bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–01–07
sixty papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse.
  2. Gene therapy for mitochondrial disorders.
  3. Mitochondrial genome editing: strategies, challenges, and applications.
  4. Mitochondrial Stress and Mitokines: Therapeutic Perspectives for the Treatment of Metabolic Diseases.
  5. 3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights into MFN-2 Mediated Changes.
  6. H+-slip correlated to rotor free-wheeling as cause of F1 FO -ATPase dysfunction in primary mitochondrial disorders.
  7. Fission-independent compartmentalization of mitochondria during budding yeast cell division.
  8. Mitochondrial-derived vesicles in metabolism, disease, and aging.
  9. LARP4 Is an RNA-Binding Protein That Binds Nuclear-Encoded Mitochondrial mRNAs To Promote Mitochondrial Function.
  10. MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion.
  11. Engineering TALE-linked deaminases to facilitate precision adenine base editing in mitochondrial DNA.
  12. Mitochondrial transplantation: the advance to therapeutic application and molecular modulation.
  13. Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.
  14. Small RNA-big impact: exosomal miRNAs in mitochondrial dysfunction in various diseases.
  15. Protein biomarkers GDF15 and FGF21 to differentiate mitochondrial hepatopathies from other pediatric liver diseases.
  16. Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis.
  17. The mitochondrial protease PARL is required for spermatogenesis.
  18. The biology of mitochondrial carrier homolog 2.
  19. VAP spatially stabilizes dendritic mitochondria to locally support synaptic plasticity.
  20. Mitochondria as secretory organelles and therapeutic cargos.
  21. Mitochondrial Dynamics at Different Levels: From Cristae Dynamics to Interorganellar Cross Talk.
  22. Clinical Spectrum of Biopsy Proven Mitochondrial Myopathy.
  23. CHCHD4-TRIAP1 regulation of innate immune signaling mediates skeletal muscle adaptation to exercise.
  24. Acylspermidines are conserved mitochondrial sirtuin-dependent metabolites.
  25. Critical contribution of mitochondria in the development of cardiomyopathy linked to desmin mutation.
  26. Mitochondrial lipid dynamics regulated by MITOL-mediated ubiquitination.
  27. Moderate Replacement of Fish Oil with Palmitic Acid-Stimulated Mitochondrial Fusion Promotes β-oxidation by Mfn2 Interacting with Cpt1α via Its GTPase-domain.
  28. Curvature sensing lipid dynamics in a mitochondrial inner membrane model.
  29. Exploiting Nuclear-Mitochondrial Cross-Talk in Theranostics: Enhancing Drug Delivery and Diagnostic Precision.
  30. An interactive web application for exploring human plasma and fibroblast metabolomics data from patients with inborn errors of metabolism.
  31. The nascent polypeptide-associated complex subunit Egd1 is required for efficient selective mitochondrial degradation in budding yeast.
  32. CRISPR/Cas9-mediated base editors and their prospects for mitochondrial genome engineering.
  33. A naturally occurring variant of SHLP2 is a protective factor in Parkinson's disease.
  34. The DEAD Box Protein Mrh4 Functions in the Assembly of the Mitochondrial Large Ribosomal Subunit.
  35. Show MERCI on mobile mitochondria.
  36. Mitochondrial Esterase Activity Measured at the Single Organelle Level by Nano-flow Cytometry.
  37. Integrated metabolomics and transcriptomics to reveal biomarkers and mitochondrial metabolic dysregulation of premature ovarian insufficiency.
  38. High number of candidate gene variants are identified as disease-causing in a period of 4 years.
  39. SYNJ2BP ameliorates intervertebral disc degeneration by facilitating mitochondria-associated endoplasmic reticulum membrane formation and mitochondrial Zn2+ homeostasis.
  40. Cannabinoids improve mitochondrial function in skeletal muscle of exhaustive exercise training rats by inhibiting mitophagy through the Pink1/Parkin and Bnip3 pathways.
  41. The solute carrier SLC25A17 sustains peroxisomal redox homeostasis in diverse mammalian cell lines.
  42. NAD+-A Hub of Energy Metabolism in Heart Failure.
  43. A new physiological medium uncovers biochemical and cellular alterations in Lesch-Nyhan disease fibroblasts.
  44. Toolkit for cellular studies of mammalian mitochondrial inorganic polyphosphate.
  45. FORGEdb: a tool for identifying candidate functional variants and uncovering target genes and mechanisms for complex diseases.
  46. Multiomic analysis in fibroblasts of patients with inborn errors of cobalmin metabolism reveals concordance with clinical and metabolic variability.
  47. The cost of proband and trio exome and genome analysis in rare disease: a micro-costing study.
  48. eXNVerify: coverage analysis for long and short-read sequencing data in clinical context.
  49. Loss of cardiac mitochondrial complex I persulfidation impairs NAD+ homeostasis in aging.
  50. Engineering Exosomes to Specifically Target the Mitochondria of Brain Cells.
  51. Trem2 expression in microglia is required to maintain normal neuronal bioenergetics during development.
  52. Selected humanization of yeast U1 snRNP leads to global suppression of pre-mRNA splicing and mitochondrial dysfunction in the budding yeast.
  53. Detection of mosaic and population-level structural variants with Sniffles2.
  54. CADD v1.7: using protein language models, regulatory CNNs and other nucleotide-level scores to improve genome-wide variant predictions.
  55. Multiple omics analysis reveals the regulation of SIRT5 on mitochondrial function and lipid metabolism during the differentiation of bovine preadipocytes.
  56. Reducing Time to Diagnosis of Rare Genetic Diseases in a Medically Underserved Hispanic Population- Lessons Learned for Meaningful Engagement.
  57. Potential roles for mitochondria-to-HSF1 signaling in health and disease.
  58. RDmaster: A novel phenotype-oriented dialogue system supporting differential diagnosis of rare disease.
  59. Mitochondrial-derived peptides: Antidiabetic functions and evolutionary perspectives.
  60. Mitochondrial quality control in liver fibrosis: Epigenetic hallmarks and therapeutic strategies.
  1. EMBO J. 2024 Jan 02.
    Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse.
    Zhan Yin, Ahmed-Noor A Agip, Hannah R Bridges, Judy Hirst.
      Respiratory complex I (NADH:ubiquinone oxidoreductase) is essential for cellular energy production and NAD+ homeostasis. Complex I mutations cause neuromuscular, mitochondrial diseases, such as Leigh Syndrome, but their molecular-level consequences remain poorly understood. Here, we use a popular complex I-linked mitochondrial disease model, the ndufs4-/- mouse, to define the structural, biochemical, and functional consequences of the absence of subunit NDUFS4. Cryo-EM analyses of the complex I from ndufs4-/- mouse hearts revealed a loose association of the NADH-dehydrogenase module, and discrete classes containing either assembly factor NDUFAF2 or subunit NDUFS6. Subunit NDUFA12, which replaces its paralogue NDUFAF2 in mature complex I, is absent from all classes, compounding the deletion of NDUFS4 and preventing maturation of an NDUFS4-free enzyme. We propose that NDUFAF2 recruits the NADH-dehydrogenase module during assembly of the complex. Taken together, the findings provide new molecular-level understanding of the ndufs4-/- mouse model and complex I-linked mitochondrial disease.
    Keywords:  Complex I; Cryo-EM; Leigh Syndrome; Mitochondria; NADH:Ubiquinone Oxidoreductase
    DOI:  https://doi.org/10.1038/s44318-023-00001-4
  2. J Inherit Metab Dis. 2024 Jan 03.
    Gene therapy for mitochondrial disorders.
    Nandaki Keshavan, Michal Minczuk, Carlo Viscomi, Shamima Rahman.
      In this review, we detail the current state of application of gene therapy to primary mitochondrial disorders (PMDs). Recombinant adeno-associated virus-based (rAAV) gene replacement approaches for nuclear gene disorders have been undertaken successfully in more than ten preclinical mouse models of PMDs which has been made possible by the development of novel rAAV technologies that achieve more efficient organ targeting. So far, however, the greatest progress has been made for Leber Hereditary Optic Neuropathy, for which phase 3 clinical trials of lenadogene nolparvovec demonstrated efficacy and good tolerability. Other methods of treating mitochondrial DNA (mtDNA) disorders have also had traction, including refinements to nucleases that degrade mtDNA molecules with pathogenic variants, including transcription activator-like effector nucleases, zinc-finger nucleases, and meganucleases (mitoARCUS). rAAV-based approaches have been used successfully to deliver these nucleases in vivo in mice. Exciting developments in CRISPR-Cas9 gene editing technology have achieved in vivo gene editing in mouse models of PMDs due to nuclear gene defects and new CRISPR-free gene editing approaches have shown great potential for therapeutic application in mtDNA disorders. We conclude the review by discussing the challenges of translating gene therapy in patients both from the point of view of achieving adequate organ transduction as well as clinical trial design.
    Keywords:  AAV; CRISPR; LHON; gene editing; gene therapy; mitochondrial disease
    DOI:  https://doi.org/10.1002/jimd.12699
  3. BMB Rep. 2024 Jan 05. pii: 6125. [Epub ahead of print]
    Mitochondrial genome editing: strategies, challenges, and applications.
    Kayeong Lim.
      Mitochondrial DNA (mtDNA), a multicopy genome found in mitochondria, is crucial for oxidative phosphorylation. Mutations in mtDNA can lead to severe mitochondrial dysfunction in tissues and organs with high energy demand. MtDNA mutations are closely associated with mitochondrial and age-related disease. To better understand the functional role of mtDNA and work toward developing therapeutics, it is essential to advance technology that is capable of manipulating the mitochondrial genome. This review discusses ongoing efforts in mitochondrial genome editing with mtDNA nucleases and base editors, including the tools, delivery strategies, and applications. Future advances in mitochondrial genome editing to address challenges regarding their efficiency and specificity can achieve the promise of therapeutic genome editing.
  4. Diabetes Metab J. 2024 Jan 03.
    Mitochondrial Stress and Mitokines: Therapeutic Perspectives for the Treatment of Metabolic Diseases.
    Benyuan Zhang, Joon Young Chang, Min Hee Lee, Sang-Hyeon Ju, Hyon-Seung Yi, Minho Shong.
      Mitochondrial stress and the dysregulated mitochondrial unfolded protein response (UPRmt) are linked to various diseases, including metabolic disorders, neurodegenerative diseases, and cancer. Mitokines, signaling molecules released by mitochondrial stress response and UPRmt, are crucial mediators of inter-organ communication and influence systemic metabolic and physiological processes. In this review, we provide a comprehensive overview of mitokines, including their regulation by exercise and lifestyle interventions and their implications for various diseases. The endocrine actions of mitokines related to mitochondrial stress and adaptations are highlighted, specifically the broad functions of fibroblast growth factor 21 and growth differentiation factor 15, as well as their specific actions in regulating inter-tissue communication and metabolic homeostasis. Finally, we discuss the potential of physiological and genetic interventions to reduce the hazards associated with dysregulated mitokine signaling and preserve an equilibrium in mitochondrial stress-induced responses. This review provides valuable insights into the mechanisms underlying mitochondrial regulation of health and disease by exploring mitokine interactions and their regulation, which will facilitate the development of targeted therapies and personalized interventions to improve health outcomes and quality of life.
    Keywords:  Fibroblast growth factor 21; Growth differentiation factor 15; Metabolic diseases; Mitochondria; Unfolded protein response
    DOI:  https://doi.org/10.4093/dmj.2023.0115
  5. bioRxiv. 2023 Dec 14. pii: 2023.11.13.566502. [Epub ahead of print]
    3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights into MFN-2 Mediated Changes.
    Estevão Scudese, Zer Vue, Prassana Katti, Andrea Marshall, Larry Vang, Edgar Garza López, Kit Neikirk, Dominique Stephens, Duane D Hall, Rahmati Rostami, Jian-Qiang Shao, Margaret Mungai, Salma T AshShareef, Innes Hicsasmaz, Sasha Manus, Celestine Wanjalla, Aaron Whiteside, Clintoria Williams, Steven M Damo, Jennifer A Gaddy, Annet Kirabo, Brian Glancy, Estélio Henrique Martin Dantas, André Kinder, Fabiana Scartoni, Matheus Baffi, Melanie R McReynolds, Mark A Phillips, Anthonya Cooper, Sandra A Murray, Vernat Exil, Bret C Mobley, Antentor Hinton.
      Sarcopenia is an age-related loss of skeletal muscle, characterized by loss of mass, strength, endurance, and oxidative capacity during aging. Notably, bioenergetics and protein turnover studies have shown that mitochondria mediate this decline in function. Although mitochondrial aging is associated with decreased mitochondrial capacity, the three-dimensional (3D) mitochondrial structure associated with morphological changes in skeletal muscle during aging still requires further elucidation. Although exercise has been the only therapy to mitigate sarcopenia, the mechanisms that govern these changes remain unclear. We hypothesized that aging causes structural remodeling of mitochondrial 3D architecture representative of dysfunction, and this effect is mitigated by exercise. We used serial block-face scanning electron microscopy to image human skeletal tissue samples, followed by manual contour tracing using Amira software for 3D reconstruction and subsequent analysis of mitochondria. We then applied a rigorous in vitro and in vivo exercise regimen during aging. We found that mitochondria became less complex with age. Specifically, mitochondria lost surface area, complexity, and perimeter, indicating age-related declines in ATP synthesis and interaction capacity. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), which we show is required for mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved with Marf, the MFN2 ortholog in Drosophila , as Marf knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusins.
