bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–09–15
forty-one papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Targeted protein degradation in the mitochondrial matrix and its application to chemical control of mitochondrial morphology.
  2. 26th Annual Symposium of the United Mitochondrial Disease Foundation -Mitochondrial Medicine 2023 - Abstracts.
  3. Variant load of mitochondrial DNA in single human mesenchymal stem cells.
  4. Novel imaging tools to study mitochondrial morphology in Caenorhabditis elegans.
  5. Visualizing mitochondrial dynamics at the nanoscale.
  6. CHCHD2 mutant mice display mitochondrial protein accumulation and disrupted energy metabolism.
  7. Organization of a functional glycolytic metabolon on mitochondria for metabolic efficiency.
  8. Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.
  9. Mitochondrial tRNAGlu 14693A>G Mutation, an "Enhancer" to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy.
  10. A promising therapeutic: Exosome-mediated mitochondrial transplantation.
  11. Robust Mitochondrial Isolation from Rodent Cardiac Tissue.
  12. Mitophagy protects against ferroptosis.
  13. Disruption of Mitochondrial Quality Control in Inherited Metabolic Disorders.
  14. Cascade testing in mitochondrial diseases: a cross-sectional retrospective study.
  15. Pregnancy in women with mitochondrial disease-A literature review and suggested guidance for preconception and pregnancy care.
  16. Mitochondrial STED Imaging and Membrane Potential Monitoring with a Cationic Molecular Probe.
  17. Disruption of nucleotide biosynthesis reprograms mitochondrial metabolism to inhibit adipogenesis.
  18. Role of Mitochondrial Dysfunctions in Neurodegenerative Disorders: Advances in Mitochondrial Biology.
  19. The multifaceted effects of mitochondria in kidney diseases.
  20. Unilateral Hearing Loss and Auditory Asymmetry in Mitochondrial Disease: A Scoping Review.
  21. Antibody conjugated targeted nanotherapy epigenetically inhibits calpain-mediated mitochondrial dysfunction to attenuate Parkinson's disease.
  22. Characterization of two iPSC lines from patients with maternally inherited leigh (MILS) and neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome carrying the MT-ATP6 m.8993 T>G mutation at different degrees of heteroplasmy.
  23. Akt1 deficiency does not affect fiber type composition or mitochondrial protein expression in skeletal muscle of male mice.
  24. Mitochondrial acyl carrier protein, Acp1, required for iron-sulfur cluster assembly in mitochondria and cytoplasm in Saccharomyces cerevisiae.
  25. Proteome dynamics in iPSC-derived human dopaminergic neurons.
  26. Neurodegenerative disorders, metabolic icebergs, and mitohormesis.
  27. Antisense Oligonucleotide STK-002 Increases OPA1 in Retina and Improves Mitochondrial Function in Autosomal Dominant Optic Atrophy Cells.
  28. Etomoxir repurposed as a promiscuous fatty acid mimetic chemoproteomic probe.
  29. Mitochondrial RNA cytosolic leakage drives the SASP.
  30. Non-coding variants are a rare cause of recessive developmental disorders in trans with coding variants.
  31. Spastin regulates ER-mitochondrial contact sites and mitochondrial homeostasis.
  32. Integrating digital gait data with metabolomics and clinical data to predict outcomes in Parkinson's disease.
  33. Astrocytic LRRK2 Controls Synaptic Connectivity via Regulation of ERM Phosphorylation.
  34. Ocular genetics in the Japanese population.
  35. Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells.
  36. CHCHD10P80L knock-in zebrafish display a mild ALS-like phenotype.
  37. Haplotype variability in mitochondrial rRNA predisposes to metabolic syndrome.
  38. Cell-to-cell tunnels rescue neurons from degeneration.
  39. Quinone chemistry in respiratory complex I involves protonation of a conserved aspartic acid residue.
  40. SUMOylation modulates mitochondrial dynamics in an in vitro rotenone model of Parkinson's disease.
  41. Case Report: Lethal mitochondrial cardiomyopathy linked to a compound heterozygous variant of PARS2.
  1. Chem Sci. 2024 Aug 28.
    Targeted protein degradation in the mitochondrial matrix and its application to chemical control of mitochondrial morphology.
    Wakana Yamada, Shusuke Tomoshige, Sho Nakamura, Shinichi Sato, Minoru Ishikawa.
      Dysfunction of mitochondria is implicated in various diseases, including cancer and neurodegenerative disorders, but drug discovery targeting mitochondria and mitochondrial proteins has so far made limited progress. Targeted protein degradation (TPD) technologies represented by proteolysis targeting chimeras (PROTACs) are potentially applicable for this purpose, but most existing TPD approaches leverage the ubiquitin-proteasome system or lysosomes, which are absent in mitochondria, and TPD in mitochondria (mitoTPD) remains little explored. Herein, we describe the design and synthesis of a bifunctional molecule comprising TR79, an activator of the mitochondrial protease complex caseinolytic protease P (ClpP), linked to desthiobiotin. This compound successfully induced the degradation of monomeric streptavidin (mSA) and its fusion proteins localized to the mitochondrial matrix. Furthermore, in cells overexpressing mSA fused to short transmembrane protein 1 (mSA-STMP1), which enhances mitochondrial fission, our mitochondrial mSA degrader restored the mitochondrial morphology by reducing the level of mSA-STMP1. A preliminary structure-activity relationship study indicated that a longer linker length enhances the degradation activity towards mSA. These findings highlight the potential of mitoTPD as a tool for drug discovery targeting mitochondria and for research in mitochondrial biology, as well as the utility of mSA as a degradation tag for mitochondrial protein.
    DOI:  https://doi.org/10.1039/d4sc03145h
  2. Ther Adv Rare Dis. 2023 Jan-Dec;4:4 26330040231199665
    26th Annual Symposium of the United Mitochondrial Disease Foundation -Mitochondrial Medicine 2023 - Abstracts.
      
    DOI:  https://doi.org/10.1177/26330040231199665
  3. Sci Rep. 2024 09 09. 14(1): 20989
    Variant load of mitochondrial DNA in single human mesenchymal stem cells.
    Daniel Hipps, Angela Pyle, Anna L R Porter, Philip F Dobson, Helen Tuppen, Conor Lawless, Oliver M Russell, Doug M Turnbull, David J Deehan, Gavin Hudson.
