00125-X. [Epub ahead of print] 101994
    Metabolic plasticity in a Pde6bSTOP/STOP retinitis pigmentosa mouse model following rescue.
    Monika Ayten, Nundehui Díaz-Lezama, Hanaa Ghanawi, Felia C Haffelder, Jacqueline Kajtna, Tobias Straub, Marco Borso, Axel Imhof, Stefanie M Hauck, Susanne F Koch.
      Retinitis pigmentosa (RP) is a hereditary retinal disease characterized by progressive photoreceptor degeneration, leading to vision loss. The best hope for a cure for RP lies in gene therapy. However, given that RP patients are most often diagnosed in the midst of ongoing photoreceptor degeneration, it is important to determine how the retinal proteome changes as RP disease progresses, and to identify which changes can be prevented, halted, or reversed by gene therapy. Here, we used our Pde6b-deficient RP gene therapy mouse model and demonstrated that Pde6b gene restoration led to a novel form of homeostatic plasticity in rod phototransduction which functionally compensates for the decreased number of rods. By profiling protein levels of metabolic genes and measuring metabolites, we observed an upregulation of proteins associated with oxidative phosphorylation in mutant and treated photoreceptors. Thus, the metabolic demands of the retina differ in our Pde6b-deficient RP mouse model and are not rescued by gene therapy treatment. These findings provide novel insights into features of both RP disease progression and long-term rescue with gene therapy.
    Keywords:  Gene therapy; Inflammation; Metabolism; OXPHOS; Phototransduction; Proteomics; Retina; Retinal plasticity; Retinitis pigmentosa
    DOI:  https://doi.org/10.1016/j.molmet.2024.101994
  42. JCI Insight. 2024 Jul 25. pii: e180906. [Epub ahead of print]
    Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
    Joseph R Visker, Ahmad A Cluntun, Jesse N Velasco-Silva, David R Eberhardt, Luis Cedeno-Rosario, Thirupura S Shankar, Rana Hamouche, Jing Ling, Hyoin Kwak, J Yanni Hillas, Ian Aist, Eleni Tseliou, Sutip Navankasattusas, Dipayan Chaudhuri, Gregory S Ducker, Stavros G Drakos, Jared Rutter.
      The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart, however the rapid re-introduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the final myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and re-directing pyruvate towards oxidation can blunt hypertrophy. We hypothesized this pathway might be important during I/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. Post-I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (∆Ψ), and Ca2+, increased pyruvate entry to TCA cycle, increased oxygen consumption, improved myocardial salvage and functional outcomes following I/R. Our data suggests normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I/R injury.
    Keywords:  Carbohydrate metabolism; Cardiology; Cardiovascular disease; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.180906
  43. Otol Neurotol. 2024 Jul 25.
    Mendelian Randomization Study Reveals a Predicted Relationship between Sensorineural Hearing Loss and Mitochondrial Proteins.
    Jiangyu Yan, Linrong Wu, Mengmeng Zheng, Yuan Lv, Feng Jiang, Weibo Gao, Fangfang Pan.
      BACKGROUND: Mitochondrial proteins assume a pivotal role in the onset and progression of diverse diseases. Nonetheless, the causal interconnections with sensorineural hearing loss (SNHL) demand meticulous exploration. Mendelian randomization analysis is a method used in observational epidemiological studies to predict the relationship between exposure factors and outcomes using genetic variants as instrumental variables. In this study, we applied this analytical approach to two distinct samples to predict the causal impact of mitochondrial proteins on SNHL.METHODS: Two-sample Mendelian randomization analyses were executed to scrutinize the predicted associations between 63 mitochondrial proteins (nuclear-encoded) and SNHL, utilizing summary statistics derived from genome-wide association studies. Assessments of pleiotropy and heterogeneity were carried out to gauge the robustness of the obtained findings.
    RESULTS: Four mitochondrial proteins exhibited a suggestive causal relationship with the susceptibility to SNHL. Dihydrolipoamide dehydrogenase (DLD; OR = 0.9706, 95% CI = 0.9382-0.9953, p = 0.0230) was linked to a diminished risk of SNHL. Conversely, elevated levels of mitochondrial ribosomal protein L34 (MRPL34; OR = 1.0458, 95% CI = 1.0029-1.0906, p = 0.0362), single-pass membrane protein with aspartate-rich tail 1 (SMDT1; OR = 1.0619, 95% CI = 1.0142-1.1119, p = 0.0104), and superoxide dismutase 2 (SOD2; OR = 1.0323, 95% CI = 1.0020-1.0634, p = 0.0364) were associated with an elevated risk of SNHL.