    DOI:  https://doi.org/10.1101/2023.11.13.566502
  6. Med Res Rev. 2024 Jan 03.
    H+-slip correlated to rotor free-wheeling as cause of F1 FO -ATPase dysfunction in primary mitochondrial disorders.
    Salvatore Nesci, Giovanni Romeo.
      Inborn errors of metabolism are related to mitochondrial disorders caused by dysfunction of the oxidative phosphorylation (OXPHOS) system. Congenital hypermetabolism in the infant is a rare disease belonging to Luft syndrome, nonthyroidal hypermetabolism, arising from a singular example of a defect in OXPHOS. The mitochondria lose coupling of mitochondrial substrates oxidation from the ADP phosphorylation. Since Luft syndrome is due to uncoupled cell respiration responsible for deficient in ATP production that originates in the respiratory complexes, a de novo heterozygous variant in the catalytic subunit of mitochondrial F1 FO -ATPase arises as the main cause of an autosomal dominant syndrome of hypermetabolism associated with dysfunction in ATP production, which does not involve the respiratory complexes. The F1 FO -ATPase works as an embedded molecular machine with a rotary action using two different motor engines. The FO , which is an integral domain in the membrane, dissipates the chemical potential difference for H+ , a proton motive force (Δp), across the inner membrane to generate a torsion. The F1 domain-the hydrophilic portion responsible for ATP turnover-is powered by the molecular rotary action to synthesize ATP. The structural and functional coupling of F1 and FO domains support the energy transduction for ATP synthesis. The dissipation of Δp by means of an H+ slip correlated to rotor free-wheeling of the F1 FO -ATPase has been discovered to cause enzyme dysfunction in primary mitochondrial disorders. In this insight, we try to offer commentary and analysis of the molecular mechanism in these impaired mitochondria.
    Keywords:  ATP synthase; bioenergetic failure; congenital hypermetabolism; de novo mutation; mitochondria
    DOI:  https://doi.org/10.1002/med.22013
  7. J Cell Biol. 2024 Mar 04. pii: e202211048. [Epub ahead of print]223(3):
    Fission-independent compartmentalization of mitochondria during budding yeast cell division.
    Saori R Yoshii, Yves Barral.
      Lateral diffusion barriers compartmentalize membranes to generate polarity or asymmetrically partition membrane-associated macromolecules. Budding yeasts assemble such barriers in the endoplasmic reticulum (ER) and the outer nuclear envelope at the bud neck to retain aging factors in the mother cell and generate naïve and rejuvenated daughter cells. However, little is known about whether other organelles are similarly compartmentalized. Here, we show that the membranes of mitochondria are laterally compartmentalized at the bud neck and near the cell poles. The barriers in the inner mitochondrial membrane are constitutive, whereas those in the outer membrane form in response to stresses. The strength of mitochondrial diffusion barriers is regulated positively by spatial cues from the septin axis and negatively by retrograde (RTG) signaling. These data indicate that mitochondria are compartmentalized in a fission-independent manner. We propose that these diffusion barriers promote mitochondrial polarity and contribute to mitochondrial quality control.
    DOI:  https://doi.org/10.1083/jcb.202211048
  8. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00446-1. [Epub ahead of print]36(1): 21-35
    Mitochondrial-derived vesicles in metabolism, disease, and aging.
    Tim König, Heidi M McBride.
      Mitochondria are central hubs of cellular metabolism and are tightly connected to signaling pathways. The dynamic plasticity of mitochondria to fuse, divide, and contact other organelles to flux metabolites is central to their function. To ensure bona fide functionality and signaling interconnectivity, diverse molecular mechanisms evolved. An ancient and long-overlooked mechanism is the generation of mitochondrial-derived vesicles (MDVs) that shuttle selected mitochondrial cargoes to target organelles. Just recently, we gained significant insight into the mechanisms and functions of MDV transport, ranging from their role in mitochondrial quality control to immune signaling, thus demonstrating unexpected and diverse physiological aspects of MDV transport. This review highlights the origin of MDVs, their biogenesis, and their cargo selection, with a specific focus on the contribution of MDV transport to signaling across cell and organ barriers. Additionally, the implications of MDVs in peroxisome biogenesis, neurodegeneration, metabolism, aging, and cancer are discussed.
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.014
  9. RNA. 2023 Dec 20. pii: rna.079799.123. [Epub ahead of print]
    LARP4 Is an RNA-Binding Protein That Binds Nuclear-Encoded Mitochondrial mRNAs To Promote Mitochondrial Function.
    Benjamin M Lewis, Chae Yun Cho, Hsuan-Lin Her, Orel Mizrahi, Tony Hunter, Gene W Yeo.
      Mitochondria-associated RNA-binding proteins (RBPs) have emerged as key contributors to mitochondrial biogenesis and homeostasis. With few examples known, we set out to identify RBPs that regulate nuclear-encoded mitochondrial mRNAs (NEMmRNAs). Our systematic analysis of RNA targets of 150 RBPs identified RBPs with a preference for binding NEMmRNAs, including LARP4, a La RBP family member. We show that LARP4's targets are particularly enriched in mRNAs that encode respiratory chain complex proteins (RCCPs) and mitochondrial ribosome proteins (MRPs) across multiple human cell lines. Through quantitative proteomics, we demonstrate that depletion of LARP4 leads to a significant reduction in RCCP and MRP protein levels. Furthermore, we show that LARP4 depletion reduces mitochondrial function, and that LARP4 re-expression rescues this phenotype. Our findings shed light on a novel function for LARP4 as an RBP that binds to and positively regulates NEMmRNAs to promote mitochondrial respiratory function.
    Keywords:  La module protein; Mitochondria; RNA binding protein; Translation; eCLIP
    DOI:  https://doi.org/10.1261/rna.079799.123
  10. EMBO Rep. 2023 Dec 14.
    MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion.
    Andres Goldman, Michael Mullokandov, Yehudit Zaltsman, Limor Regev, Smadar Levin-Zaidman, Atan Gross.
      Fusion of the outer mitochondrial membrane (OMM) is regulated by mitofusin 1 (MFN1) and 2 (MFN2), yet the differential contribution of each of these proteins is less understood. Mitochondrial carrier homolog 2 (MTCH2) also plays a role in mitochondrial fusion, but its exact function remains unresolved. MTCH2 overexpression enforces MFN2-independent mitochondrial fusion, proposedly by modulating the phospholipid lysophosphatidic acid (LPA), which is synthesized by glycerol-phosphate acyl transferases (GPATs) in the endoplasmic reticulum (ER) and the OMM. Here we report that MTCH2 requires MFN1 to enforce mitochondrial fusion and that fragmentation caused by loss of MTCH2 can be specifically counterbalanced by overexpression of MFN2 but not MFN1, partially independent of its GTPase activity and mitochondrial localization. Pharmacological inhibition of GPATs (GPATi) or silencing ER-resident GPATs suppresses MFN2's ability to compensate for the loss of MTCH2. Loss of either MTCH2, MFN2, or GPATi does not impair stress-induced mitochondrial fusion, whereas the combined loss of MTCH2 and GPATi or the combined loss of MTCH2 and MFN2 does. Taken together, we unmask two cooperative mechanisms that sustain mitochondrial fusion.
    Keywords:  LPA; MFN2; MTCH2; Mitochondria-ER Communication; Mitochondrial Fusion
    DOI:  https://doi.org/10.1038/s44319-023-00009-1
  11. Cell. 2024 Jan 04. pii: S0092-8674(23)01321-1. [Epub ahead of print]187(1): 95-109.e26
    Engineering TALE-linked deaminases to facilitate precision adenine base editing in mitochondrial DNA.
    Sung-Ik Cho, Kayeong Lim, Seongho Hong, Jaesuk Lee, Annie Kim, Chae Jin Lim, Seungmin Ryou, Ji Min Lee, Young Geun Mok, Eugene Chung, Sanghun Kim, Seunghun Han, Sang-Mi Cho, Jieun Kim, Eun-Kyoung Kim, Ki-Hoan Nam, Yeji Oh, Minkyung Choi, Tae Hyeon An, Kyoung-Jin Oh, Seonghyun Lee, Hyunji Lee, Jin-Soo Kim.
      DddA-derived cytosine base editors (DdCBEs) and transcription activator-like effector (TALE)-linked deaminases (TALEDs) catalyze targeted base editing of mitochondrial DNA (mtDNA) in eukaryotic cells, a method useful for modeling of mitochondrial genetic disorders and developing novel therapeutic modalities. Here, we report that A-to-G-editing TALEDs but not C-to-T-editing DdCBEs induce tens of thousands of transcriptome-wide off-target edits in human cells. To avoid these unwanted RNA edits, we engineered the substrate-binding site in TadA8e, the deoxy-adenine deaminase in TALEDs, and created TALED variants with fine-tuned deaminase activity. Our engineered TALED variants not only reduced RNA off-target edits by >99% but also minimized off-target mtDNA mutations and bystander edits at a target site. Unlike wild-type versions, our TALED variants were not cytotoxic and did not cause developmental arrest of mouse embryos. As a result, we obtained mice with pathogenic mtDNA mutations, associated with Leigh syndrome, which showed reduced heart rates.
    Keywords:  CRISPR-adenine base editor; Leigh syndrome; RNA off-target; TALE-linked adenine deaminase; TALED; genetic disease; in vivo genome editing; mitochondria; mitochondrial genome editing; mtDNA
    DOI:  https://doi.org/10.1016/j.cell.2023.11.035
  12. Front Cardiovasc Med. 2023 ;10 1268814
    Mitochondrial transplantation: the advance to therapeutic application and molecular modulation.
    James D McCully, Pedro J Del Nido, Sitaram M Emani.
      Mitochondrial transplantation provides a novel methodology for rescue of cell viability and cell function following ischemia-reperfusion injury and applications for other pathologies are expanding. In this review we present our methods and acquired data and evidence accumulated to support the use of mitochondrial transplantation.
    Keywords:  heart; mitochondria; mitochondrial transplantation; proteomics; transcriptomics
    DOI:  https://doi.org/10.3389/fcvm.2023.1268814
  13. Nat Commun. 2024 Jan 02. 15(1): 168
    Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.
    Jun Dong, Li Chen, Fei Ye, Junhui Tang, Bing Liu, Jiacheng Lin, Pang-Hu Zhou, Bin Lu, Min Wu, Jia-Hong Lu, Jing-Jing He, Simone Engelender, Qingtao Meng, Zhiyin Song, He He.
      Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.
    DOI:  https://doi.org/10.1038/s41467-023-44057-6
  14. RNA Biol. 2024 Jan;21(1): 1-20
    Small RNA-big impact: exosomal miRNAs in mitochondrial dysfunction in various diseases.
    Xiaqing Li, Yi Han, Yu Meng, Lianghong Yin.
      Mitochondria are multitasking organelles involved in maintaining the cell homoeostasis. Beyond its well-established role in cellular bioenergetics, mitochondria also function as signal organelles to propagate various cellular outcomes. However, mitochondria have a self-destructive arsenal of factors driving the development of diseases caused by mitochondrial dysfunction. Extracellular vesicles (EVs), a heterogeneous group of membranous nano-sized vesicles, are present in a variety of bodily fluids. EVs serve as mediators for intercellular interaction. Exosomes are a class of small EVs (30-100 nm) released by most cells. Exosomes carry various cargo including microRNAs (miRNAs), a class of short noncoding RNAs. Recent studies have closely associated exosomal miRNAs with various human diseases, including diseases caused by mitochondrial dysfunction, which are a group of complex multifactorial diseases and have not been comprehensively described. In this review, we first briefly introduce the characteristics of EVs. Then, we focus on possible mechanisms regarding exosome-mitochondria interaction through integrating signalling networks. Moreover, we summarize recent advances in the knowledge of the role of exosomal miRNAs in various diseases, describing how mitochondria are changed in disease status. Finally, we propose future research directions to provide a novel therapeutic strategy that could slow the disease progress mediated by mitochondrial dysfunction.
    Keywords:  Exosome; Extracellular vesicle; diseases; miRNA; mitochondrial dysfunction
    DOI:  https://doi.org/10.1080/15476286.2023.2293343
  15. Hepatol Commun. 2024 Jan 01. pii: e0361. [Epub ahead of print]8(1):
    Protein biomarkers GDF15 and FGF21 to differentiate mitochondrial hepatopathies from other pediatric liver diseases.