      Heteroplasmic mitochondrial DNA (mtDNA) variants accumulate as humans age, particularly in the stem-cell compartments, and are an important contributor to age-related disease. Mitochondrial dysfunction has been observed in osteoporosis and somatic mtDNA pathogenic variants have been observed in animal models of osteoporosis. However, this has never been assessed in the relevant human tissue. Mesenchymal stem cells (MSCs) are the progenitors to many cells of the musculoskeletal system and are critical to skeletal tissues and bone vitality. Investigating mtDNA in MSCs could provide novel insights into the role of mitochondrial dysfunction in osteoporosis. To determine if this is possible, we investigated the landscape of somatic mtDNA variation in MSCs through a combination of fluorescence-activated cell sorting and single-cell next-generation sequencing. Our data show that somatic heteroplasmic variants are present in individual patient-derived MSCs, can reach high heteroplasmic fractions and have the potential to be pathogenic. The identification of somatic heteroplasmic variants in MSCs of patients highlights the potential for mitochondrial dysfunction to contribute to the pathogenesis of osteoporosis.
    Keywords:  Bone disease; Mesenchymal stem cells; Osteoporosis; Somatic mtDNA variation
    DOI:  https://doi.org/10.1038/s41598-024-71822-4
  4. Life Sci Alliance. 2024 Nov;pii: e202402918. [Epub ahead of print]7(11):
    Novel imaging tools to study mitochondrial morphology in Caenorhabditis elegans.
    Miriam Valera-Alberni, Pallas Yao, Silvia Romero-Sanz, Anne Lanjuin, William B Mair.
      Mitochondria exhibit a close interplay between their structure and function. Understanding this intricate relationship requires advanced imaging techniques that can capture the dynamic nature of mitochondria and their impact on cellular processes. However, much of the work on mitochondrial dynamics has been performed in single celled organisms or in vitro cell culture. Here, we introduce novel genetic tools for live imaging of mitochondrial morphology in the nematode Caenorhabditis elegans, addressing a pressing need for advanced techniques in studying organelle dynamics within live intact multicellular organisms. Through a comprehensive analysis, we directly compare our tools with existing methods, demonstrating their advantages for visualizing mitochondrial morphology and contrasting their impact on organismal physiology. We reveal limitations of conventional techniques, whereas showcasing the utility and versatility of our approaches, including endogenous CRISPR tags and ectopic labeling. By providing a guide for selecting the most suitable tools based on experimental goals, our work advances mitochondrial research in C. elegans and enhances the strategic integration of diverse imaging modalities for a holistic understanding of organelle dynamics in living organisms.
    DOI:  https://doi.org/10.26508/lsa.202402918
  5. Light Sci Appl. 2024 Sep 09. 13(1): 244
    Visualizing mitochondrial dynamics at the nanoscale.
    Till Stephan, Peter Ilgen, Stefan Jakobs.
      The study of mitochondria is a formidable challenge for super-resolution microscopy due to their dynamic nature and complex membrane architecture. In this issue, Ren et al. introduce HBmito Crimson, a fluorogenic and photostable mitochondrial probe for STED microscopy and investigate how mitochondrial dynamics influence the spatial organization of mitochondrial DNA.
    DOI:  https://doi.org/10.1038/s41377-024-01582-3
  6. bioRxiv. 2024 Aug 31. pii: 2024.08.30.610586. [Epub ahead of print]
    CHCHD2 mutant mice display mitochondrial protein accumulation and disrupted energy metabolism.
    Szu-Chi Liao, Kohei Kano, Sadhna Phanse, Mai Nguyen, Elyssa Margolis, YuHong Fu, Jonathan Meng, Mohamed Taha Moutaoufik, Zac Chatterton, Hiroyuki Aoki, Jeffrey Simms, Ivy Hsieh, Felecia Suteja, Yoshitaka Sei, Eric J Huang, Kevin McAvoy, Giovanni Manfredi, Glenda Halliday, Mohan Babu, Ken Nakamura.
      Mutations in the mitochondrial cristae protein CHCHD2 lead to a late-onset autosomal dominant form of Parkinson's disease (PD) which closely resembles idiopathic PD, providing the opportunity to gain new insights into the mechanisms of mitochondrial dysfunction contributing to PD. To begin to address this, we used CRISPR genome-editing to generate CHCHD2 T61I point mutant mice. CHCHD2 T61I mice had normal viability, and had only subtle motor deficits with no signs of premature dopaminergic (DA) neuron degeneration. Nonetheless, CHCHD2 T61I mice exhibited robust molecular changes in the brain including increased CHCHD2 insolubility, accumulation of CHCHD2 protein preferentially in the substantia nigra (SN), and elevated levels of α-synuclein. Metabolic analyses revealed an increase in glucose metabolism through glycolysis relative to the TCA cycle with increased respiratory exchange ratio, and immune-electron microscopy revelated disrupted mitochondria in DA neurons. Moreover, spatial genomics revealed decreased expression of mitochondrial complex I and III respiratory chain proteins, while proteomics revealed increased respiratory chain and other mitochondrial protein-protein interactions. As such, the CHCHD2 T61I point-mutation mice exhibit robust mitochondrial disruption and a consequent metabolic shift towards glycolysis. These findings thus establish CHCHD2 T61I mice as a new model for mitochondrial-based PD, and implicate disrupted respiratory chain function as a likely causative driver.
    DOI:  https://doi.org/10.1101/2024.08.30.610586
  7. Nat Metab. 2024 Sep 11.
    Organization of a functional glycolytic metabolon on mitochondria for metabolic efficiency.
    Haoming Wang, John W Vant, Andrew Zhang, Richard G Sanchez, Youjun Wu, Mary L Micou, Vincent Luczak, Zachary Whiddon, Natasha M Carlson, Seungyoon B Yu, Mirna Jabbo, Seokjun Yoon, Ahmed A Abushawish, Majid Ghassemian, Takeya Masubuchi, Quan Gan, Shigeki Watanabe, Eric R Griffis, Marc Hammarlund, Abhishek Singharoy, Gulcin Pekkurnaz.