    CONCLUSION: This research utilized Mendelian randomization analysis to predict the relationship between mitochondrial proteins and SNHL. It provides a potential viewpoint on the etiology and diagnosis.
    DOI:  https://doi.org/10.1097/MAO.0000000000004266
  44. Nat Commun. 2024 Jul 23. 15(1): 6209
    Membrane remodeling by FAM92A1 during brain development regulates neuronal morphology, synaptic function, and cognition.
    Liang Wang, Ziyun Yang, Fudo Satoshi, Xavier Prasanna, Ziyi Yan, Helena Vihinen, Yaxing Chen, Yue Zhao, Xiumei He, Qian Bu, Hongchun Li, Ying Zhao, Linhong Jiang, Feng Qin, Yanping Dai, Ni Zhang, Meng Qin, Weihong Kuang, Yinglan Zhao, Eija Jokitalo, Ilpo Vattulainen, Tommi Kajander, Hongxia Zhao, Xiaobo Cen.
      The Bin/Amphiphysin/Rvs (BAR) domain protein FAM92A1 is a multifunctional protein engaged in regulating mitochondrial ultrastructure and ciliogenesis, but its physiological role in the brain remains unclear. Here, we show that FAM92A1 is expressed in neurons starting from embryonic development. FAM92A1 knockout in mice results in altered brain morphology and age-associated cognitive deficits, potentially due to neuronal degeneration and disrupted synaptic plasticity. Specifically, FAM92A1 deficiency impairs diverse neuronal membrane morphology, including the mitochondrial inner membrane, myelin sheath, and synapses, indicating its roles in membrane remodeling and maintenance. By determining the crystal structure of the FAM92A1 BAR domain, combined with atomistic molecular dynamics simulations, we uncover that FAM92A1 interacts with phosphoinositide- and cardiolipin-containing membranes to induce lipid-clustering and membrane curvature. Altogether, these findings reveal the physiological role of FAM92A1 in the brain, highlighting its impact on synaptic plasticity and neural function through the regulation of membrane remodeling and endocytic processes.
    DOI:  https://doi.org/10.1038/s41467-024-50565-w
  45. Nat Metab. 2024 Jul 24.
    Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.
    Joshua S Stoolman, Rogan A Grant, Taylor A Poor, Samuel E Weinberg, Karis B D'Alessandro, Jerica Tan, Jennifer Yuan-Shih Hu, Megan E Zerrer, Walter A Wood, Madeline C Harding, Sahil Soni, Karen M Ridge, Paul T Schumacker, G R Scott Budinger, Navdeep S Chandel.
      Microglia are necessary for central nervous system (CNS) function during development and play roles in ageing, Alzheimer's disease and the response to demyelinating injury1-5. The mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses7-10. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Uqcrfs1 (Rieske iron-sulfur polypeptide 1) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation and adult CNS function in vivo. Notably, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA sequencing analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia. Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.
    DOI:  https://doi.org/10.1038/s42255-024-01080-1
  46. Nat Med. 2024 Jul 22.
    Blood proteins predict the risk of many diseases years before onset.
      
    DOI:  https://doi.org/10.1038/s41591-024-03145-w
  47. J Inherit Metab Dis. 2024 Jul 23.
    The natural history of dihydrolipoamide dehydrogenase deficiency in Israel.
    Ben Pode-Shakked, Yuval E Landau, Nava Shaul Lotan, Joshua Manor, Nitsan Haham, Eyal Kristal, Eli Hershkovitz, Guy Hazan, Yarden Haham, Shlomo Almashanu, Yair Anikster, Orna Staretz-Chacham.