    Childhood Liver Disease Research Network (ChiLDReN)
       BACKGROUND: Mitochondrial hepatopathies (MHs) are primary mitochondrial genetic disorders that can present as childhood liver disease. No recognized biomarkers discriminate MH from other childhood liver diseases. The protein biomarkers growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) differentiate mitochondrial myopathies from other myopathies. We evaluated these biomarkers to determine if they discriminate MH from other liver diseases in children.
    METHODS: Serum biomarkers were measured in 36 children with MH (17 had a genetic diagnosis); 38 each with biliary atresia, α1-antitrypsin deficiency, and Alagille syndrome; 20 with NASH; and 186 controls.
    RESULTS: GDF15 levels compared to controls were mildly elevated in patients with α1-antitrypsin deficiency, Alagille syndrome, and biliary atresia-young subgroup, but markedly elevated in MH (p<0.001). FGF21 levels were mildly elevated in NASH and markedly elevated in MH (p<0.001). Both biomarkers were higher in patients with MH with a known genetic cause but were similar in acute and chronic presentations. Both markers had a strong performance to identify MH with a molecular diagnosis with the AUC for GDF15 0.93±0.04 and for FGF21 0.90±0.06. Simultaneous elevation of both markers >98th percentile of controls identified genetically confirmed MH with a sensitivity of 88% and specificity of 96%. In MH, independent predictors of survival without requiring liver transplantation were international normalized ratio and either GDF15 or FGF21 levels, with levels <2000 ng/L predicting survival without liver transplantation (p<0.01).
    CONCLUSIONS: GDF15 and FGF21 are significantly higher in children with MH compared to other childhood liver diseases and controls and, when combined, were predictive of MH and had prognostic implications.
    DOI:  https://doi.org/10.1097/HC9.0000000000000361
  16. Mol Cell. 2023 Dec 20. pii: S1097-2765(23)01027-4. [Epub ahead of print]
    Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis.
    Xiaojian Shi, Marisa DeCiucis, Kariona A Grabinska, Jean Kanyo, Adam Liu, Tukiet T Lam, Hongying Shen.
      Organelle transporters define metabolic compartmentalization, and how this metabolite transport process can be modulated is poorly explored. Here, we discovered that human SLC25A39, a mitochondrial transporter critical for mitochondrial glutathione uptake, is a short-lived protein under dual regulation at the protein level. Co-immunoprecipitation mass spectrometry and CRISPR knockout (KO) in mammalian cells identified that mitochondrial m-AAA protease AFG3L2 is responsible for degrading SLC25A39 through the matrix loop 1. SLC25A39 senses mitochondrial iron-sulfur cluster using four matrix cysteine residues and inhibits its degradation. SLC25A39 protein regulation is robust in developing and mature neurons. This dual transporter regulation, by protein quality control and metabolic sensing, allows modulating mitochondrial glutathione level in response to iron homeostasis, opening avenues for exploring regulation of metabolic compartmentalization. Neuronal SLC25A39 regulation connects mitochondrial protein quality control, glutathione, and iron homeostasis, which were previously unrelated biochemical features in neurodegeneration.
    Keywords:  AFG3L2; SLC25A39; glutathione; iron; mitochondrial transporter; protein quality control
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.008
  17. Commun Biol. 2024 Jan 05. 7(1): 44
    The mitochondrial protease PARL is required for spermatogenesis.
    Sarah Schumacher, Laura Klose, Jessica Lambertz, Dieter Lütjohann, Ronald Biemann, Stefanie Kuerten, Lars Fester.
      Mitochondrial function plays an important role in the maintenance of male fertility. However, the mechanisms underlying mitochondrial defect-related infertility remain mostly unclear. Here we show that a deficiency of PARL (Parl-/-), a mitochondrial protease, causes complete arrest of spermatogenesis during meiosis I. PARL deficiency led to severe downregulation of proteins of respiratory chain complex IV in testes that did not occur in other tested organs, causing a deficit in complex IV activity and ATP production. Furthermore, Parl-/- testes showed an almost complete loss of HSD17B3, a protein of the sER responsible for the last step in testosterone synthesis. While testosterone production appeared to be restored by overexpression of HSD17B12, loss of the canonical testosterone synthesis led to an upregulation of luteinizing hormone (LH) and of LH-regulated responses. These results suggest an important impact of the downstream regulation of mitochondrial defects that manifest in a cell-type-specific manner and extend beyond mitochondria.
    DOI:  https://doi.org/10.1038/s42003-023-05703-3
  18. Mitochondrion. 2023 Dec 27. pii: S1567-7249(23)00117-4. [Epub ahead of print]75 101837
    The biology of mitochondrial carrier homolog 2.
    Xiaohe Zheng, Binxiang Chu.
      The mitochondrial carrier system is in charge of small molecule transport between the mitochondria and the cytoplasm as well as being an integral portion of the core mitochondrial function. One member of the mitochondrial carrier family of proteins, mitochondrial carrier homolog 2 (MTCH2), is characterized as a critical mitochondrial outer membrane protein insertase participating in mitochondrial homeostasis. Accumulating evidence demonstrate that MTCH2 is integrally linked to cell death and mitochondrial metabolism, and its genetic alterations cause a variety of disease phenotypes, ranging from obesity, Alzheimer's disease, and tumor. To provide a comprehensive insight into the current understanding of MTCH2, we present a detailed description of the physiopathological functions of MTCH2, ranging from apoptosis, mitochondrial dynamics, and metabolic homeostasis regulation. Moreover, we summarized the impact of MTCH2 in human diseases, and highlighted tumors, to assess the role of MTCH2 mutations or variable expression on pathogenesis and target therapeutic options.
    Keywords:  Apoptosis; Lipid metabolism; MTCH2; Mitochondria; Tumor
    DOI:  https://doi.org/10.1016/j.mito.2023.101837
  19. Nat Commun. 2024 Jan 04. 15(1): 205
    VAP spatially stabilizes dendritic mitochondria to locally support synaptic plasticity.
    Ojasee Bapat, Tejas Purimetla, Sarah Kruessel, Monil Shah, Ruolin Fan, Christina Thum, Fiona Rupprecht, Julian D Langer, Vidhya Rangaraju.
      Synapses are pivotal sites of plasticity and memory formation. Consequently, synapses are energy consumption hotspots susceptible to dysfunction when their energy supplies are perturbed. Mitochondria are stabilized near synapses via the cytoskeleton and provide the local energy required for synaptic plasticity. However, the mechanisms that tether and stabilize mitochondria to support synaptic plasticity are unknown. We identified proteins exclusively tethering mitochondria to actin near postsynaptic spines. We find that VAP, the vesicle-associated membrane protein-associated protein implicated in amyotrophic lateral sclerosis, stabilizes mitochondria via actin near the spines. To test if the VAP-dependent stable mitochondrial compartments can locally support synaptic plasticity, we used two-photon glutamate uncaging for spine plasticity induction and investigated the induced and adjacent uninduced spines. We find VAP functions as a spatial stabilizer of mitochondrial compartments for up to ~60 min and as a spatial ruler determining the ~30 μm dendritic segment supported during synaptic plasticity.
    DOI:  https://doi.org/10.1038/s41467-023-44233-8
  20. Exp Mol Med. 2024 Jan 04.
    Mitochondria as secretory organelles and therapeutic cargos.
    Joonho Suh, Yun-Sil Lee.
      Mitochondria have been primarily considered intracellular organelles that are responsible for generating energy for cell survival. However, accumulating evidence suggests that mitochondria are secreted into the extracellular space under physiological and pathological conditions, and these secreted mitochondria play diverse roles by regulating metabolism, the immune response, or the differentiation/maturation in target cells. Furthermore, increasing amount of research shows the therapeutic effects of local or systemic administration of mitochondria in various disease models. These findings have led to growing interest in exploring mitochondria as potential therapeutic agents. Here, we discuss the emerging roles of mitochondria as extracellularly secreted organelles to shed light on their functions beyond energy production. Additionally, we provide information on therapeutic outcomes of mitochondrial transplantation in animal models of diseases and an update on ongoing clinical trials, underscoring the potential of using mitochondria as a novel therapeutic intervention.
    DOI:  https://doi.org/10.1038/s12276-023-01141-7
  21. Annu Rev Biophys. 2024 Jan 02.
    Mitochondrial Dynamics at Different Levels: From Cristae Dynamics to Interorganellar Cross Talk.
    Arun Kumar Kondadi, Andreas S Reichert.
      Mitochondria are essential organelles performing important cellular functions ranging from bioenergetics and metabolism to apoptotic signaling and immune responses. They are highly dynamic at different structural and functional levels. Mitochondria have been shown to constantly undergo fusion and fission processes and dynamically interact with other organelles such as the endoplasmic reticulum, peroxisomes, and lipid droplets. The field of mitochondrial dynamics has evolved hand in hand with technological achievements including advanced fluorescence super-resolution nanoscopy. Dynamic remodeling of the cristae membrane within individual mitochondria, discovered very recently, opens up a further exciting layer of mitochondrial dynamics. In this review, we discuss mitochondrial dynamics at the following levels: (a) within an individual mitochondrion, (b) among mitochondria, and (c) between mitochondria and other organelles. Although the three tiers of mitochondrial dynamics have in the past been classified in a hierarchical manner, they are functionally connected and must act in a coordinated manner to maintain cellular functions and thus prevent various human diseases. Expected final online publication date for the Annual Review of Biophysics, Volume 53 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biophys-030822-020736
  22. Neurol India. 2023 Nov-Dec;71(6):71(6): 1192-1196
    Clinical Spectrum of Biopsy Proven Mitochondrial Myopathy.
    Deepak Menon, Sruthi S Nair, Neelima Radhakrishnan, Udit Umesh Saraf, Muralidharan Nair.
       Objectives: Clinical spectrum of mitochondrial myopathy extends beyond chronic progressive external ophthalmoplegia (CPEO). While information on encephalomyopathies is abundant, clinical data on predominant myopathic presentation of mitochondrial disorders are lacking.
    Materials and Methods: Clinical, electrophysiological, biochemical, and follow-up data of patients with predominant myopathic presentation and muscle biopsy confirmed primary mitochondrial myopathy was obtained. We excluded known syndromes of mitochondrial cytopathies and encephalomyopathies.
    Results: Among 16 patients, 7 had CPEO, 4 had CPEO with limb-girdle muscle weakness (LGMW), and 5 had isolated LGMW. Systemic features included seizures with photosensitivity (n = 3), diabetes (n = 1), cardiomyopathy (n = 1), and sensorineural hearing loss (n = 1) and were more common in isolated LGMW. Elevated serum creatine kinase (CK) and lactate levels and electromyography (EMG) myopathic potentials were more frequent with LGMW. During follow-up, LGMW had more severe progression of weakness.
    Conclusion: We identified three subsets of mitochondrial myopathy with distinct clinical features and evolutionary patterns. Isolated LGMW was seen in 30% of patients and would represent severe end of the spectrum.
    Keywords:  Chronic progressive external ophthalmoplegia; limb-girdle muscle weakness; mitochondrial myopathy; muscle biopsy; photosensitive epilepsy
    DOI:  https://doi.org/10.4103/0028-3886.391399
  23. Cell Rep. 2023 Dec 28. pii: S2211-1247(23)01637-6. [Epub ahead of print]43(1): 113626
    CHCHD4-TRIAP1 regulation of innate immune signaling mediates skeletal muscle adaptation to exercise.
    Jin Ma, Ping-Yuan Wang, Jie Zhuang, Annie Y Son, Alexander K Karius, Abu Mohammad Syed, Masahiro Nishi, Zhichao Wu, Mateus P Mori, Young-Chae Kim, Paul M Hwang.
      Exercise training can stimulate the formation of fatty-acid-oxidizing slow-twitch skeletal muscle fibers, which are inversely correlated with obesity, but the molecular mechanism underlying this transformation requires further elucidation. Here, we report that the downregulation of the mitochondrial disulfide relay carrier CHCHD4 by exercise training decreases the import of TP53-regulated inhibitor of apoptosis 1 (TRIAP1) into mitochondria, which can reduce cardiolipin levels and promote VDAC oligomerization in skeletal muscle. VDAC oligomerization, known to facilitate mtDNA release, can activate cGAS-STING/NFKB innate immune signaling and downregulate MyoD in skeletal muscle, thereby promoting the formation of oxidative slow-twitch fibers. In mice, CHCHD4 haploinsufficiency is sufficient to activate this pathway, leading to increased oxidative muscle fibers and decreased fat accumulation with aging. The identification of a specific mediator regulating muscle fiber transformation provides an opportunity to understand further the molecular underpinnings of complex metabolic conditions such as obesity and could have therapeutic implications.
    Keywords:  CHCHD4; CP: Immunology; MyoD; TRIAP1; VDAC; cardiolipin; exercise adaptation; innate immune signaling; mitochondria; mtDNA; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2023.113626
  24. Nat Chem Biol. 2024 Jan 02.
    Acylspermidines are conserved mitochondrial sirtuin-dependent metabolites.