      Glucose, the primary cellular energy source, is metabolized through glycolysis initiated by the rate-limiting enzyme hexokinase (HK). In energy-demanding tissues like the brain, HK1 is the dominant isoform, primarily localized on mitochondria, and is crucial for efficient glycolysis-oxidative phosphorylation coupling and optimal energy generation. This study unveils a unique mechanism regulating HK1 activity, glycolysis and the dynamics of mitochondrial coupling, mediated by the metabolic sensor enzyme O-GlcNAc transferase (OGT). OGT catalyses reversible O-GlcNAcylation, a post-translational modification influenced by glucose flux. Elevated OGT activity induces dynamic O-GlcNAcylation of the regulatory domain of HK1, subsequently promoting the assembly of the glycolytic metabolon on the outer mitochondrial membrane. This modification enhances the mitochondrial association with HK1, orchestrating glycolytic and mitochondrial ATP production. Mutation in HK1's O-GlcNAcylation site reduces ATP generation in multiple cell types, specifically affecting metabolic efficiency in neurons. This study reveals a previously unappreciated pathway that links neuronal metabolism and mitochondrial function through OGT and the formation of the glycolytic metabolon, providing potential strategies for tackling metabolic and neurological disorders.
    DOI:  https://doi.org/10.1038/s42255-024-01121-9
  8. EMBO J. 2024 Sep 11.
    Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.
    Hilda Delgado de la Herran, Denis Vecellio Reane, Yiming Cheng, Máté Katona, Fabian Hosp, Elisa Greotti, Jennifer Wettmarshausen, Maria Patron, Hermine Mohr, Natalia Prudente de Mello, Margarita Chudenkova, Matteo Gorza, Safal Walia, Michael Sheng-Fu Feng, Anja Leimpek, Dirk Mielenz, Natalia S Pellegata, Thomas Langer, György Hajnóczky, Matthias Mann, Marta Murgia, Fabiana Perocchi.
      The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake. We identify 89 high-confidence interactors that link MCUC to several mitochondrial complexes and pathways, half of which are associated with human disease. As a proof-of-concept, we validate the mitochondrial intermembrane space protein EFHD1 as a binding partner of the MCUC subunits MCU, EMRE, and MCUB. We further show a MICU1-dependent inhibitory effect of EFHD1 on calcium uptake. Next, we systematically survey compensatory mechanisms and functional consequences of mitochondrial calcium dyshomeostasis by analyzing the MCU interactome upon EMRE, MCUB, MICU1, or MICU2 knockdown. While silencing EMRE reduces MCU interconnectivity, MCUB loss-of-function leads to a wider interaction network. Our study provides a comprehensive and high-confidence resource to gain insights into players and mechanisms regulating mitochondrial calcium signaling and their relevance in human diseases.
    Keywords:  Calcium Signaling; Mitochondria; Mitochondrial Calcium Uniporter; Organelle; Proteomics
    DOI:  https://doi.org/10.1038/s44318-024-00219-w
  9. Adv Sci (Weinh). 2024 Sep 12. e2401856
    Mitochondrial tRNAGlu 14693A>G Mutation, an "Enhancer" to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy.
    Lihao Jin, Dingyi Gan, Wentao He, Na Wu, Shuchenlu Xiang, Yinsheng Wei, Gilbert Eriani, Yanchun Ji, Min-Xin Guan, Meng Wang.
      Leber's hereditary optic neuropathy (LHON), a maternally inherited ocular disease, is predominantly caused by mitochondrial DNA (mtDNA) mutations. Mitochondrial tRNA variants are hypothesized to amplify the pathogenic impact of three primary mutations. However, the exact mechanisms remained unclear. In the present study, the synergistic effect of the tRNAGlu 14693A>G and ND6 14484T>C mutations in three Chinese families affected by LHON is investigated. The m.14693A>G mutation nearly abolishes the pseudouridinylation at position 55 of tRNAGlu, leading to structural abnormalities, decreased stability, aberrant mitochondrial protein synthesis, and increased autophagy. In contrast, the ND6 14484T>C mutation predominantly impairs complex I function, resulting in heightened apoptosis and virtually no induction of mitochondrial autophagy compared to control cell lines. The presence of dual mutations in the same cell lines exhibited a coexistence of both upregulated cellular stress responses to mitochondrial damage, indicating a scenario of autophagy and mutation dysregulation within these dual-mutant cell lines. The data proposes a novel hypothesis that mitochondrial tRNA gene mutations generally lead to increased mitochondrial autophagy, while mutations in genes encoding mitochondrial proteins typically induce apoptosis, shedding light on the intricate interplay between different genetic factors in the manifestation of LHON.
    Keywords:  apoptosis; leber's hereditary optic neuropathy; mitochondrial tRNA mutation; mitophagy; phenotypic expression
    DOI:  https://doi.org/10.1002/advs.202401856
  10. Int Immunopharmacol. 2024 Sep 12. pii: S1567-5769(24)01625-4. [Epub ahead of print]142(Pt A): 113104
    A promising therapeutic: Exosome-mediated mitochondrial transplantation.
    Meiling Cao, Jiahui Zou, Mingyue Shi, Danyang Zhao, Chang Liu, Yanshan Liu, Lei Li, Hongkun Jiang.
      Mitochondrial dysfunction has been identified as a trigger for cellular autophagy dysfunction and programmed cell death. Emerging studies have revealed that, in pathological contexts, intercellular transfer of mitochondria takes place, facilitating the restoration of mitochondrial function, energy metabolism, and immune homeostasis. Extracellular vesicles, membranous structures released by cells, exhibit reduced immunogenicity and enhanced stability during the transfer of mitochondria. Thus, this review provides a concise overview of mitochondrial dysfunction related diseases and the mechanism of mitochondrial dysfunction in diseases progression, and the composition and functions of the extracellular vesicles, along with elucidating the principal mechanisms underlying intercellular mitochondrial transfer. In this article, we will focus on the advancements in both animal models and clinical trials concerning the therapeutic efficacy of extracellular vesicle-mediated mitochondrial transplantation across various systemic diseases in neurodegenerative diseases and cardiovascular diseases. Additionally, the review delves into the multifaceted roles of extracellular vesicle-transplanted mitochondria, encompassing anti-inflammatory actions, promotion of tissue repair, enhancement of cellular function, and modulation of metabolic and immune homeostasis within diverse pathological contexts, aiming to provide novel perspectives for extracellular vesicle transplantation of mitochondria in the treatment of various diseases.
    Keywords:  Extracellular vesicles; Mitochondria; Mitochondrial transfer; Mitochondrial transplantation; Organ damage; Therapy
    DOI:  https://doi.org/10.1016/j.intimp.2024.113104
  11. J Vis Exp. 2024 Aug 23.
    Robust Mitochondrial Isolation from Rodent Cardiac Tissue.