      Dihydrolipoamide dehydrogenase (DLD) deficiency is an ultra-rare autosomal-recessive inborn error of metabolism, affecting no less than five mitochondrial multienzyme complexes. With approximately 30 patients reported to date, DLD deficiency was associated with three major clinical presentations: an early-onset encephalopathic phenotype with metabolic acidosis, a predominantly hepatic presentation with liver failure, and a rare myopathic phenotype. To elucidate the demographic, phenotypic, and molecular characteristics of patients with DLD deficiency within the Israeli population, data were collected from metabolic disease specialists in four large tertiary medical centers in the center and south of Israel. Pediatric and adult patients with biallelic variants in DLD were included in the study. A total of 53 patients of 35 families were included in the cohort. Age at presentation ranged between birth and 10 years. Wide phenotypic variability was observed, from asymptomatic individuals in their sixth decade of life, to severe, neonatal-onset disease with devastating neurological sequelae. Six DLD variants were noted, the most common of which was the c.685G>T (p.G229C) variant in homozygous form (24/53 patients, 45.3%; 13/35 families), observed mostly among patients of Ashkenazi-Jewish descent, followed by the homozygous c.1436A>T (p.D479V) variant, found in 20 patients of Bedouin descent (37.7%; 16/35 families). Overall, patients did not necessarily present as one of the previously described distinct clinical phenotypes. DLD deficiency is a panethnic disorder, with significant phenotypic variability, and comprises a continuum, rather than three distinct clinical presentations.
    Keywords:  DLD; E3; dihydrolipoamide dehydrogenase (DLD) deficiency; lipoamide dehydrogenase (LADH)
    DOI:  https://doi.org/10.1002/jimd.12778
  48. Brain. 2024 Jul 25. pii: awae241. [Epub ahead of print]
    BOK-engaged mitophagy alleviates neuropathology in Alzheimer's disease.
    Yang Yang, Hui Chen, Shuwen Huang, Hao Chen, Alexei Verkhratsky, Jianqin Niu, Yibo Qu, Chenju Yi.
      Mitochondrial malfunction associated with impaired mitochondrial quality control and self-renewal machinery, known as mitophagy, is an under-appreciated mechanism precipitating synaptic loss and cognitive impairments in Alzheimer's disease (AD). Promoting mitophagy has been shown to improve cognitive function in AD animals. However, the regulatory mechanism was unclear, which formed the aim of this study. Here, we found that a neuron-specific loss of Bcl-2 family member BOK in AD patients and APPswe/PS1dE9 (APP/PS1) mice is closely associated with mitochondrial damage and mitophagy defects. We further revealed that BOK is the key to the Parkin-mediated mitophagy through competitive binding to the MCL1/Parkin complex, resulting in Parkin release and translocation to damaged mitochondria to initiate mitophagy. Furthermore, overexpressing bok in hippocampal neurons of APP/PS1 mice alleviated mitophagy and mitochondrial malfunction, resulting in improved cognitive function. Conversely, the knockdown of bok worsened the aforementioned AD-related changes. Our findings uncover a novel mechanism of BOK signaling through regulating Parkin-mediated mitophagy to mitigate amyloid pathology, mitochondrial and synaptic malfunctions, and cognitive decline in AD, thus representing a promising therapeutic target.
    Keywords:  amyloid-β; cognitive decline; mitochondrial dysfunction; mitophagy; synaptophysin loss
    DOI:  https://doi.org/10.1093/brain/awae241
  49. Orphanet J Rare Dis. 2024 Jul 22. 19(1): 275
    Rare disease 101: an online resource teaching on over 7000 rare diseases in one short course.
    Thomas Frederick Dunne, Daniel Jeffries, Lucy Mckay.
      BACKGROUND: An estimated 3.5 million people in the UK live with a rare disease however due to the rarity of each individual condition this is not currently reflected in mainstream medical education. As a result, common features of living with a rare condition include diagnostic delay, poor coordination of health and social care and lack of access to specialist care and treatment. This is well documented in reports published by patient advocacy groups collating the patient experience and has been highlighted by the Department of Health and Social Care in its UK Rare Diseases Framework. One of the four priority areas outlined in this policy published in 2021 is 'increasing awareness amongst healthcare professionals'. Medics4RareDiseases (M4RD), a charity based in the UK, has proposed a disease-agnostic approach to educating doctors about rare disease, focusing on the common challenges experienced across this heterogeneous collection of conditions, rather than on the minutiae of each of the > 7000 rare conditions. A literature search using MEDLINE, PubMed Central and Bookshelf confirmed a lack of broad rare disease teaching in medical literature; none of the 10 final resources identified focused on the topic as a whole.RESULTS: To address this, M4RD created the course 'Rare Disease 101'. It is accessed online using a learning management system that is free, contains interactive lessons, hosts a discussion board and is easily updated. In the 29 months since going live, 942 individuals have registered with 204 having completed the course; early feedback from 33 respondents was unanimously positive (all participants rated at least good (76%: excellent)) demonstrating that both clinicians and patients can benefit from broad rare disease education. The course is freely available to all at https://learn.m4rd.org/ .