    Bingsen Zhang, James Mullmann, Andreas H Ludewig, Irma R Fernandez, Tyler R Bales, Robert S Weiss, Frank C Schroeder.
      Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent protein lysine deacylases regulating metabolism and stress responses; however, characterization of the removed acyl groups and their downstream metabolic fates remains incomplete. Here we employed untargeted comparative metabolomics to reinvestigate mitochondrial sirtuin biochemistry. First, we identified N-glutarylspermidines as metabolites downstream of the mitochondrial sirtuin SIR-2.3 in Caenorhabditis elegans and demonstrated that SIR-2.3 functions as a lysine deglutarylase and that N-glutarylspermidines can be derived from O-glutaryl-ADP-ribose. Subsequent targeted analysis of C. elegans, mouse and human metabolomes revealed a chemically diverse range of N-acylspermidines, and formation of N-succinylspermidines and/or N-glutarylspermidines was observed downstream of mammalian mitochondrial sirtuin SIRT5 in two cell lines, consistent with annotated functions of SIRT5. Finally, N-glutarylspermidines were found to adversely affect C. elegans lifespan and mammalian cell proliferation. Our results indicate that N-acylspermidines are conserved metabolites downstream of mitochondrial sirtuins that facilitate annotation of sirtuin enzymatic activities in vivo and may contribute to sirtuin-dependent phenotypes.
    DOI:  https://doi.org/10.1038/s41589-023-01511-2
  25. Stem Cell Res Ther. 2024 Jan 02. 15(1): 10
    Critical contribution of mitochondria in the development of cardiomyopathy linked to desmin mutation.
    Yeranuhi Hovhannisyan, Zhenlin Li, Domitille Callon, Rodolphe Suspène, Vivien Batoumeni, Alexis Canette, Jocelyne Blanc, Hakim Hocini, Cécile Lefebvre, Nora El-Jahrani, Maria Kitsara, Aurore L'honoré, Ekaterini Kordeli, Paul Fornes, Jean-Paul Concordet, Gérard Tachdjian, Anne-Marie Rodriguez, Jean-Pierre Vartanian, Anthony Béhin, Karim Wahbi, Pierre Joanne, Onnik Agbulut.
       BACKGROUND: Beyond the observed alterations in cellular structure and mitochondria, the mechanisms linking rare genetic mutations to the development of heart failure in patients affected by desmin mutations remain unclear due in part, to the lack of relevant human cardiomyocyte models.
    METHODS: To shed light on the role of mitochondria in these mechanisms, we investigated cardiomyocytes derived from human induced pluripotent stem cells carrying the heterozygous DESE439K mutation that were either isolated from a patient or generated by gene editing. To increase physiological relevance, cardiomyocytes were either cultured on an anisotropic micropatterned surface to obtain elongated and aligned cardiomyocytes, or as a cardiac spheroid to create a micro-tissue. Moreover, when applicable, results from cardiomyocytes were confirmed with heart biopsies of suddenly died patient of the same family harboring DESE439K mutation, and post-mortem heart samples from five control healthy donors.
    RESULTS: The heterozygous DESE439K mutation leads to dramatic changes in the overall cytoarchitecture of cardiomyocytes, including cell size and morphology. Most importantly, mutant cardiomyocytes display altered mitochondrial architecture, mitochondrial respiratory capacity and metabolic activity reminiscent of defects observed in patient's heart tissue. Finally, to challenge the pathological mechanism, we transferred normal mitochondria inside the mutant cardiomyocytes and demonstrated that this treatment was able to restore mitochondrial and contractile functions of cardiomyocytes.
    CONCLUSIONS: This work highlights the deleterious effects of DESE439K mutation, demonstrates the crucial role of mitochondrial abnormalities in the pathophysiology of desmin-related cardiomyopathy, and opens up new potential therapeutic perspectives for this disease.
    Keywords:  Cardiomyocytes; Desmin; Dilated cardiomyopathy; Heart failure; Mitochondria; Myofibrillar myopathy; Stem cells; iPSC
    DOI:  https://doi.org/10.1186/s13287-023-03619-7
  26. J Biochem. 2023 Dec 29. pii: mvad117. [Epub ahead of print]
    Mitochondrial lipid dynamics regulated by MITOL-mediated ubiquitination.
    Koji Yamano, Hiroki Kinefuchi, Waka Kojima.
      Mitochondria-endoplasmic reticulum (ER) contact sites in mammals provide platforms for various reactions such as calcium signaling, lipid metabolism, organelle dynamics and autophagy. To fulfill these tasks, a number of proteins assemble at the contact sites including MITOL/MARCHF5, a critical mitochondrial ubiquitin ligase. How MITOL regulates mitochondrial function from the contact site, however, has been largely unresolved. Recently, a new role for MITOL in the active transport of phosphatidic acid from the ER to mitochondria was reported. In this commentary, we briefly summarize our current understanding of mitochondria-ER contact sites and discuss the recently elucidated mechanism of MITOL fine-tuning phospholipid transfer activity through ubiquitination.
    Keywords:  contact site; mitochondria; phospholipid; ubiquitin; ubiquitin ligase
    DOI:  https://doi.org/10.1093/jb/mvad117
  27. J Nutr Biochem. 2023 Dec 27. pii: S0955-2863(23)00292-9. [Epub ahead of print] 109559
    Moderate Replacement of Fish Oil with Palmitic Acid-Stimulated Mitochondrial Fusion Promotes β-oxidation by Mfn2 Interacting with Cpt1α via Its GTPase-domain.
    Yu-Feng Song, Ling-Jiao Wang, Zhi Luo, Christer Hogstrand, Xiao-Hong Lai, Fei-Fei Zheng.
      The mitochondrial matrix serves as the principal locale for the process of fatty acids (FAs) β-oxidation. Preserving the integrity and homeostasis of mitochondria, which is accomplished through ongoing fusion and fission events, is of paramount importance for the effective execution of FAs β-oxidation. There has been no investigation to date into whether and how mitochondrial fusion directly enhances FAs β-oxidation. The underlying mechanism of a balanced FAs ratio favoring hepatic lipid homeostasis remains largely unclear. To address such gaps, the present study was conducted to investigate the mechanism through which a balanced dietary FAs ratio enhances hepatic FAs β-oxidation. The investigation specifically focused on the involvement of Mfn2-mediated mitochondrial fusion in the regulation of Cpt1α in this process. In the present study, the yellow catfish (Pelteobagrus fulvidraco), recognized as a model organism for lipid metabolism, were subjected to eight weeks of in vivo feeding with six distinct diets featuring varying FAs ratios. Additionally, in vitro experiments were conducted to inhibit Mfn2-mediated mitochondrial fusion in isolated hepatocytes, achieved through the transfection of hepatocytes with si-mfn2. Further, deletion mutants for both Mfn2 and Cpt1α were constructed to elucidate the critical regions responsible for the interactions between these two proteins within the system. The key findings were: 1. Substituting palmitic acid (PA) for fish oil (FO) proved to be enhanced in reducing hepatic lipid accumulation. This beneficial effect was primarily attributed to the activation of mitochondrial FAs β-oxidation; 2. The balanced replacement of PA stimulated Mfn2-mediated mitochondrial fusion by diminishing Mfn2 ubiquitination, thereby enhancing its protein retention within the mitochondria; 3. Mfn2-mediated mitochondrial fusion promoted FAs β-oxidation through direct interaction between Mfn2 and Cpt1α via its GTPase-domains, which is essential for the maintenance of Cpt1 activity. Notably, the present research results unveil a previously undisclosed mechanism wherein Mfn2-mediated mitochondrial fusion promotes FAs β-oxidation by directly augmenting the capacity for FA transport into mitochondria (MT), in addition to expanding the mitochondrial matrix. This underscores the pivotal role of mitochondrial fusion in preserving hepatic lipid homeostasis. The present results further confirm that these mechanisms are evolutionarily conserved, extending their relevance from fish to mammals.
    Keywords:  Cpt1α; Fatty Acids Ratio; Mfn2; Mitochondrial Fusion; β-oxidation
    DOI:  https://doi.org/10.1016/j.jnutbio.2023.109559
  28. Commun Biol. 2024 Jan 05. 7(1): 29
    Curvature sensing lipid dynamics in a mitochondrial inner membrane model.
    Vinaya Kumar Golla, Kevin J Boyd, Eric R May.
      Membrane curvature is essential for many cellular structures and processes, and factors such as leaflet asymmetry, lipid composition, and proteins all play important roles. Cardiolipin is the signature lipid of mitochondrial membranes and is essential for maintaining the highly curved shapes of the inner mitochondrial membrane (IMM) and the spatial arrangement of membrane proteins. In this study, we investigate the partitioning behavior of various lipids present in the IMM using coarse-grained molecular dynamics simulations. This study explores curved bilayer systems containing phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CDL) in binary and ternary component mixtures. Curvature properties such as mean and Gaussian curvatures, as well as the distribution of lipids into the various curved regions of the cristae models, are quantified. Overall, this work represents an advance beyond previous studies on lipid curvature sensing by simulating these systems in a geometry that has the morphological features and scales of curvature consistent with regions of the IMM. We find that CDL has a stronger preference for accumulating in regions of negative curvature than PE lipids, in agreement with previous results. Furthermore, we find lipid partitioning propensity is dominated by sensitivity to mean curvature, while there is a weaker correlation with Gaussian curvature.
    DOI:  https://doi.org/10.1038/s42003-023-05657-6
  29. Mitochondrion. 2023 Dec 27. pii: S1567-7249(23)00119-8. [Epub ahead of print] 101839
    Exploiting Nuclear-Mitochondrial Cross-Talk in Theranostics: Enhancing Drug Delivery and Diagnostic Precision.
    Dilpreet Singh.
      The dynamic interplay between nuclear and mitochondrial processes plays a pivotal role in cellular homeostasis and disease progression. Exploiting this nuclear-mitochondrial cross-talk has emerged as a promising avenue in the field of theranostics, offering enhanced drug delivery and diagnostic precision for a wide range of medical conditions, particularly cancer. This abstract provides a brief overview of the key concepts and recent advancements in this rapidly evolving field. Recent research has elucidated the significance of mitochondrial dysfunction in various diseases, including cancer. Mitochondria, often referred to as the "powerhouses" of the cell, not only regulate energy production but also contribute to critical processes such as apoptosis, ROS generation, and metabolic signaling. Dysregulation of these mitochondrial functions is frequently associated with disease pathogenesis. In theranostics, the targeted modulation of mitochondrial function holds great promise. Mitochondria-targeted drug delivery systems have been designed to selectively deliver therapeutic agents to these organelles, thereby mitigating mitochondrial dysfunction while minimizing off-target effects. This precise drug delivery enhances the therapeutic efficacy of anticancer drugs and reduces the risk of drug resistance. Moreover, the diagnostic potential of nuclear-mitochondrial cross-talk is being harnessed to develop novel biomarkers and imaging techniques. Mitochondrial DNA mutations and alterations in mitochondrial metabolism serve as valuable indicators of disease progression and drug responsiveness. Non-invasive imaging modalities, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), have been employed to visualize mitochondrial activity and assess therapeutic outcomes.
    Keywords:  Cross-Talk; Diagnostic Precision; Drug Delivery; Nuclear-Mitochondria; Theranostics
    DOI:  https://doi.org/10.1016/j.mito.2023.101839
  30. bioRxiv. 2023 Dec 12. pii: 2023.12.11.571124. [Epub ahead of print]
    An interactive web application for exploring human plasma and fibroblast metabolomics data from patients with inborn errors of metabolism.
    Ling Cai, Hieu S Vu, Wen Gu, Hongli Chen, Jordan Franklin, Lea Abou Haidar, Zheng Wu, Chunxiao Pan, Feng Cai, Phong Nguyen, Bookyung Ko, Chendong Yang, Lauren G Zacharias, Jessica Sudderth, Sarah Montgomery, Crescenda Uhles, Heather Fisher, Julianna Hudnall, Callie Hornbuckle, Christine Quinn, Donnice Michel, Luis Umaña, Angela Scheuerle, Markey C McNutt, Garrett K Gotway, Bushra Afroze, Min Ni, Ralph DeBerardinis.
      Metabolomic profiling is instrumental in understanding the systemic and cellular impact of inborn errors of metabolism (IEMs), monogenic disorders caused by pathogenic genomic variants in genes involved in metabolism. This study encompasses untargeted metabolomics analysis of plasma from 474 individuals and fibroblasts from 67 subjects, incorporating healthy controls, patients with 65 different monogenic diseases, and numerous undiagnosed cases. We introduce a web application designed for the in-depth exploration of this extensive metabolomics database. The application offers a user-friendly interface for data review, download, and detailed analysis of metabolic deviations linked to IEMs at the level of individual patients or groups of patients with the same diagnosis. It also provides interactive tools for investigating metabolic relationships and offers comparative analyses of plasma and fibroblast profiles. This tool emphasizes the metabolic interplay within and across biological matrices, enriching our understanding of metabolic regulation in health and disease. As a resource, the application provides broad utility in research, offering novel insights into metabolic pathways and their alterations in various disorders.