    Alyssa C Vadovsky, Melissa Quinn, Tianyi Xia, Yan Levitsky, Jason N Bazil.
      Mitochondrial isolation has been practiced for decades, following procedures established by pioneers in the fields of molecular biology and biochemistry to study metabolic impairments and disease. Consistent mitochondrial quality is necessary to properly investigate mitochondrial physiology and bioenergetics; however, many different published isolation methods are available for researchers. Although different experimental strategies require different isolation methods, the basic principles and procedures are similar. This protocol details a method capable of extracting well-coupled mitochondria from a variety of tissue sources, including small animals and cells. The steps outlined include organ dissection, mitochondrial purification, protein quantification, and various quality control checks. The primary quality control metric used to identify high-quality mitochondria is the respiratory control ratio (RCR). The RCR is the ratio of the respiratory rate during oxidative phosphorylation to the rate in the absence of ADP. Alternative metrics are discussed. While high RCR values relative to their tissue source are obtained using this protocol, several steps can be optimized to suit the individual needs of researchers. This procedure is robust and has consistently resulted in isolated mitochondria with above-average RCR values across animal models and tissue sources.
    DOI:  https://doi.org/10.3791/67093
  12. Nat Cell Biol. 2024 Sep;26(9): 1374
    Mitophagy protects against ferroptosis.
    Petra Gross.
      
    DOI:  https://doi.org/10.1038/s41556-024-01507-7
  13. Mol Neurobiol. 2024 Sep 09.
    Disruption of Mitochondrial Quality Control in Inherited Metabolic Disorders.
    Manuela Bianchin Marcuzzo, Josyane de Andrade Silveira, Emílio L Streck, Jerry Vockley, Guilhian Leipnitz.
      Inherited metabolic disorders (IMDs) are genetic disorders often characterized by the accumulation of toxic metabolites in patient tissues and bodily fluids. Although the pathophysiologic effect of these metabolites and their direct effect on cellular function is not yet established for many of these disorders, animal and cellular studies have shown that mitochondrial bioenergetic dysfunction with impairment of citric acid cycle activity and respiratory chain, along with secondary damage induced by oxidative stress are prominent in some. Mitochondrial quality control, requiring the coordination of multiple mechanisms such as mitochondrial biogenesis, dynamics, and mitophagy, is responsible for the correction of such defects. For inborn errors of enzymes located in the mitochondria, secondary abnormalities in quality control this organelle could play a role in their pathophysiology. This review summarizes preclinical data (animal models and patient-derived cells) on mitochondrial quality control disturbances in selected IMDs.
    Keywords:  Biogenesis; Fission; Fusion; Inherited Metabolic Disorders; Mitochondrial Quality Control; Mitophagy
    DOI:  https://doi.org/10.1007/s12035-024-04467-z
  14. BMC Neurol. 2024 Sep 13. 24(1): 343
    Cascade testing in mitochondrial diseases: a cross-sectional retrospective study.
    Sameen Haque, Karen Crawley, Deborah Schofield, Rupendra Shrestha, Carolyn M Sue.
       BACKGROUND: Cascade testing can offer improved surveillance and timely introduction of clinical management for the at-risk biological relatives. Data on cascade testing and costs in mitochondrial diseases are lacking. To address this gap, we performed a cross-sectional retrospective study to provide a framework for cascade testing in mitochondrial diseases, to estimate the eligibility versus real-time uptake of cascade testing and to evaluate the cost of the genetic diagnosis of index cases and the cost of predictive cascade testing.
    METHODS: Data was collected through retrospective chart review. The variant inheritance pattern guided the identification of eligible first-degree relatives: (i) Males with mitochondrial DNA (mtDNA) single nucleotide variants (SNVs) - siblings and mothers. (ii) Females with mtDNA SNVs - siblings, mothers and offspring. (iii) Autosomal Dominant (AD) nuclear DNA (nDNA) variants - siblings, offspring and both parents. (iv) Autosomal Recessive (AR) nDNA variants - siblings.
    RESULTS: We recruited 99 participants from the Adult Mitochondrial Disease Clinic in Sydney. The uptake of cascade testing was 55.2% in the mtDNA group, 55.8% in the AD nDNA group and 0% in AR nDNA group. Of the relatives in mtDNA group who underwent cascade testing, 65.4% were symptomatic, 20.5% were oligosymptomatic and 14.1% were asymptomatic. The mean cost of cascade testing for eligible first-degree relatives (mtDNA group: $694.7; AD nDNA group: $899.1) was lower than the corresponding index case (mtDNA group: $4578.4; AD nDNA group: $5715.1) (p < 0.001).
    CONCLUSION: The demand for cascade testing in mitochondrial diseases varies according to the genotype and inheritance pattern. The real-time uptake of cascade testing can be influenced by multiple factors. Early diagnosis of at-risk biological relatives of index cases through cascade testing, confirms the diagnosis in those who are symptomatic and facilitates implementation of surveillance strategies and clinical care at an early stage of the disease.
    Keywords:  Cascade screening; Cascade testing; Genetic predisposition to disease; Genetic testing; Mitochondrial diseases; Neuromuscular diseases; Pedigree
    DOI:  https://doi.org/10.1186/s12883-024-03850-6
  15. Aust N Z J Obstet Gynaecol. 2024 Sep 11.
    Pregnancy in women with mitochondrial disease-A literature review and suggested guidance for preconception and pregnancy care.
    Lisa Hui, Pema Hayman, Ali Buckland, Michael C Fahey, David A Mackey, Andrew J Mallett, Daniel R Schweitzer, Clare P Stuart, Wai Yan Yau, John Christodoulou.
      Mitochondrial donation to reduce the risk of primary mitochondrial disease transmission from mother to child is now permitted under Australian law as part of a clinical trial. The energy demands of pregnancy have the potential to worsen mitochondrial disease symptoms and severity in affected women. We conducted a systematic literature review on mitochondrial disease in pregnancy; five cohort studies and 19 case reports were included. For many women with mitochondrial disease, pregnancy does not have a negative effect on health status. However, serious adverse outcomes may occur. We provide suggested guidelines for preconception counselling and antenatal care.
    Keywords:  assisted reproductive techniques; genetics; mitochondrial disease; pregnancy; pregnancy complications
    DOI:  https://doi.org/10.1111/ajo.13874
  16. Small Methods. 2024 Sep 13. e2400525
    Mitochondrial STED Imaging and Membrane Potential Monitoring with a Cationic Molecular Probe.