    CONCLUSIONS: Disease-agnostic training about rare disease as a large patient population, focusing on its unique profile of unmet needs, is required. Rare Disease 101 provides a pragmatic approach to an educational challenge that leads to poor patient outcomes. Early results suggest that the educational programme is well-received but further evaluation and assessment is needed.
    Keywords:  Advocacy; Education; Genomics; Interactive learning; Learning management system; Online education; Patient experience; Patient expert; Rare disease
    DOI:  https://doi.org/10.1186/s13023-024-03286-8
  50. Int J Mol Sci. 2024 Jul 16. pii: 7782. [Epub ahead of print]25(14):
    De Novo DNM1L Mutation in a Patient with Encephalopathy, Cardiomyopathy and Fatal Non-Epileptic Paroxysmal Refractory Vomiting.
    Beatrice Berti, Daniela Verrigni, Alessia Nasca, Michela Di Nottia, Daniela Leone, Alessandra Torraco, Teresa Rizza, Emanuele Bellacchio, Andrea Legati, Concetta Palermo, Silvia Marchet, Costanza Lamperti, Antonio Novelli, Eugenio Maria Mercuri, Enrico Silvio Bertini, Marika Pane, Daniele Ghezzi, Rosalba Carrozzo.
      Mitochondrial fission and fusion are vital dynamic processes for mitochondrial quality control and for the maintenance of cellular respiration; they also play an important role in the formation and maintenance of cells with high energy demand including cardiomyocytes and neurons. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family that is responsible for the fission of mitochondria; it is ubiquitous but highly expressed in the developing neonatal heart. De novo heterozygous pathogenic variants in the DNM1L gene have been previously reported to be associated with neonatal or infantile-onset encephalopathy characterized by hypotonia, developmental delay and refractory epilepsy. However, cardiac involvement has been previously reported only in one case. Next-Generation Sequencing (NGS) was used to genetically assess a baby girl characterized by developmental delay with spastic-dystonic, tetraparesis and hypertrophic cardiomyopathy of the left ventricle. Histochemical analysis and spectrophotometric determination of electron transport chain were performed to characterize the muscle biopsy; moreover, the morphology of mitochondria and peroxisomes was evaluated in cultured fibroblasts as well. Herein, we expand the phenotype of DNM1L-related disorder, describing the case of a girl with a heterozygous mutation in DNM1L and affected by progressive infantile encephalopathy, with cardiomyopathy and fatal paroxysmal vomiting correlated with bulbar transitory abnormal T2 hyperintensities and diffusion-weighted imaging (DWI) restriction areas, but without epilepsy. In patients with DNM1L mutations, careful evaluation for cardiac involvement is recommended.
    Keywords:  DNM1L; cardiomyopathy; mitochondrial disorders; mitochondrial dynamics; mitochondrial fission; paroxysmal vomiting
    DOI:  https://doi.org/10.3390/ijms25147782
  51. Biomedicines. 2024 Jul 12. pii: 1555. [Epub ahead of print]12(7):
    Evaluation of Neuroinflammatory Contribution to Neurodegeneration in LRRK2 Drosophila Models.
    Hoai Nam Nguyen, Grazia Galleri, Antonio Rassu, Cristina Ciampelli, Roberto Bernardoni, Manuela Galioto, Diego Albani, Claudia Crosio, Ciro Iaccarino.
      Pathological mutations in the LRRK2 gene are the major genetic cause of Parkinson's disease (PD). Although several animal models with either LRRK2 down- or over-expression have been developed, the physiological function of LRRK2 remains elusive. LRRK2 is constitutively expressed in various tissues including neurons and glial cells, but importantly, it is expressed at low levels in dopaminergic neurons, further contributing to the cryptic function of LRRK2. Significant levels of LRRK2 protein and mRNA have been detected in peripheral blood mononuclear cells, lymph nodes, the spleen, and primary microglia, strongly suggesting the contribution of inflammatory cells to neuronal degeneration. In this research article, using Drosophila LRRK2 models, we were able to demonstrate a significant contribution of glial cells to the LRRK2 pathological phenotype. Furthermore, in Drosophila, neurodegeneration is associated with a significant and important increase in specific inflammatory peptides. Finally, levetiracetam, a compound widely used in human therapy to treat epilepsy, was able to rescue both neuronal degeneration and neuroinflammation.