    DOI:  https://doi.org/10.1101/2023.12.11.571124
  31. Sci Rep. 2024 Jan 04. 14(1): 546
    The nascent polypeptide-associated complex subunit Egd1 is required for efficient selective mitochondrial degradation in budding yeast.
    Yuan Tian, Koji Okamoto.
      Selective degradation of dysfunctional or excess mitochondria is a fundamental process crucial for cell homeostasis in almost all eukaryotes. This process relies on autophagy, an intracellular self-eating system conserved from yeast to humans and is thus called mitophagy. Detailed mechanisms of mitophagy remain to be fully understood. Here we show that mitochondrial degradation in budding yeast, which requires the pro-mitophagic protein Atg32, is strongly reduced in cells lacking Egd1, a beta subunit of the nascent polypeptide-associated complex acting in cytosolic ribosome attachment and protein targeting to mitochondria. By contrast, loss of the sole alpha subunit Egd2 or the beta subunit paralogue Btt1 led to only a partial or slight reduction in mitophagy. We also found that phosphorylation of Atg32, a crucial step for priming mitophagy, is decreased in the absence of Egd1. Forced Atg32 hyperphosphorylation almost completely restored mitophagy in egd1-null cells. Together, we propose that Egd1 acts in Atg32 phosphorylation to facilitate mitophagy.
    DOI:  https://doi.org/10.1038/s41598-023-50245-7
  32. Gene Ther. 2024 Jan 04.
    CRISPR/Cas9-mediated base editors and their prospects for mitochondrial genome engineering.
    Shahin Eghbalsaied, Clancy Lawler, Björn Petersen, Raul A Hajiyev, Steve R Bischoff, Stephen Frankenberg.
      Base editors are a type of double-stranded break (DSB)-free gene editing technology that has opened up new possibilities for precise manipulation of mitochondrial DNA (mtDNA). This includes cytosine and adenosine base editors and more recently guanosine base editors. Because of having low off-target and indel rates, there is a growing interest in developing and evolving this research field. Here, we provide a detailed update on DNA base editors. While base editing has widely been used for nuclear genome engineering, the growing interest in applying this technology to mitochondrial DNA has been faced with several challenges. While Cas9 protein has been shown to enter mitochondria, use of smaller Cas proteins, such as Cas12a, has higher import efficiency. However, sgRNA transfer into mitochondria is the most challenging step. sgRNA structure and ratio of Cas protein to sgRNA are both important factors for efficient sgRNA entry into mitochondria. In conclusion, while there are still several challenges to be addressed, ongoing research in this field holds the potential for new treatments and therapies for mitochondrial disorders.
    DOI:  https://doi.org/10.1038/s41434-023-00434-w
  33. Mol Psychiatry. 2024 Jan 03.
    A naturally occurring variant of SHLP2 is a protective factor in Parkinson's disease.
    Su-Jeong Kim, Brendan Miller, Nicolas G Hartel, Ricardo Ramirez, Regina Gonzalez Braniff, Naphada Leelaprachakul, Amy Huang, Yuzhu Wang, Thalida Em Arpawong, Eileen M Crimmins, Penglong Wang, Xianbang Sun, Chunyu Liu, Daniel Levy, Kelvin Yen, Giselle M Petzinger, Nicholas A Graham, Michael W Jakowec, Pinchas Cohen.
      Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) have been associated with a reduced risk of developing Parkinson's disease (PD), yet the underlying mechanisms remain elusive. In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived peptide (MDP) Small Humanin-like Peptide 2 (SHLP2). We identify m.2158 T > C, a mtSNP associated with reduced PD risk, within the small open reading frame encoding SHLP2. This mtSNP results in an alternative form of SHLP2 (lysine 4 replaced with arginine; K4R). Using targeted mass spectrometry, we detect specific tryptic fragments of SHLP2 in neuronal cells and demonstrate its binding to mitochondrial complex 1. Notably, we observe that the K4R variant, associated with reduced PD risk, exhibits increased stability compared to WT SHLP2. Additionally, both WT and K4R SHLP2 show enhanced protection against mitochondrial dysfunction in in vitro experiments and confer protection against a PD-inducing toxin, a mitochondrial complex 1 inhibitor, in a mouse model. This study sheds light on the functional consequences of the m.2158 T > C mtSNP on SHLP2 and provides insights into the potential mechanisms by which this mtSNP may reduce the risk of PD.
    DOI:  https://doi.org/10.1038/s41380-023-02344-0
  34. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00448-5. [Epub ahead of print]36(1): 222
    The DEAD Box Protein Mrh4 Functions in the Assembly of the Mitochondrial Large Ribosomal Subunit.
    Dasmanthie De Silva, Flavia Fontanesi, Antoni Barrientos.
      
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.016
  35. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00468-0. [Epub ahead of print]36(1): 5-7
    Show MERCI on mobile mitochondria.
    Jelle van den Ameele, Patrick F Chinnery.
      There is emerging evidence that mitochondria can move between cells, particularly from immune cells into cancers. Recent work from Zhang et al. in Cancer Cell employs single-cell RNA- and mitochondrial DNA-sequencing in co-culture experiments and patient tumor samples to detect mitochondrial transfer. However, the mechanisms, scale, and implications remain uncertain.
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.017
  36. Anal Chem. 2024 Jan 04.
    Mitochondrial Esterase Activity Measured at the Single Organelle Level by Nano-flow Cytometry.
    Liyun Su, Kaimin Gao, Ye Tian, Xu Xiao, Cheng Lu, Jingyi Xu, Xiaomei Yan.
      Monitoring mitochondrial esterase activity is crucial not only for investigating mitochondrial metabolism but also for assessing the effectiveness of mitochondrial-targeting prodrugs. However, accurately detecting esterase activity within mitochondria poses challenges due to its ubiquitous presence in cells and the uncontrolled localization of fluorogenic probes. To overcome this hurdle and reveal variations among different mitochondria, we isolated mitochondria and preserved their activity and functionality in a buffered environment. Subsequently, we utilized a laboratory-built nano-flow cytometer in conjunction with an esterase-responsive calcein-AM fluorescent probe to measure the esterase activity of individual mitochondria. This approach enabled us to investigate the influence of temperature, pH, metal ions, and various compounds on the mitochondrial esterase activity without any interference from other cellular constituents. Interestingly, we observed a decline in the mitochondrial esterase activity following the administration of mitochondrial respiratory chain inhibitors. Furthermore, we found that mitochondrial esterase activity was notably higher in the presence of a high concentration of ATP compared to that of ADP and AMP. Additionally, we noticed a correlation between elevated levels of complex IV and increased mitochondrial esterase activity. These findings suggest a functional connection between the mitochondrial respiratory chain and mitochondrial esterase activity. Moreover, we detected an upsurge in mitochondrial esterase activity during the early stages of apoptosis, while cellular esterase activity decreased. This highlights the significance of analyzing enzyme activity within specific organelle subregions. In summary, the integration of a nano-flow cytometer and fluorescent dyes introduces a novel method for quantifying mitochondrial enzyme activity with the potential to uncover the alterations and unique functions of other mitochondrial enzymes.
    DOI:  https://doi.org/10.1021/acs.analchem.3c04321
  37. Front Endocrinol (Lausanne). 2023 ;14 1280248
    Integrated metabolomics and transcriptomics to reveal biomarkers and mitochondrial metabolic dysregulation of premature ovarian insufficiency.
    Zhaoyang Yu, Weilong Peng, Feiwen Li, Xiaoqian Fu, Jiajia Wang, Hongfan Ding, Mujun Li, Huimei Wu.
       Background: The metabolic characteristics of premature ovarian insufficiency (POI), a reproductive endocrine disease characterized by abnormal sex hormone metabolism and follicle depletion, remain unclear. Metabolomics is a powerful tool for exploring disease phenotypes and biomarkers. This study aims to identify metabolic markers and construct diagnostic models, and elucidate the underlying pathological mechanisms for POI.
    Methods: Non-targeted metabolomics was utilized to characterize the plasma metabolic profile of 40 patients. The metabolic markers were identified through bioinformatics and machine learning, and constructed an optimal diagnostic model by classified multi-model analysis. Enzyme-linked immunosorbent assay (ELISA) was used to verify antioxidant indexes, mitochondrial enzyme complexes, and ATP levels. Finally, integrated transcriptomics and metabolomics were used to reveal the dysregulated pathways and molecular regulatory mechanisms of POI.
    Results: The study identified eight metabolic markers significantly correlated with ovarian reserve function. The XGBoost diagnostic model was developed based on six machine learning models, demonstrating its robust diagnostic performance and clinical applicability through the evaluation of receiver operating characteristic (ROC) curve, decision curve analysis (DCA), calibration curve, and precise recall (PR) curve. Multi-omics analysis showed that mitochondrial respiratory chain electron carrier (CoQ10) and enzyme complex subunits were down-regulated in POI. ELISA validation revealed an elevation in oxidative stress markers and a reduction in the activities of antioxidant enzymes, CoQ10, and mitochondrial enzyme complexes in POI.
    Conclusion: Our findings highlight that mitochondrial dysfunction and energy metabolism disorders are closely related to the pathogenesis of POI. The identification of metabolic markers and predictive models holds significant implications for the diagnosis, treatment, and monitoring of POI.
    Keywords:  biomarkers; machine learning; metabolomics; mitochondrial dysfunction; premature ovarian insufficiency; transcriptomics
    DOI:  https://doi.org/10.3389/fendo.2023.1280248
  38. Am J Med Genet A. 2023 Dec 29.
    High number of candidate gene variants are identified as disease-causing in a period of 4 years.
    Sonia Hills, Qifei Li, Jill A Madden, Casie A Genetti, Catherine A Brownstein, Klaus Schmitz-Abe, Alan H Beggs, Pankaj B Agrawal.
      Advances in bioinformatic tools paired with the ongoing accumulation of genetic knowledge and periodic reanalysis of genomic sequencing data have led to an improvement in genetic diagnostic rates. Candidate gene variants (CGVs) identified during sequencing or on reanalysis but not yet implicated in human disease or associated with a phenotypically distinct condition are often not revisited, leading to missed diagnostic opportunities. Here, we revisited 33 such CGVs from our previously published study and determined that 16 of them are indeed disease-causing (novel or phenotype expansion) since their identification. These results emphasize the need to focus on previously identified CGVs during sequencing or reanalysis and the importance of sharing that information with researchers around the world, including relevant functional analysis to establish disease causality.
    Keywords:  candidate gene variants; clinical exome reanalysis; gene-disease association; rare disease
    DOI:  https://doi.org/10.1002/ajmg.a.63509
  39. Free Radic Biol Med. 2023 Dec 27. pii: S0891-5849(23)01184-X. [Epub ahead of print]212 220-233
    SYNJ2BP ameliorates intervertebral disc degeneration by facilitating mitochondria-associated endoplasmic reticulum membrane formation and mitochondrial Zn2+ homeostasis.
    Yu Song, Wen Geng, Dingchao Zhu, Huaizhen Liang, Zhi Du, Bide Tong, Kun Wang, Shuai Li, Yong Gao, Xiaobo Feng, Zhiwei Liao, Rongcheng Mei, Cao Yang.
      Nucleus pulposus (NP) cell function-loss is one main contributor during intervertebral disc degeneration (IDD) progression. Both mitochondria and endoplasmic reticulum (ER) play vital roles in sustaining NP cell homeostasis, while the precise function of ER-mitochondria tethering and cross talk in IDD remain to be clarified. Here, we demonstrated that a notable disruption of mitochondria-associated ER membrane (MAM) was identified in degenerated discs and TBHP-induced NP cells, accompanied by mitochondrial Zn2+ overload and NP cell senescence. Importantly, experimental coupling of MAM contacts by MFN2, a critical regulator of MAM formation, could enhance NLRX1-SLC39A7 complex formation and mitochondrial Zn2+ homeostasis. Further using the sequencing data from TBHP-induced degenerative model of NP cells, combining the reported MAM proteomes, we demonstrated that SYNJ2BP loss was one critical pathological characteristic of NP cell senescence and IDD progression, which showed close relationship with MAM disruption. Overexpression of SYNJ2BP could facilitate MAM contact organization and NLRX1-SLC39A7 complex formation, thus promoted mitochondrial Zn2+ homeostasis, NP cell proliferation and intervertebral disc rejuvenation. Collectively, our present study revealed a critical role of SYNJ2BP in maintaining mitochondrial Zn2+ homeostasis in NP cells during IDD progression, partially via sustaining MAM contact and NLRX1-SLC39A7 complex formation.
    Keywords:  Intervertebral disc degeneration; Mitochondria-associated ER membrane; NLRX1; Nucleus pulposus; SLC39A7; SYNJ2BP
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.028
  40. Chem Biol Interact. 2024 Jan 03. pii: S0009-2797(24)00001-2. [Epub ahead of print] 110855
    Cannabinoids improve mitochondrial function in skeletal muscle of exhaustive exercise training rats by inhibiting mitophagy through the Pink1/Parkin and Bnip3 pathways.