    Lu Gao, Rana Dalapati, Beibei Gao, Xiaoyu Huang, Dan Zhao, Fu Wang, Ling Zang.
      Mitochondria are essential organelles that not only undergo dynamic morphological changes but also exhibit functional activities such as mitochondrial membrane potential (MMP). While super-resolution techniques such as stimulated emission depletion (STED) nanoscopy can visualize the ultrastructure of mitochondria and the MMP probe can monitor mitochondria function, few dyes meet both demands. Here, a small molecule (MitoPDI-90) based on perylene diimide with cationic groups is reported and used for mitochondrial STED imaging and MMP indication. Characterized by excellent photostability, biocompatibility, and high quantum yield, MitoPDI-90 exhibits STED imaging compatibility, facilitating visualization of mitochondrial cristae and time-lapse imaging of highly dynamic mitochondria in living cells. Besides, MitoPDI-90 targets the mitochondria through electrical potential, also enabling live-cell MMP monitoring. MitoPDI-90 allows for super-resolution visualization and time-lapse imaging of mitochondria, and more importantly, indication of changes in MMP, providing insight into the functional activity of live-cell mitochondria.
    Keywords:  STED microscopy; cationic molecular; cristae; mitochondrial membrane potential
    DOI:  https://doi.org/10.1002/smtd.202400525
  17. J Lipid Res. 2024 Sep 06. pii: S0022-2275(24)00146-9. [Epub ahead of print] 100641
    Disruption of nucleotide biosynthesis reprograms mitochondrial metabolism to inhibit adipogenesis.
    Julia A Pinette, Jacob W Myers, Woo Yong Park, Heather G Bryant, Alex M Eddie, Genesis A Wilson, Claudia Montufar, Zayedali Shaikh, Zer Vue, Elizabeth R Nunn, Ryoichi Bessho, Matthew A Cottam, Volker H Haase, Antentor O Hinton, Jessica B Spinelli, Jean-Philippe Cartailler, Elma Zaganjor.
      A key organismal response to overnutrition involves the development of new adipocytes through the process of adipogenesis. Preadipocytes sense changes in the systemic nutrient status and metabolites can directly modulate adipogenesis. We previously identified a role of de novo nucleotide biosynthesis in adipogenesis induction, whereby inhibition of nucleotide biosynthesis suppresses the expression of the transcriptional regulators PPARγ and C/EBPα. Here, we set out to identify the global transcriptomic changes associated with the inhibition of nucleotide biosynthesis. Through RNA sequencing (RNAseq), we discovered that mitochondrial signatures were the most altered in response to inhibition of nucleotide biosynthesis. Blocking nucleotide biosynthesis induced rounded mitochondrial morphology, and altered mitochondrial function, and metabolism, reducing levels of tricarboxylic acid cycle intermediates, and increasing fatty acid oxidation (FAO). The loss of mitochondrial function induced by suppression of nucleotide biosynthesis was rescued by exogenous expression of PPARγ. Moreover, inhibition of FAO restored PPARγ expression, mitochondrial protein expression, and adipogenesis in the presence of nucleotide biosynthesis inhibition, suggesting a regulatory role of nutrient oxidation in differentiation. Collectively, our studies shed light on the link between substrate oxidation and transcription in cell fate determination.
    Keywords:  adipocytes; adipogenesis; fatty acid oxidation; lipid droplets; metabolism; nucleotides; purine; pyrimidine
    DOI:  https://doi.org/10.1016/j.jlr.2024.100641
  18. Mol Neurobiol. 2024 Sep 13.
    Role of Mitochondrial Dysfunctions in Neurodegenerative Disorders: Advances in Mitochondrial Biology.
    Divya Sri Kathiresan, Rubadevi Balasubramani, Kamalesh Marudhachalam, Piyush Jaiswal, Nivedha Ramesh, Suruthi Gunna Sureshbabu, Vinayaga Moorthi Puthamohan, Murali Vijayan.
      Mitochondria, essential organelles responsible for cellular energy production, emerge as a key factor in the pathogenesis of neurodegenerative disorders. This review explores advancements in mitochondrial biology studies that highlight the pivotal connection between mitochondrial dysfunctions and neurological conditions such as Alzheimer's, Parkinson's, Huntington's, ischemic stroke, and vascular dementia. Mitochondrial DNA mutations, impaired dynamics, and disruptions in the ETC contribute to compromised energy production and heightened oxidative stress. These factors, in turn, lead to neuronal damage and cell death. Recent research has unveiled potential therapeutic strategies targeting mitochondrial dysfunction, including mitochondria targeted therapies and antioxidants. Furthermore, the identification of reliable biomarkers for assessing mitochondrial dysfunction opens new avenues for early diagnosis and monitoring of disease progression. By delving into these advancements, this review underscores the significance of understanding mitochondrial biology in unraveling the mechanisms underlying neurodegenerative disorders. It lays the groundwork for developing targeted treatments to combat these devastating neurological conditions.
    Keywords:  Biogenesis; Mitochondria; MtDNA dynamics; Neurodegeneration; Oxidative stress; Therapeutics
    DOI:  https://doi.org/10.1007/s12035-024-04469-x
  19. Mitochondrion. 2024 Sep 11. pii: S1567-7249(24)00115-6. [Epub ahead of print] 101957
    The multifaceted effects of mitochondria in kidney diseases.
    Jia-Le Xue, Jia-Ling Ji, Yan Zhou, Yao Zhang, Bi-Cheng Liu, Rui-Xia Ma, Zuo-Lin Li.
      Mitochondria serve as the primary site for aerobic respiration within cells, playing a crucial role in maintaining cellular homeostasis. To maintain homeostasis and meet the diverse demands of the cells, mitochondria have evolved intricate systems of quality control, mainly including mitochondrial dynamics, mitochondrial autophagy (mitophagy) and mitochondrial biogenesis. The kidney, characterized by its high energy requirements, is particularly abundant in mitochondria. Interestingly, the mitochondria display complex behaviors and functions. When the kidney is suffered from obstructive, ischemic, hypoxic, oxidative, or metabolic insults, the dysfunctional mitochondrial derived from the defects in the mitochondrial quality control system contribute to cellular inflammation, cellular senescence, and cell death, posing a threat to the kidney. However, in addition to causing injury to the kidney in several cases, mitochondria also exhibit protective effect on the kidney. In recent years, accumulating evidence indicated that mitochondria play a crucial role in adaptive repair following kidney diseases caused by various etiologies. In this article, we comprehensively reviewed the current understanding about the multifaceted effects of mitochondria on kidney diseases and their therapeutic potential.