    Keywords:  LRRK2; Parkinson’s disease; glial cells; levetiracetam; neuroinflammation
    DOI:  https://doi.org/10.3390/biomedicines12071555
  52. Nat Med. 2024 Jul 22.
    Proteomic signatures improve risk prediction for common and rare diseases.
    Julia Carrasco-Zanini, Maik Pietzner, Jonathan Davitte, Praveen Surendran, Damien C Croteau-Chonka, Chloe Robins, Ana Torralbo, Christopher Tomlinson, Florian Grünschläger, Natalie Fitzpatrick, Cai Ytsma, Tokuwa Kanno, Stephan Gade, Daniel Freitag, Frederik Ziebell, Simon Haas, Spiros Denaxas, Joanna C Betts, Nicholas J Wareham, Harry Hemingway, Robert A Scott, Claudia Langenberg.
      For many diseases there are delays in diagnosis due to a lack of objective biomarkers for disease onset. Here, in 41,931 individuals from the United Kingdom Biobank Pharma Proteomics Project, we integrated measurements of ~3,000 plasma proteins with clinical information to derive sparse prediction models for the 10-year incidence of 218 common and rare diseases (81-6,038 cases). We then compared prediction models developed using proteomic data with models developed using either basic clinical information alone or clinical information combined with data from 37 clinical assays. The predictive performance of sparse models including as few as 5 to 20 proteins was superior to the performance of models developed using basic clinical information for 67 pathologically diverse diseases (median delta C-index = 0.07; range = 0.02-0.31). Sparse protein models further outperformed models developed using basic information combined with clinical assay data for 52 diseases, including multiple myeloma, non-Hodgkin lymphoma, motor neuron disease, pulmonary fibrosis and dilated cardiomyopathy. For multiple myeloma, single-cell RNA sequencing from bone marrow in newly diagnosed patients showed that four of the five predictor proteins were expressed specifically in plasma cells, consistent with the strong predictive power of these proteins. External replication of sparse protein models in the EPIC-Norfolk study showed good generalizability for prediction of the six diseases tested. These findings show that sparse plasma protein signatures, including both disease-specific proteins and protein predictors shared across several diseases, offer clinically useful prediction of common and rare diseases.
    DOI:  https://doi.org/10.1038/s41591-024-03142-z
  53. Magn Reson Med. 2024 Jul 23.
    Acute nicotinamide riboside supplementation increases human cerebral NAD+ levels in vivo.
    Ravi Prakash Reddy Nanga, Corinde E Wiers, Mark A Elliott, Neil E Wilson, Fang Liu, Quy Cao, Sophie Swago, Paul S Jacobs, Ryan Armbruster, Damodara Reddy, Joseph A Baur, Walter R Witschey, John A Detre, Ravinder Reddy.
      PURPOSE: The purpose of this study was to determine the effect of acute nicotinamide riboside (NR) supplementation on cerebral nicotinamide adenine dinucleotide (NAD+) levels in the human brain in vivo by means of downfield proton MRS (DF 1H MRS).METHODS: DF 1H MRS was performed on 10 healthy volunteers in a 7.0 T MRI scanner with spectrally selective excitation and spatially selective localization to determine cerebral NAD+ levels on two back-to-back days: once after an overnight fast (baseline) and once 4 h after oral ingestion of nicotinamide riboside (900 mg). Additionally, two more baseline scans were performed following the same paradigm to assess test-retest reliability of the NAD+ levels in the absence of NR.
    RESULTS: NR supplementation increased mean NAD+ concentration compared to the baseline (0.458 ± 0.053 vs. 0.392 ± 0.058 mM; p < 0.001). The additional two baseline scans demonstrated no differences in mean NAD+ concentrations (0.425 ± 0.118 vs. 0.405 ± 0.082 mM; p = 0.45), and no difference from the first baseline scan (F(2, 16) = 0.907; p = 0.424).