    Juncheng Si, Lili Sun, Ying Qin, Lina Peng, Yongshan Gong, Chun Gao, Wenhui Shen, Mengqi Li.
      Cannabidiol (CBD) is a pure natural phytocannabinoid derived from cannabis that has anti-inflammatory, antiapoptotic and antioxidative stress abilities. In recent years, an increasing number of studies have reported the regulatory effect of CBD on skeletal muscle injury induced by exercise, but its mechanism is still unclear. Mitochondria are the main organelles responsible for the energy supply within eukaryotic cells, and their function has been closely linked to cellular health. Moderate exercise improves mitochondrial function, but the excessive exercise has a negative impact on mitochondria. Therefore, we speculate that CBD may promote exercise induced skeletal muscle cell damage by improving mitochondrial function. In this study, by establishing an animal model of exhaustive exercise training in rats, the effects of CBD on the protective effect of CBD on skeletal muscle mitochondrial structure and function was elaborated, and the possible molecular mechanism was discussed based on transcriptomics. Our results indicate that skeletal muscle mitochondrial structure and function were improved after CBD intervention. GO and KEGG pathway enrichment analysis showed that exhaustive exercise training induced mitochondrial dysfunction in skeletal muscle is associated with excessive autophagy/mitophagy, the signaling pathways involved in FOXO3 and GABARAPL1 may play important roles. After CBD intervention, the protein expression of Pink1, Parkin and Bnip3 was down-regulated, indicating that CBD may improve the mitochondrial function by inhibiting mitophagy through the Pink1/Parkin and Bnip3 pathway.
    Keywords:  Cannabinoid; Exhaustive exercise; Mitophagy; Skeletal muscle; Transcriptome
    DOI:  https://doi.org/10.1016/j.cbi.2024.110855
  41. Free Radic Biol Med. 2023 Dec 29. pii: S0891-5849(23)01191-7. [Epub ahead of print]212 241-254
    The solute carrier SLC25A17 sustains peroxisomal redox homeostasis in diverse mammalian cell lines.
    Cláudio F Costa, Celien Lismont, Serhii Chornyi, Janet Koster, Hongli Li, Mohamed A F Hussein, Paul P Van Veldhoven, Hans R Waterham, Marc Fransen.
      Despite the crucial role of peroxisomes in cellular redox maintenance, little is known about how these organelles transport redox metabolites across their membrane. In this study, we sought to assess potential associations between the cellular redox landscape and the human peroxisomal solute carrier SLC25A17, also known as PMP34. This carrier has been reported to function as a counter-exchanger of adenine-containing cofactors such as coenzyme A (CoA), dephospho-CoA, flavin adenine dinucleotide, nicotinamide adenine dinucleotide (NAD+), adenosine 3',5'-diphosphate, flavin mononucleotide, and adenosine monophosphate. We found that inactivation of SLC25A17 resulted in a shift toward a more reductive state in the glutathione redox couple (GSSG/GSH) across HEK-293 cells, HeLa cells, and SV40-transformed mouse embryonic fibroblasts, with variable impact on the NADPH levels and the NAD+/NADH redox couple. This phenotype could be rescued by the expression of Candida boidinii Pmp47, a putative SLC25A17 orthologue reported to be essential for the metabolism of medium-chain fatty acids in yeast peroxisomes. In addition, we provide evidence that the alterations in the redox state are not caused by changes in peroxisomal antioxidant enzyme expression, catalase activity, H2O2 membrane permeability, or mitochondrial fitness. Furthermore, treating control and ΔSLC25A17 cells with dehydroepiandrosterone, a commonly used glucose-6-phosphate dehydrogenase inhibitor affecting NADPH regeneration, revealed a kinetic disconnection between the peroxisomal and cytosolic glutathione pools. Additionally, these experiments underscored the impact of SLC25A17 loss on peroxisomal NADPH metabolism. The relevance of these findings is discussed in the context of the still ambiguous substrate specificity of SLC25A17 and the recent observation that the mammalian peroxisomal membrane is readily permeable to both GSH and GSSG.
    Keywords:  CoA; Glutathione; Metabolite transport; NADPH; PMP34; Peroxisomes; Redox compartmentalization; SLC25A17
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.035
  42. Int J Med Sci. 2024 ;21(2): 369-375
    NAD+-A Hub of Energy Metabolism in Heart Failure.
    Yaoxin Wu, Zuowei Pei, Peng Qu.
      Heart failure is a condition where reduced levels of adenosine triphosphate (ATP) affect energy supply in myocardial cells. Nicotinamide adenine dinucleotide (NAD+) plays a crucial role as a coenzyme for electron transfer in energy metabolism. Decreased NAD+ levels in myocardial cells lead to inadequate ATP production and increased susceptibility to heart failure. Researchers are exploring ways to increase NAD+ levels to alleviate heart failure. Targets such as sirtuin2 (sirt2), sirtuin3 (sirt3), Poly (ADP-ribose) polymerase (PARP), and diastolic regulatory proteins are being investigated. NAD+ supplementation has shown promise, even in heart failure with preserved ejection fraction (HFpEF). By focusing on NAD+ as a central component of energy metabolism, it is possible to improve myocardial activity, heart function, and address energy deficiency in heart failure.
    Keywords:  Energy Metabolism; Heart Failure; Mitochondria; NAD+
    DOI:  https://doi.org/10.7150/ijms.89370
  43. Mol Med. 2024 Jan 03. 30(1): 3
    A new physiological medium uncovers biochemical and cellular alterations in Lesch-Nyhan disease fibroblasts.
    Paula Escudero-Ferruz, Neus Ontiveros, Claudia Cano-Estrada, Diane J Sutcliffe, H A Jinnah, Rosa J Torres, José M López.
       BACKGROUND: Lesch-Nyhan disease (LND) is a severe neurological disorder caused by the genetic deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGprt), an enzyme involved in the salvage synthesis of purines. To compensate this deficiency, there is an acceleration of the de novo purine biosynthetic pathway. Most studies have failed to find any consistent abnormalities of purine nucleotides in cultured cells obtained from the patients. Recently, it has been shown that 5-aminoimidazole-4-carboxamide riboside 5'-monophosphate (ZMP), an intermediate of the de novo pathway, accumulates in LND fibroblasts maintained with RPMI containing physiological levels (25 nM) of folic acid (FA), which strongly differs from FA levels of regular cell culture media (2200 nM). However, RPMI and other standard media contain non-physiological levels of many nutrients, having a great impact in cell metabolism that does not precisely recapitulate the in vivo behavior of cells.
    METHODS: We prepared a new culture medium containing physiological levels of all nutrients, including vitamins (Plasmax-PV), to study the potential alterations of LND fibroblasts that may have been masked by the usage of non-physiological media. We quantified ZMP accumulation under different culture conditions and evaluated the activity of two known ZMP-target proteins (AMPK and ADSL), the mRNA expression of the folate carrier SLC19A1, possible mitochondrial alterations and functional consequences in LND fibroblasts.
    RESULTS: LND fibroblasts maintained with Plasmax-PV show metabolic adaptations such a higher glycolytic capacity, increased expression of the folate carrier SCL19A1, and functional alterations such a decreased mitochondrial potential and reduced cell migration compared to controls. These alterations can be reverted with high levels of folic acid, suggesting that folic acid supplements might be a potential treatment for LND.
    CONCLUSIONS: A complete physiological cell culture medium reveals new alterations in Lesch-Nyhan disease. This work emphasizes the importance of using physiological cell culture conditions when studying a metabolic disorder.
    Keywords:  AICAR; Folic acid; Lesch-Nyhan disease; Plasmax; Purine nucleotides; ZMP
    DOI:  https://doi.org/10.1186/s10020-023-00774-8
  44. Front Cell Dev Biol. 2023 ;11 1302585
    Toolkit for cellular studies of mammalian mitochondrial inorganic polyphosphate.
    Vedangi Hambardikar, Yaw A Akosah, Ernest R Scoma, Mariona Guitart-Mampel, Pedro Urquiza, Renata T Da Costa, Matheus M Perez, Lindsey M Riggs, Rajesh Patel, Maria E Solesio.
      Introduction: Inorganic polyphosphate (polyP) is an ancient polymer which is extremely well-conserved throughout evolution, and found in every studied organism. PolyP is composed of orthophosphates linked together by high-energy bonds, similar to those found in ATP. The metabolism and the functions of polyP in prokaryotes and simple eukaryotes are well understood. However, little is known about its physiological roles in mammalian cells, mostly due to its unknown metabolism and lack of systematic methods and effective models for the study of polyP in these organisms. Methods: Here, we present a comprehensive set of genetically modified cellular models to study mammalian polyP. Specifically, we focus our studies on mitochondrial polyP, as previous studies have shown the potent regulatory role of mammalian polyP in the organelle, including bioenergetics, via mechanisms that are not yet fully understood. Results: Using SH-SY5Y cells, our results show that the enzymatic depletion of mitochondrial polyP affects the expression of genes involved in the maintenance of mitochondrial physiology, as well as the structure of the organelle. Furthermore, this depletion has deleterious effects on mitochondrial respiration, an effect that is dependent on the length of polyP. Our results also show that the depletion of mammalian polyP in other subcellular locations induces significant changes in gene expression and bioenergetics; as well as that SH-SY5Y cells are not viable when the amount and/or the length of polyP are increased in mitochondria. Discussion: Our findings expand on the crucial role of polyP in mammalian mitochondrial physiology and place our cell lines as a valid model to increase our knowledge of both mammalian polyP and mitochondrial physiology.
    Keywords:  bioenergetics; inorganic polyphosphate; mammalian cells; mitochondria; polyP; toolkit
    DOI:  https://doi.org/10.3389/fcell.2023.1302585
  45. Genome Biol. 2024 Jan 02. 25(1): 3
    FORGEdb: a tool for identifying candidate functional variants and uncovering target genes and mechanisms for complex diseases.
    Charles E Breeze, Eric Haugen, María Gutierrez-Arcelus, Xiaozheng Yao, Andrew Teschendorff, Stephan Beck, Ian Dunham, John Stamatoyannopoulos, Nora Franceschini, Mitchell J Machiela, Sonja I Berndt.
      The majority of disease-associated variants identified through genome-wide association studies are located outside of protein-coding regions. Prioritizing candidate regulatory variants and gene targets to identify potential biological mechanisms for further functional experiments can be challenging. To address this challenge, we developed FORGEdb ( https://forgedb.cancer.gov/ ; https://forge2.altiusinstitute.org/files/forgedb.html ; and https://doi.org/10.5281/zenodo.10067458 ), a standalone and web-based tool that integrates multiple datasets, delivering information on associated regulatory elements, transcription factor binding sites, and target genes for over 37 million variants. FORGEdb scores provide researchers with a quantitative assessment of the relative importance of each variant for targeted functional experiments.
    Keywords:  Activity-by-contact (ABC); CRISPR (clustered regularly interspaced short palindromic repeats); DNase-seq; Expression quantitative trait locus (eQTL); Functional annotation; Gene regulation; Genome-wide association study (GWAS); Massively parallel reporter assay (MPRA); Regulatory elements; Single guide RNA (sgRNA); Transcription factor (TF); Variant scoring
    DOI:  https://doi.org/10.1186/s13059-023-03126-1
  46. EBioMedicine. 2024 Jan 01. pii: S2352-3964(23)00477-2. [Epub ahead of print]99 104911
    Multiomic analysis in fibroblasts of patients with inborn errors of cobalmin metabolism reveals concordance with clinical and metabolic variability.
    Arnaud Wiedemann, Abderrahim Oussalah, Rosa-Maria Guéant Rodriguez, Elise Jeannesson, Marc Mertens, Irina Rotaru, Jean-Marc Alberto, Okan Baspinar, Charif Rashka, Ziad Hassan, Youssef Siblini, Karim Matmat, Manon Jeandel, Celine Chery, Aurélie Robert, Guillaume Chevreux, Laurent Lignières, Jean-Michel Camadro, François Feillet, David Coelho, Jean-Louis Guéant.
       BACKGROUND: The high variability in clinical and metabolic presentations of inborn errors of cobalamin (cbl) metabolism (IECM), such as the cblC/epicblC types with combined deficits in methylmalonyl-coA mutase (MUT) and methionine synthase (MS), are not well understood. They could be explained by the impaired expression/activity of enzymes from other metabolic pathways.
    METHODS: We performed metabolomic, genomic, proteomic, and post-translational modification (PTM) analyses in fibroblasts from three cblC cases and one epi-cblC case compared with three cblG cases with specific MS deficits and control fibroblasts.