    Keywords:  Kidney diseases; Mitochondria; Mitochondrial quality control system; Treatment strategy
    DOI:  https://doi.org/10.1016/j.mito.2024.101957
  20. J Clin Med. 2024 Aug 26. pii: 5044. [Epub ahead of print]13(17):
    Unilateral Hearing Loss and Auditory Asymmetry in Mitochondrial Disease: A Scoping Review.
    Marianna Manuelli, Andrea Migliorelli, Chiara Bianchini, Francesco Stomeo, Stefano Pelucchi, Elisabetta Genovese, Daniele Monzani, Silvia Palma, Andrea Ciorba.
      Background/Objectives: Mitochondrial transfer RNA mutations are one of the most important causes of hereditary hearing loss in humans. In most cases, its presentation is bilateral and symmetrical; however, there are numerous cases of single-sided presentation or asymmetrical onset described in the literature that may represent a diagnostic challenge. The aim of this review is to present the evidence of auditory asymmetry in mitochondrial diseases, highlighting the possible presence of cases with atypical presentation. Methods: A review of the English literature to date on hearing loss and mitochondrial diseases was performed using PubMed, Scopus, and Google Scholar databases. The literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines for scoping review. Results: A total of 10 full-text articles were included in this review, comprising 25 patients with single-sided or asymmetrical hearing loss associated with mitochondrial disease. Conclusions: Sensorineural hearing loss due to mitochondrial disease can represent a complex diagnostic challenge in cases of asymmetric or unilateral presentation. It is critical to recognize this clinical variant and to diagnose it in daily clinical practice.
    Keywords:  deafness; hearing loss; mitochondrial disease; unilateral hearing loss
    DOI:  https://doi.org/10.3390/jcm13175044
  21. Carbohydr Polym. 2024 Dec 15. pii: S0144-8617(24)00801-4. [Epub ahead of print]346 122575
    Antibody conjugated targeted nanotherapy epigenetically inhibits calpain-mediated mitochondrial dysfunction to attenuate Parkinson's disease.
    Liku Biswal, Vikas Kumar Sahu, Mohammed Nadim Sardoiwala, Surajit Karmakar, Subhasree Roy Choudhury.
      Many neurodegenerative and psychiatric malignancies like Parkinson' disease (PD) originate from an imbalance of 17β-Estradiol (E2) in the human brain. However, the peripheral side effects of the usage of E2 for PD therapy and less understanding of the molecular mechanism hinder establishing its neurotherapeutic potential. In the present work, systemic side effects were overcome by targeted delivery using Dopamine receptor D3 (DRD3) conjugated E2-loaded chitosan nanoparticles (Ab-ECSnps) that showed a promising delivery to the brain. E2 is a specific calpain inhibitor that fosters neurodegeneration by disrupting mitochondrial function, while B-cell-specific Moloney murine leukemia virus integration region 1 (BMI1), an epigenetic regulator, is crucial in preserving mitochondrial homeostasis. We showed the administration of Ab-ECSnps inhibits calpain's translocation into mitochondria while promoting the translocation of BMI1 to mitochondria, thereby conferring neurotherapeutic benefits by enhancing cell viability, increasing mitochondrial DNA copy number, and preserving mitochondrial membrane potential. Further, we showed a novel molecular mechanism of BMI1 regulation by calpain that might contribute to maintaining mitochondrial homeostasis for attenuating PD. Concomitantly, Ab-ECSnps showed neurotherapeutic potential in the in vivo PD model. We showed for the first time that our brain-specific targeted delivery might regulate calpain-mediated BMI1 expression, thereby preserving mitochondrial homeostasis to alleviate PD.
    Keywords:  17β-Estradiol; Antibody conjugate; Calpain; Chitosan nanoparticles; Mitochondrial homeostasis; Parkinson's disease (PD)
    DOI:  https://doi.org/10.1016/j.carbpol.2024.122575
  22. Stem Cell Res. 2024 Sep 06. pii: S1873-5061(24)00245-9. [Epub ahead of print]81 103547
    Characterization of two iPSC lines from patients with maternally inherited leigh (MILS) and neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome carrying the MT-ATP6 m.8993 T>G mutation at different degrees of heteroplasmy.
    Anna Maria Haschke, Sebastian Diecke, Markus Schuelke.
      Human-derived experimental systems such as induced pluripotent stem cell (iPSC)-derived models are useful tools to study mechanisms and potential therapeutic approaches for mitochondrial disorders. Here, we generated two iPSC lines from fibroblasts of patients carrying mutations at MT-ATP6 (m.8993 T>G). One patient with 96 % heteroplasmy suffered from Neuropathy, Ataxia, and Retinitis pigmentosa (NARP) syndrome, while the other patient with a homoplasmic mutation suffered from Maternally Inherited Leigh Syndrome (MILS). For reprogramming, we delivered reprogramming factors using Sendai virus and evaluated the pluripotency characteristics of the derived iPSCs. The degree of heteroplasmy remained stable after reprogramming.
    DOI:  https://doi.org/10.1016/j.scr.2024.103547
  23. Physiol Rep. 2024 Sep;12(17): e70048
    Akt1 deficiency does not affect fiber type composition or mitochondrial protein expression in skeletal muscle of male mice.
    Tatsuya Miyaji, Ryuichi Kasuya, Atsushi Sawada, Daisuke Sawamura, Yu Kitaoka, Mitsunori Miyazaki.
      Insulin-like growth factor-1-induced activation of ATP citrate lyase (ACLY) improves muscle mitochondrial function through an Akt-dependent mechanism. In this study, we examined whether Akt1 deficiency alters skeletal muscle fiber type and mitochondrial function by regulating ACLY-dependent signaling in male Akt1 knockout (KO) mice (12-16 weeks old). Akt1 KO mice exhibited decreased body weight and muscle wet weight, with reduced cross-sectional areas of slow- and fast-type muscle fibers. Loss of Akt1 did not affect the phosphorylation status of ACLY in skeletal muscle. The skeletal muscle fiber type and expression of mitochondrial oxidative phosphorylation complex proteins were unchanged in Akt1 KO mice compared with the wild-type control. These observations indicate that Akt1 is important for the regulation of skeletal muscle fiber size, whereas the regulation of muscle fiber type and muscle mitochondrial content occurs independently of Akt1 activity.