    CONCLUSION: These preliminary results confirm that acute NR supplementation increases cerebral NAD+ levels in healthy human volunteers and shows the promise of DF 1H MRS utility for robust detection of NAD+ in humans in vivo.
    Keywords:  DF 1H MRS; NAD+; NR; downfield proton MRS; nicotinamide adenine dinucleotide; nicotinamide riboside
    DOI:  https://doi.org/10.1002/mrm.30227
  54. Int J Neonatal Screen. 2024 Jun 21. pii: 42. [Epub ahead of print]10(3):
    The Multi-Omic Approach to Newborn Screening: Opportunities and Challenges.
    Alex J Ashenden, Ayesha Chowdhury, Lucy T Anastasi, Khoa Lam, Tomas Rozek, Enzo Ranieri, Carol Wai-Kwan Siu, Jovanka King, Emilie Mas, Karin S Kassahn.
      Newborn screening programs have seen significant evolution since their initial implementation more than 60 years ago, with the primary goal of detecting treatable conditions within the earliest possible timeframe to ensure the optimal treatment and outcomes for the newborn. New technologies have driven the expansion of screening programs to cover additional conditions. In the current era, the breadth of screened conditions could be further expanded by integrating omic technologies such as untargeted metabolomics and genomics. Genomic screening could offer opportunities for lifelong care beyond the newborn period. For genomic newborn screening to be effective and ready for routine adoption, it must overcome barriers such as implementation cost, public acceptability, and scalability. Metabolomics approaches, on the other hand, can offer insight into disease phenotypes and could be used to identify known and novel biomarkers of disease. Given recent advances in metabolomic technologies, alongside advances in genomics including whole-genome sequencing, the combination of complementary multi-omic approaches may provide an exciting opportunity to leverage the best of both approaches and overcome their respective limitations. These techniques are described, along with the current outlook on multi-omic-based NBS research.
    Keywords:  dried bloodspot; genomic screening; mass spectrometry; metabolomics; multi-omics; newborn screening; public acceptability; whole-genome sequencing
    DOI:  https://doi.org/10.3390/ijns10030042
  55. Nat Metab. 2024 Jul 24.
    Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.
    Bella Mora-Romero, Nicolas Capelo-Carrasco, Juan J Pérez-Moreno, María I Alvarez-Vergara, Laura Trujillo-Estrada, Carmen Romero-Molina, Emilio Martinez-Marquez, Noelia Morano-Catalan, Marisa Vizuete, Jose Lopez-Barneo, Jose L Nieto-Gonzalez, Pablo Garcia-Junco-Clemente, Javier Vitorica, Antonia Gutierrez, David Macias, Alicia E Rosales-Nieves, Alberto Pascual.
      Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs.
    DOI:  https://doi.org/10.1038/s42255-024-01081-0
  56. Nature. 2024 Jul;631(8022): 742-743
    AI produces gibberish when trained on too much AI-generated data.
    Emily Wenger.
      
    Keywords:  Computer science; Machine learning; Technology
    DOI:  https://doi.org/10.1038/d41586-024-02355-z
  57. Nat Genet. 2024 Jul 26.
    Unravelling the origins and forces that shape mtDNA mutations in human cells.
      
    DOI:  https://doi.org/10.1038/s41588-024-01837-0
  58. Proc Natl Acad Sci U S A. 2024 Jul 30. 121(31): e2407472121
    The ISR downstream target ATF4 represses long-term memory in a cell type-specific manner.
    Niaz Mahmood, Jung-Hyun Choi, Pei You Wu, Sean W Dooling, Trent A Watkins, Ziying Huang, Jesse Lipman, Hanjie Zhao, Anqi Yang, Jake Silversmith, Yanis Inglebert, Constantinos Koumenis, Vijendra Sharma, Jean-Claude Lacaille, Wayne S Sossin, Arkady Khoutorsky, R Anne McKinney, Mauro Costa-Mattioli, Nahum Sonenberg.