    FINDINGS: CblC patients had metabolic profilings consistent with altered urea cycle, glycine, and energy mitochondrial metabolism. Metabolomic analysis showed partial disruption and increased glutamate/ketoglutarate anaplerotic pathway of the tricarboxylic acid cycle (TCA), in patient fibroblasts. RNA-seq analysis showed decreased expression of MT-TT (mitochondrial tRNA threonine), MT-TP (mitochondrial tRNA proline), OXCT1 (succinyl CoA:3-oxoacid CoA transferase deficiency), and MT-CO1 (cytochrome C oxidase subunit 1). Proteomic changes were observed for key mitochondrial enzymes, including NADH:ubiquinone oxidoreductase subunit A8 (NDUFA8), carnitine palmitoyltransferase 2 (CPT2), and ubiquinol-cytochrome C reductase, complex III subunit X (UQCR10). Propionaldehyde addition in ornithine aminotransferase was the predominant PTM in cblC cells and could be related with the dramatic cellular increase in propionate and methylglyoxalate. It is consistent with the decreased concentration of ornithine reported in 3 cblC cases. Whether the changes detected after multi-omic analyses underlies clinical features in cblC and cblG types of IECM, such as peripheral and central neuropathy, cardiomyopathy, pulmonary hypertension, development delay, remains to be investigated.
    INTERPRETATION: The omics-related effects of IECM on other enzymes and metabolic pathways are consistent with the diversity and variability of their age-related metabolic and clinical manifestations. PTMs are expected to produce cumulative effects, which could explain the influence of age on neurological manifestations.
    FUNDING: French Agence Nationale de la Recherche (Projects PREDICTS and EpiGONE) and Inserm.
    Keywords:  Inborn errors of metabolism; MMACHC; Methionine synthase; Methylmalonyl-CoA mutase; One-carbon metabolism; Vitamin B12 deficiency
    DOI:  https://doi.org/10.1016/j.ebiom.2023.104911
  47. Genet Med. 2023 Dec 29. pii: S1098-3600(23)01074-2. [Epub ahead of print] 101058
    The cost of proband and trio exome and genome analysis in rare disease: a micro-costing study.
    Dylan A Mordaunt, Francisco Santos Gonzalez, Sebastian Lunke, Stefanie Eggers, Simon Sadedin, Belinda Chong, Kim Dalziel, Zornitza Stark, Ilias Goranitis.
       INTRODUCTION: Rare disease genomic testing is a complex process involving various resources. Accurate resource estimation is required for informed prioritization and reimbursement decisions. This study aims to analyze the costs and cost drivers of clinical genomic testing.
    METHODS: Based on genomic sequencing workflows we microcosted limited virtual panel analysis on exome sequencing (ES) backbone, proband and trio exome (ES-P and ES-T) and genome testing for proband and trio analysis (GS-P and GS-T) in 2023 Australian Dollars ($). Deterministic and probabilistic sensitivity analyses were undertaken.
    RESULTS: Panel testing costs AUD $2,373 ($733 - 6,166), and exome sequencing costs $2,823 ($802-$7,206) and $5,670 ($2,006-$11,539) for proband and trio analysis respectively. Genome sequencing (GS) costs $4,840 ($2,153-$9,890) and $11,589 ($5,842-$16,562) for proband and trio analysis. The most expensive cost component of genomic testing was sequencing (36.9% - 69.4% of total cost), with labor accounting for 27.1% - 63.2% of total cost.
    CONCLUSION: We provide a comprehensive analysis of rare disease genomic testing costs, for a range of clinical testing types and contexts. This information will accurately inform economic evaluations of rare disease genomic testing and decision-making on policy settings that assist with implementation, such as genomic testing reimbursement.
    Keywords:  Genomics; Health Policy; Healthcare Financing; Microcosting; Rare Disease; Reimbursement
    DOI:  https://doi.org/10.1016/j.gim.2023.101058
  48. F1000Res. 2022 ;11 645
    eXNVerify: coverage analysis for long and short-read sequencing data in clinical context.
    Sebastian Porębski, Tomasz Stokowy.
      Accurate identification of genetic variants to a large extent is based on the type of experimental technology, quality of the material and coverage of sequencing data obtained. The latter, coverage quality, highly influences variant calling accuracy and final diagnosis. Our motivation was to create a tool that will evaluate genome coverage and accelerate the introduction of long-read sequencing to medical diagnostics and clinical practice. The implementation was guided by the ease of use of the tool by users who are not proficient in using complex software. A Docker container is perfect for this purpose. Using Docker's advantages (flexibility, mobility and ease of use of the proposed tools), we created eXNVerify. This is a tool for inspection of clinical data in the context of pathogenic variants search. The tool calculates clinical depth coverage (CDC) - a measure of coverage which we introduce to evaluate loci with pathogenic germline and somatic variants reported in ClinVar. The tool additionally provides visualization options for user-defined genes of interest. Finally, we present examples of BRCA1, TP53, CFTR application and results of a test conducted in the Extensive Sequence Dataset of Gold-Standard Samples for Benchmarking and Development. eXNVerify improves the diagnostic process of patients related to important genetic diseases and facilitates the assessment of genetic samples by diagnosticians. The use of Docker allows to run an analysis package and does not require any special technical preparation. Detailed examples are included in the GitHub project documentation and the package can be downloaded directly from DockerHub using the command: docker pull porebskis/exnverify:1.0.
    Keywords:  long-read technology; sequencing coverage; single nucleotide variants; whole genome sequencing
    DOI:  https://doi.org/10.12688/f1000research.121775.1
  49. Redox Biol. 2023 Dec 25. pii: S2213-2317(23)00415-9. [Epub ahead of print]69 103014
    Loss of cardiac mitochondrial complex I persulfidation impairs NAD+ homeostasis in aging.
    Maria-Kyriaki Drekolia, Christina Karantanou, Ilka Wittig, Yuanyuan Li, Dominik C Fuhrmann, Bernhard Brüne, Antonia Katsouda, Jiong Hu, Andreas Papapetropoulos, Sofia-Iris Bibli.
      Protein persulfidation is a significant post-translational modification that involves addition of a sulfur atom to the cysteine thiol group and is facilitated by sulfide species. Persulfidation targets reactive cysteine residues within proteins, influencing their structure and/or function across various biological systems. This modification is evolutionarily conserved and plays a crucial role in preventing irreversible cysteine overoxidation, a process that becomes prominent with aging. While, persulfidation decreases with age, its levels in the aged heart and the functional implications of such a reduction in cardiac metabolism remain unknown. Here we interrogated the cardiac persulfydome in wild-type adult mice and age-matched mice lacking the two sulfide generating enzymes, namely cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3MST). Our findings revealed that cardiac persulfidated proteins in wild type hearts are less abundant compared to those in other organs, with a primary involvement in mitochondrial metabolic processes. We further focused on one specific target, NDUFB7, which undergoes persulfidation by both CSE and 3MST derived sulfide species. In particular, persulfidation of cysteines C80 and C90 in NDUFB7 protects the protein from overoxidation and maintains the complex I activity in cardiomyocytes. As the heart ages, the levels of CSE and 3MST in cardiomyocytes decline, leading to reduced NDUFB7 persulfidation and increased cardiac NADH/NAD+ ratio. Collectively, our data provide compelling evidence for a direct link between cardiac persulfidation and mitochondrial complex I activity, which is compromised in aging.
    Keywords:  3MST; CSE; Cardiac aging; NDUFB7; Persulfidation
    DOI:  https://doi.org/10.1016/j.redox.2023.103014
  50. ACS Omega. 2023 Dec 26. 8(51): 48984-48993
    Engineering Exosomes to Specifically Target the Mitochondria of Brain Cells.
    Xin Yan, Xinqian Chen, Zhiying Shan, Lanrong Bi.
      Mitochondrial dysfunction is associated with various health conditions, including cardiovascular and neurodegenerative diseases. Mitochondrial-targeting therapy aims to restore or enhance mitochondrial function to treat or alleviate these conditions. Exosomes, small vesicles that cells secrete, containing a variety of biomolecules, are critical in cell-to-cell communication and have been studied as potential therapeutic agents. Exosome-based therapy has the potential to treat both cardiovascular and neurodegenerative diseases. Combining these two approaches involves using exosomes as carriers to transport mitochondrial-targeting agents to dysfunctional or damaged mitochondria within target cells. This article presents a new technique for engineering brain-derived exosomes that target mitochondria and has demonstrated promise in initial tests with primary neuron cells and healthy rats. This promising development represents a significant step forward in treating these debilitating conditions.
    DOI:  https://doi.org/10.1021/acsomega.3c06617
  51. Immunity. 2023 Dec 27. pii: S1074-7613(23)00533-2. [Epub ahead of print]
    Trem2 expression in microglia is required to maintain normal neuronal bioenergetics during development.
    Erica Tagliatti, Genni Desiato, Sara Mancinelli, Matteo Bizzotto, Maria C Gagliani, Elisa Faggiani, Rebeca Hernández-Soto, Andrea Cugurra, Paola Poliseno, Matteo Miotto, Rafael J Argüello, Fabia Filipello, Katia Cortese, Raffaella Morini, Simona Lodato, Michela Matteoli.
      Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in brain microglia, with variants that are associated with neurodegenerative diseases, including Alzheimer's disease. Trem2 is essential for microglia-mediated synaptic refinement, but whether Trem2 contributes to shaping neuronal development remains unclear. Here, we demonstrate that Trem2 plays a key role in controlling the bioenergetic profile of pyramidal neurons during development. In the absence of Trem2, developing neurons in the hippocampal cornus ammonis (CA)1 but not in CA3 subfield displayed compromised energetic metabolism, accompanied by reduced mitochondrial mass and abnormal organelle ultrastructure. This was paralleled by the transcriptional rearrangement of hippocampal pyramidal neurons at birth, with a pervasive alteration of metabolic, oxidative phosphorylation, and mitochondrial gene signatures, accompanied by a delay in the maturation of CA1 neurons. Our results unveil a role of Trem2 in controlling neuronal development by regulating the metabolic fitness of neurons in a region-specific manner.
    Keywords:  TREM2; hippocampus; metabolism; microglia; mitochondria; neurodevelopment
    DOI:  https://doi.org/10.1016/j.immuni.2023.12.002
  52. bioRxiv. 2023 Dec 15. pii: 2023.12.15.571893. [Epub ahead of print]
    Selected humanization of yeast U1 snRNP leads to global suppression of pre-mRNA splicing and mitochondrial dysfunction in the budding yeast.
    Subbaiah Chalivendra, Shasha Shi, Xueni Li, Zhiling Kuang, Joseph Giovinazzo, Lingdi Zhang, John Rossi, Anthony J Saviola, Jingxin Wang, Robb Welty, Shiheng Liu, Katherine Vaeth, Z Hong Zhou, Kirk C Hansen, J Matthew Taliaferro, Rui Zhao.
      The recognition of 5' splice site (5' ss) is one of the earliest steps of pre-mRNA splicing. To better understand the mechanism and regulation of 5' ss recognition, we selectively humanized components of the yeast U1 snRNP to reveal the function of these components in 5' ss recognition and splicing. We targeted U1C and Luc7, two proteins that interact with and stabilize the yeast U1 (yU1) snRNA and the 5' ss RNA duplex. We replaced the Zinc-Finger (ZnF) domain of yU1C with its human counterpart, which resulted in cold-sensitive growth phenotype and moderate splicing defects. Next, we added an auxin-inducible degron to yLuc7 protein and found that Luc7-depleted yU1 snRNP resulted in the concomitant loss of PRP40 and Snu71 (two other essential yeast U1 snRNP proteins), and further biochemical analyses suggest a model of how these three proteins interact with each other in the U1 snRNP. The loss of these proteins resulted in a significant growth retardation accompanied by a global suppression of pre-mRNA splicing. The splicing suppression led to mitochondrial dysfunction as revealed by a release of Fe 2+ into the growth medium and an induction of mitochondrial reactive oxygen species. Together, these observations indicate that the human U1C ZnF can substitute that of yeast, Luc7 is essential for the incorporation of the Luc7-Prp40-Snu71 trimer into yeast U1 snRNP, and splicing plays a major role in the regulation of mitochondria function in yeast.
    DOI:  https://doi.org/10.1101/2023.12.15.571893
  53. Nat Biotechnol. 2024 Jan 02.
    Detection of mosaic and population-level structural variants with Sniffles2.
    Moritz Smolka, Luis F Paulin, Christopher M Grochowski, Dominic W Horner, Medhat Mahmoud, Sairam Behera, Ester Kalef-Ezra, Mira Gandhi, Karl Hong, Davut Pehlivan, Sonja W Scholz, Claudia M B Carvalho, Christos Proukakis, Fritz J Sedlazeck.
      Calling structural variations (SVs) is technically challenging, but using long reads remains the most accurate way to identify complex genomic alterations. Here we present Sniffles2, which improves over current methods by implementing a repeat aware clustering coupled with a fast consensus sequence and coverage-adaptive filtering. Sniffles2 is 11.8 times faster and 29% more accurate than state-of-the-art SV callers across different coverages (5-50×), sequencing technologies (ONT and HiFi) and SV types. Furthermore, Sniffles2 solves the problem of family-level to population-level SV calling to produce fully genotyped VCF files. Across 11 probands, we accurately identified causative SVs around MECP2, including highly complex alleles with three overlapping SVs. Sniffles2 also enables the detection of mosaic SVs in bulk long-read data. As a result, we identified multiple mosaic SVs in brain tissue from a patient with multiple system atrophy. The identified SV showed a remarkable diversity within the cingulate cortex, impacting both genes involved in neuron function and repetitive elements.