    Keywords:  Akt1; glycolysis; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.70048
  24. Mitochondrion. 2024 Sep 07. pii: S1567-7249(24)00113-2. [Epub ahead of print]79 101955
    Mitochondrial acyl carrier protein, Acp1, required for iron-sulfur cluster assembly in mitochondria and cytoplasm in Saccharomyces cerevisiae.
    Ashutosh K Pandey, Heeyong Yoon, Jayashree Pain, Andrew Dancis, Debkumar Pain.
      Mitochondria perform vital biosynthetic processes, including fatty acid synthesis and iron-sulfur (FeS) cluster biogenesis. In Saccharomyces cerevisiae mitochondria, the acyl carrier protein Acp1 participates in type II fatty acid synthesis, requiring a 4-phosphopantetheine (PP) prosthetic group. Acp1 also interacts with the mitochondrial FeS cluster assembly complex that contains the cysteine desulfurase Nfs1. Here we investigated the role of Acp1 in FeS cluster biogenesis in mitochondria and cytoplasm. In the Acp1-depleted (Acp1↓) cells, biogenesis of mitochondrial FeS proteins was impaired, likely due to greatly reduced Nfs1 protein and/or its persulfide-forming activity. Formation of cytoplasmic FeS proteins was also deficient, suggesting a disruption in generating the (Fe-S)int intermediate, that is exported from mitochondria and is subsequently utilized for cytoplasmic FeS cluster assembly. Iron homeostasis was perturbed, with enhanced iron uptake into the cells and accumulation of iron in mitochondria. The Δppt2 strain, lacking the mitochondrial ability to add PP to Acp1, phenocopied the Acp1↓ cells. These data suggest that the holo form of Acp1 with the PP-conjugated acyl chain is required for stability of the Nfs1 protein and/or stimulation of its persulfide-forming activity. Thus, mitochondria lacking Acp1 (or Ppt2) cannot support FeS cluster biogenesis in mitochondria or cytoplasm, leading to disrupted iron homeostasis.
    Keywords:  Cysteine desulfurase; Cytoplasm; FeS cluster assembly; Iron-sulfur intermediate; Mitochondria
    DOI:  https://doi.org/10.1016/j.mito.2024.101955
  25. Mol Cell Proteomics. 2024 Sep 07. pii: S1535-9476(24)00128-2. [Epub ahead of print] 100838
    Proteome dynamics in iPSC-derived human dopaminergic neurons.
    Claudia Cavarischia-Rega, Karan Sharma, Julia C Fitzgerald, Boris Macek.
      Dopaminergic neurons participate in fundamental physiological processes and are the cell type primarily affected in Parkinson's disease. Their analysis is challenging due to the intricate nature of their function, involvement in diverse neurological processes, heterogeneity and localization in deep brain regions. Consequently, most of the research on the protein dynamics of dopaminergic neurons has been performed in animal cells ex vivo. Here we use iPSC-derived human mid-brain specific dopaminergic neurons to study general features of their proteome biology and provide datasets for protein turnover and dynamics, including a human axonal translatome. We cover the proteome to a depth of 9,409 proteins and use dynamic SILAC to measure the half-life of more than 4,300 proteins. We report uniform turnover rates of conserved cytosolic protein complexes such as the proteasome and map the variable rates of turnover of the respiratory chain complexes in these cells. We use differential dynamic SILAC labeling in combination with microfluidic devices to analyze local protein synthesis and transport between axons and soma. We report 105 potentially novel axonal markers and detect translocation of 269 proteins between axons and the soma in the time frame of our analysis (120 hours). Importantly, we provide evidence for local synthesis of 154 proteins in the axon and their retrograde transport to the soma, among them several proteins involved in RNA editing such as ADAR1 and the RNA helicase DHX30, involved in the assembly of mitochondrial ribosomes. Our study provides a workflow and resource for future applications of quantitative proteomics in iPSC-derived human neurons.
    Keywords:  axon; dopaminergic neurons; iPSC; protein turnover; proteomics
    DOI:  https://doi.org/10.1016/j.mcpro.2024.100838
  26. Transl Neurodegener. 2024 Sep 06. 13(1): 46
    Neurodegenerative disorders, metabolic icebergs, and mitohormesis.
    Matthew C L Phillips, Martin Picard.
      Neurodegenerative disorders are typically "split" based on their hallmark clinical, anatomical, and pathological features, but they can also be "lumped" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as "metabolic icebergs" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating "mitohormesis", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Hormesis; Huntington’s disease; Lumping; Mitochondria; Mitohormesis; Mitotypes; Parkinson’s disease; Splitting
    DOI:  https://doi.org/10.1186/s40035-024-00435-8
  27. Nucleic Acid Ther. 2024 Sep 12.
    Antisense Oligonucleotide STK-002 Increases OPA1 in Retina and Improves Mitochondrial Function in Autosomal Dominant Optic Atrophy Cells.
    Aditya Venkatesh, Taylor McKenty, Syed Ali, Donna Sonntag, Shobha Ravipaty, Yanyan Cui, Deirdre Slate, Qian Lin, Anne Christiansen, Sarah Jacobson, Jacob Kach, Kian Huat Lim, Vaishnavi Srinivasan, Boris Zinshteyn, Isabel Aznarez, Laryssa A Huryn, Zhiyu Li, Robert B Hufnagel, Gene Liau, Karen Anderson, Jeff Hoger.
      Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy most frequently associated with OPA1 mutations. Most variants result in haploinsufficiency, and patient cells express roughly half of the normal levels of OPA1 protein. OPA1 is a mitochondrial GTPase that is essential for normal mitochondrial function. We identified and characterized STK-002, an antisense oligonucleotide (ASO) designed to prevent the incorporation of a naturally occurring alternatively spliced nonproductive exon in OPA1. STK-002 dose dependently reduced the inclusion of this exon, and increased OPA1 protein in human cells, including ADOA patient-derived fibroblasts. ADOA patient cells manifest reduced mitochondrial respiration, and treatment with STK-002 improved the parameters of mitochondrial respiratory function in these cells. Since STK-002 increases OPA1 through the wild-type allele, we assessed retinal OPA1 in wild-type cynomolgus monkeys and rabbits after intravitreal administration of STK-002 or a rabbit-specific surrogate. Increased OPA1 protein was produced in retinal tissue in both species at 4 weeks after ASO injection and persisted in monkeys at 8 weeks. STK-002 and enhanced OPA1 immunofluorescence were visualized in retinal ganglion cells of cynomolgus monkeys treated with the ASO. Cumulatively, these data support the progression of STK-002 toward the clinic as the first potential disease-modifying treatment for ADOA.