      The integrated stress response (ISR), a pivotal protein homeostasis network, plays a critical role in the formation of long-term memory (LTM). The precise mechanism by which the ISR controls LTM is not well understood. Here, we report insights into how the ISR modulates the mnemonic process by using targeted deletion of the activating transcription factor 4 (ATF4), a key downstream effector of the ISR, in various neuronal and non-neuronal cell types. We found that the removal of ATF4 from forebrain excitatory neurons (but not from inhibitory neurons, cholinergic neurons, or astrocytes) enhances LTM formation. Furthermore, the deletion of ATF4 in excitatory neurons lowers the threshold for the induction of long-term potentiation, a cellular model for LTM. Transcriptomic and proteomic analyses revealed that ATF4 deletion in excitatory neurons leads to upregulation of components of oxidative phosphorylation pathways, which are critical for ATP production. Thus, we conclude that ATF4 functions as a memory repressor selectively within excitatory neurons.
    Keywords:  integrated stress response; learning and memory; protein synthesis; synaptic plasticity
    DOI:  https://doi.org/10.1073/pnas.2407472121
  59. Neuron. 2024 Jul 23. pii: S0896-6273(24)00491-4. [Epub ahead of print]
    Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes.
    Hannah Scheiblich, Frederik Eikens, Lena Wischhof, Sabine Opitz, Kay Jüngling, Csaba Cserép, Susanne V Schmidt, Jessica Lambertz, Tracy Bellande, Balázs Pósfai, Charlotte Geck, Jasper Spitzer, Alexandru Odainic, Sergio Castro-Gomez, Stephanie Schwartz, Ibrahim Boussaad, Rejko Krüger, Enrico Glaab, Donato A Di Monte, Daniele Bano, Ádám Dénes, Eike Latz, Ronald Melki, Hans-Christian Pape, Michael T Heneka.
      Microglia are crucial for maintaining brain health and neuron function. Here, we report that microglia establish connections with neurons using tunneling nanotubes (TNTs) in both physiological and pathological conditions. These TNTs facilitate the rapid exchange of organelles, vesicles, and proteins. In neurodegenerative diseases like Parkinson's and Alzheimer's disease, toxic aggregates of alpha-synuclein (α-syn) and tau accumulate within neurons. Our research demonstrates that microglia use TNTs to extract neurons from these aggregates, restoring neuronal health. Additionally, microglia share their healthy mitochondria with burdened neurons, reducing oxidative stress and normalizing gene expression. Disrupting mitochondrial function with antimycin A before TNT formation eliminates this neuroprotection. Moreover, co-culturing neurons with microglia and promoting TNT formation rescues suppressed neuronal activity caused by α-syn or tau aggregates. Notably, TNT-mediated aggregate transfer is compromised in microglia carrying Lrrk22(Gly2019Ser) or Trem2(T66M) and (R47H) mutations, suggesting a role in the pathology of these gene variants in neurodegenerative diseases.
    Keywords:  Lrrk2 G2019S; Trem2; alpha-synuclein; intercellular transfer; microglia; mitochondria; neurons; oxidative stress; tau; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.neuron.2024.06.029
  60. Nat Commun. 2024 Jul 24. 15(1): 6256
    NMNAT2 is a druggable target to drive neuronal NAD production.
    James R Tribble, Melissa Jöe, Carmine Varricchio, Amin Otmani, Alessio Canovai, Baninia Habchi, Evangelia Daskalakis, Romanas Chaleckis, Andrea Loreto, Jonathan Gilley, Craig E Wheelock, Gauti Jóhannesson, Raymond C B Wong, Michael P Coleman, Andrea Brancale, Pete A Williams.
      Maintenance of NAD pools is critical for neuronal survival. The capacity to maintain NAD pools declines in neurodegenerative disease. We identify that low NMNAT2, the critical neuronal NAD producing enzyme, drives retinal susceptibility to neurodegenerative insults. As proof of concept, gene therapy over-expressing full length human NMNAT2 is neuroprotective. To pharmacologically target NMNAT2, we identify that epigallocatechin gallate (EGCG) can drive NAD production in neurons through an NMNAT2 and NMN dependent mechanism. We confirm this by pharmacological and genetic inhibition of the NAD-salvage pathway. EGCG is neuroprotective in rodent (mixed sex) and human models of retinal neurodegeneration. As EGCG has poor drug-like qualities, we use it as a tool compound to generate novel small molecules which drive neuronal NAD production and provide neuroprotection. This class of NMNAT2 targeted small molecules could have an important therapeutic impact for neurodegenerative disease following further drug development.
    DOI:  https://doi.org/10.1038/s41467-024-50354-5
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