    DOI:  https://doi.org/10.1038/s41587-023-02024-y
  54. Nucleic Acids Res. 2024 Jan 05. 52(D1): D1143-D1154
    CADD v1.7: using protein language models, regulatory CNNs and other nucleotide-level scores to improve genome-wide variant predictions.
    Max Schubach, Thorben Maass, Lusiné Nazaretyan, Sebastian Röner, Martin Kircher.
      Machine Learning-based scoring and classification of genetic variants aids the assessment of clinical findings and is employed to prioritize variants in diverse genetic studies and analyses. Combined Annotation-Dependent Depletion (CADD) is one of the first methods for the genome-wide prioritization of variants across different molecular functions and has been continuously developed and improved since its original publication. Here, we present our most recent release, CADD v1.7. We explored and integrated new annotation features, among them state-of-the-art protein language model scores (Meta ESM-1v), regulatory variant effect predictions (from sequence-based convolutional neural networks) and sequence conservation scores (Zoonomia). We evaluated the new version on data sets derived from ClinVar, ExAC/gnomAD and 1000 Genomes variants. For coding effects, we tested CADD on 31 Deep Mutational Scanning (DMS) data sets from ProteinGym and, for regulatory effect prediction, we used saturation mutagenesis reporter assay data of promoter and enhancer sequences. The inclusion of new features further improved the overall performance of CADD. As with previous releases, all data sets, genome-wide CADD v1.7 scores, scripts for on-site scoring and an easy-to-use webserver are readily provided via https://cadd.bihealth.org/ or https://cadd.gs.washington.edu/ to the community.
    DOI:  https://doi.org/10.1093/nar/gkad989
  55. Genomics. 2023 Dec 27. pii: S0888-7543(23)00217-3. [Epub ahead of print]116(1): 110773
    Multiple omics analysis reveals the regulation of SIRT5 on mitochondrial function and lipid metabolism during the differentiation of bovine preadipocytes.
    Jieyun Hong, Sayed Haidar Abbas Raza, Hongming Ma, Weina Cao, Yuqing Chong, Jiao Wu, Dongmei Xi, Weidong Deng.
      Preadipocyte differentiation represents a critical stage in adipogenesis, with mitochondria playing an undeniable pivotal role. Given the intricate interplay between transcription and metabolic signaling during adipogenesis, the regulation of sirtuin 5 (SIRT5) on mitochondrial function and lipid metabolism was revealed via multiple omics analysis. The findings suggest that SIRT5 plays a crucial role in promoting mitochondrial biosynthesis and maintaining mitochondrial function during preadipocyte differentiation. Moreover, SIRT5 modulates the metabolic levels of numerous bioactive substances by extensively regulating genes expression associated with differentiation, energy metabolism, lipid synthesis, and mitochondrial function. Finally, SIRT5 was found to suppress triacylglycerols (TAG) accumulation while enhancing the proportion and diversity of unsaturated fatty acids, and providing conditions for the expansion and stability of membrane structure during mitochondrial biosynthesis through numerous gene regulations. Our findings provide a foundation for the identification of crucial functional genes, signaling pathways, and metabolic substances associated with adipose tissue differentiation and metabolism.
    Keywords:  Bovine; Lipid metabolism; Mitochondrial function; Multiple omics analysis; Preadipocyte differentiation; SIRT5
    DOI:  https://doi.org/10.1016/j.ygeno.2023.110773
  56. Res Sq. 2023 Dec 13. pii: rs.3.rs-3699740. [Epub ahead of print]
    Reducing Time to Diagnosis of Rare Genetic Diseases in a Medically Underserved Hispanic Population- Lessons Learned for Meaningful Engagement.
    Blake Vuocolo, Roberta Sierra, Dan Brooks, Christopher Holder, Lauren Urbanski, Keila Rodriguez, Jose David Gamez, Surya Narayan Mulukutla, Lori Berry, Ana Hernandez, Alberto Allegre, Humberto Hidalgo, Sarah Rodriguez, Sandy Magallan, Jeremy Gibson, Juan Carlos Bernini, Melanie Watson, Robert Nelson, Lizbeth Mellin-Sanchez, Hongzheng Dai, Claudia Soler-Alfonso, Kent Carter, Brendan Lee, Seema R Lalani.
      Background The utilization of genomic information to improve health outcomes is progressively becoming more common in clinical practice. Nonetheless, disparities persist in accessing genetic services among ethnic minorities, individuals with low socioeconomic status, and other vulnerable populations. The Rio Grande Valley at the Texas-Mexico border is predominantly Hispanic with a high poverty rate and an increased prevalence of birth defects, with very limited access to genetics services. The cost of a diagnosis is often times out of reach for these underserved families. Funded by the National Center for Advancing Translational Sciences (NCATS), Project GIVE ( G enetic I nclusion by V irtual E valuation) was launched in 2022 to shorten the time to diagnosis and alleviate healthcare inequities in this region, with the goal of improving pediatric health outcomes. Methods Utilizing Consultagene, an innovative electronic health record (EHR) agnostic virtual telehealth and educational platform, we designed the study to recruit 100 children with rare diseases over a period of two years from this region, through peer-to-peer consultation and referral. Conclusions Project GIVE study has allowed advanced genetic evaluation and delivery of genome sequencing through the virtual portal, effectively circumventing the recognized socioeconomic and other barriers within this population. This paper explores the successful community engagement process and implementation of an alternate genomics evaluation platform and testing approach, aiming to reduce the diagnostic journey for individuals with rare diseases residing in a medically underserved region.
    DOI:  https://doi.org/10.21203/rs.3.rs-3699740/v1
  57. Front Mol Biosci. 2023 ;10 1332658
    Potential roles for mitochondria-to-HSF1 signaling in health and disease.
    Johnathan Labbadia.
      The ability to respond rapidly and efficiently to protein misfolding is crucial for development, reproduction and long-term health. Cells respond to imbalances in cytosolic/nuclear protein homeostasis through the Heat Shock Response, a tightly regulated transcriptional program that enhances protein homeostasis capacity by increasing levels of protein quality control factors. The Heat Shock Response is driven by Heat Shock Factor 1, which is rapidly activated by the appearance of misfolded proteins and drives the expression of genes encoding molecular chaperones and protein degradation factors, thereby restoring proteome integrity. HSF1 is critical for organismal health, and this has largely been attributed to the preservation of cytosolic and nuclear protein homeostasis. However, evidence is now emerging that HSF1 is also a key mediator of mitochondrial function, raising the possibility that many of the health benefits conferred by HSF1 may be due to the maintenance of mitochondrial homeostasis. In this review, I will discuss our current understanding of the interplay between HSF1 and mitochondria and consider how mitochondria-to-HSF1 signaling may influence health and disease susceptibility.
    Keywords:  HSF1; ageing; development; disease; mitochondria; protein homeostasis
    DOI:  https://doi.org/10.3389/fmolb.2023.1332658
  58. Comput Biol Med. 2024 Jan 02. pii: S0010-4825(24)00008-8. [Epub ahead of print]169 107924
    RDmaster: A novel phenotype-oriented dialogue system supporting differential diagnosis of rare disease.
    Jian Yang, Liqi Shu, Mingyu Han, Jiarong Pan, Lihua Chen, Tianming Yuan, Linhua Tan, Qiang Shu, Huilong Duan, Haomin Li.
       BACKGROUND: Clinicians often lack the necessary expertise to differentially diagnose multiple underlying rare diseases (RDs) due to their complex and overlapping clinical features, leading to misdiagnoses and delayed treatments. The aim of this study is to develop a novel electronic differential diagnostic support system for RDs.
    METHOD: Through integrating two Bayesian diagnostic methods, a candidate list was generated with enhance clinical interpretability for the further Q&A based differential diagnosis (DDX). To achieve an efficient Q&A dialogue strategy, we introduce a novel metric named the adaptive information gain and Gini index (AIGGI) to evaluate the expected gain of interrogated phenotypes within real-time diagnostic states.
    RESULTS: This DDX tool called RDmaster has been implemented as a web-based platform (http://rdmaster.nbscn.org/). A diagnostic trial involving 238 published RD patients revealed that RDmaster outperformed existing RD diagnostic tools, as well as ChatGPT, and was shown to enhance the diagnostic accuracy through its Q&A system.
    CONCLUSIONS: The RDmaster offers an effective multi-omics differential diagnostic technique and outperforms existing tools and popular large language models, particularly enhancing differential diagnosis in collecting diagnostically beneficial phenotypes.
    Keywords:  Differential diagnosis; Electronic differential diagnostic support system; Human phenotype ontology; Phenomic and genomic diagnostics; Rare disease
    DOI:  https://doi.org/10.1016/j.compbiomed.2024.107924
  59. Peptides. 2023 Dec 29. pii: S0196-9781(23)00212-7. [Epub ahead of print]172 171147
    Mitochondrial-derived peptides: Antidiabetic functions and evolutionary perspectives.
    Satadeepa Kal, Sumana Mahata, Suborno Jati, Sushil K Mahata.
      Mitochondrial-derived peptides (MDPs) are a novel class of bioactive microproteins encoded by short open-reading frames (sORF) in mitochondrial DNA (mtDNA). Currently, three types of MDPs have been identified: Humanin (HN), MOTS-c (Mitochondrial ORF within Twelve S rRNA type-c), and SHLP1-6 (small Humanin-like peptide, 1 to 6). The 12 S ribosomal RNA (MT-RNR1) gene harbors the sequence for MOTS-c, whereas HN and SHLP1-6 are encoded by the 16 S ribosomal RNA (MT-RNR2) gene. Special genetic codes are used in mtDNA as compared to nuclear DNA: (i) ATA and ATT are used as start codons in addition to the standard start codon ATG; (ii) AGA and AGG are used as stop codons instead of coding for arginine; (iii) the standard stop codon UGA is used to code for tryptophan. While HN, SHLP6, and MOTS-c are encoded by the H (heavy owing to high guanine + thymine base composition)-strand of the mtDNA, SHLP1-5 are encoded by the L (light owing to less guanine + thymine base composition)-strand. MDPs attenuate disease pathology including Type 1 diabetes (T1D), Type 2 diabetes (T2D), gestational diabetes, Alzheimer's disease (AD), cardiovascular diseases, prostate cancer, and macular degeneration. The current review will focus on the MDP regulation of T2D, T1D, and gestational diabetes along with an emphasis on the evolutionary pressures for conservation of the amino acid sequences of MDPs.
    Keywords:  Diabetes; Humanin; MOTS-c; Mitochondrial peptides; and small humanin-like peptides
    DOI:  https://doi.org/10.1016/j.peptides.2023.171147
  60. Cell Signal. 2024 Jan 03. pii: S0898-6568(24)00003-2. [Epub ahead of print] 111035
    Mitochondrial quality control in liver fibrosis: Epigenetic hallmarks and therapeutic strategies.
    Lin Jia, Yang Yang, Feng Sun, Hui Tao, Chao Lu, Jing-Jing Yang.
       BACKGROUND AND AIM: Mitochondrial quality control (MQC) plays a significant role in the progression of liver fibrosis, with key processes such as mitochondrial fission, fusion, mitophagy and biogenesis maintaining mitochondrial homeostasis. To understand the molecular mechanisms underlying epigenetic regulation of mitochondrial quality control in liver fibrosis, with the aim of uncovering novel therapeutic targets for treating, mitigating, and potentially reversing liver fibrosis, in light of the most recent advances in this field.
    METHODS: We searched PubMed, Web of Science, and Scopus for published manuscripts using terms "mitochondrial quality control" "mitochondrial fission" "mitochondrial fusion" "mitochondrial biogenesis" "mitophagy" "liver fibrosis" "epigenetic regulation" "DNA methylation" "RNA methylation" "histone modification" and "non-coding RNA". Manuscripts were collated, studied and carried forward for discussion where appropriate.
    RESULTS: Mitochondrial fission, fusion, biogenesis, and mitophagy regulate the homeostasis of mitochondria, and the imbalance of mitochondrial homeostasis can induce liver fibrosis. Epigenetic regulation, including DNA methylation, RNA methylation, histone modifications, and non-coding RNAs, plays a significant role in regulating the processes of mitochondrial homeostasis.
    CONCLUSION: Mitochondrial quality control and epigenetic mechanisms are intricately linked to the pathogenesis of liver fibrosis. Understanding these molecular interactions provides insight into potential therapeutic strategies. Further research is necessary to translate these findings into clinical applications, with a focus on developing epigenetic drugs to ameliorate liver fibrosis by modulating MQC and epigenetic pathways.
    Keywords:  Epigenetics; Liver fibrosis; Mitochondrial quality control; Molecular mechanisms
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111035
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