    Keywords:  ADOA; ASO; OPA1; exon splicing; haploinsufficiency; mRNA
    DOI:  https://doi.org/10.1089/nat.2024.0022
  28. iScience. 2024 Sep 20. 27(9): 110642
    Etomoxir repurposed as a promiscuous fatty acid mimetic chemoproteomic probe.
    Joseph Choi, Danielle M Smith, Ye Jin Lee, Danfeng Cai, Mohammad J Hossain, Tamara J O'Connor, Pragney Deme, Norman J Haughey, Susanna Scafidi, Ryan C Riddle, Michael J Wolfgang.
      Etomoxir has been used for decades as a popular small molecule inhibitor of carnitine palmitoyltransferase I, Cpt1, to block mitochondrial fatty acid β-oxidation. To test the specificity of etomoxir, we generated click chemistry-enabled reagents to label etomoxir binding proteins in situ. Etomoxir bound to Cpt1, but also bound to a large array of diverse proteins that metabolize and transport fatty acids in the cytoplasm, peroxisome, and mitochondria. Many of the most abundant proteins identified in primary hepatocytes were peroxisomal proteins. The loss of Pex5, required for the import of peroxisomal matrix proteins, eliminated many of these etomoxir-labeled proteins. By utilizing the promiscuous, covalent, and fatty acid mimetic properties of etomoxir, etomoxir targets of fatty acid ω-oxidation were revealed following the loss of Pex5. These data demonstrate that etomoxir is not specific for Cpt1 and is not appropriate as a tool to distinguish the biological effects of fatty acid oxidation.
    Keywords:  Biochemistry; Chemical compound; Enzymology; Molecular biology; Molecular interaction
    DOI:  https://doi.org/10.1016/j.isci.2024.110642
  29. Res Sq. 2024 Aug 27. pii: rs.3.rs-4876596. [Epub ahead of print]
    Mitochondrial RNA cytosolic leakage drives the SASP.
    Stella Victorelli, Madeline Eppard, Seung-Hwa Woo, Stacia Everts, Helene Martini, Nicholas Pirius, Ana Catarina Franco, Yeaeun Han, Dominik Saul, Patrick Splinter, Steven O'Hara, Lucia Valenzuela-Pérez, Hyun Se Kim Lee, Diana Jurk, Nicholas LaRusso, Petra Hirsova, Joao Passos.
      Senescent cells secrete proinflammatory factors known as the senescence-associated secretory phenotype (SASP), contributing to tissue dysfunction and aging. Mitochondrial dysfunction is a key feature of senescence, influencing SASP via mitochondrial DNA (mtDNA) release and cGAS/STING pathway activation. Here, we demonstrate that mitochondrial RNA (mtRNA) also accumulates in the cytosol of senescent cells, activating RNA sensors RIG-I and MDA5, leading to MAVS aggregation and SASP induction. Inhibition of these RNA sensors significantly reduces SASP factors. Furthermore, BAX and BAK plays a key role in mtRNA leakage during senescence, and their deletion diminishes SASP expression in vitro and in a mouse model of Metabolic Dysfunction Associated Steatohepatitis (MASH). These findings highlight mtRNA's role in SASP regulation and its potential as a therapeutic target for mitigating age-related inflammation.
    DOI:  https://doi.org/10.21203/rs.3.rs-4876596/v1
  30. Genet Med. 2024 Sep 03. pii: S1098-3600(24)00183-7. [Epub ahead of print] 101249
    Non-coding variants are a rare cause of recessive developmental disorders in trans with coding variants.
    Genomics England Research Consortium
       PURPOSE: Identifying pathogenic non-coding variants is challenging. A single protein-altering variant is often identified in a recessive gene in individuals with developmental disorders (DD), but the prevalence of pathogenic non-coding 'second hits' in trans with these is unknown.
    METHODS: In 4,073 genetically undiagnosed rare disease trio probands from the 100,000 Genomes project, we identified rare heterozygous protein-altering variants in recessive DD-associated genes. We identified rare non-coding variants on the other haplotype in introns, untranslated regions (UTRs), promoters, and candidate enhancer regions. We clinically evaluated the top candidates for phenotypic fit, and performed functional testing where possible.
    RESULTS: We identified 3,761 rare heterozygous loss-of-function or ClinVar pathogenic variants in recessive DD-associated genes in 2,430 probands. For 1,366 (36.3%) of these, we identified at least one rare non-coding variant in trans. Bioinformatic filtering and clinical review, revealed seven to be a good clinical fit. After detailed characterisation, we identified likely diagnoses for three probands (in GAA, NPHP3, and PKHD1) and candidate diagnoses in a further three (PAH, LAMA2, IGHMBP2).
    CONCLUSION: We developed a systematic approach to uncover new diagnoses involving compound heterozygous coding/non-coding variants and conclude that this mechanism is likely to be a rare cause of DDs.
    Keywords:  clinical genetic testing; genomics; rare disorders; recessive disorders
    DOI:  https://doi.org/10.1016/j.gim.2024.101249
  31. iScience. 2024 Sep 20. 27(9): 110683
    Spastin regulates ER-mitochondrial contact sites and mitochondrial homeostasis.
    Amelie Raby, Sonia Missiroli, Peggy Sanatine, Dominique Langui, Julien Pansiot, Nissai Beaude, Lucie Vezzana, Rachelle Saleh, Martina Marinello, Mireille Laforge, Paolo Pinton, Ana Buj-Bello, Andrea Burgo.
      Mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) emerged to play critical roles in numerous cellular processes, and their dysregulation has been associated to neurodegenerative disorders. Mutations in the SPG4 gene coding for spastin are among the main causes of hereditary spastic paraplegia (HSP). Spastin binds and severs microtubules, and the long isoform of this protein, namely M1, spans the outer leaflet of ER membrane where it interacts with other ER-HSP proteins. Here, we showed that overexpressed M1 spastin localizes in ER-mitochondria intersections and that endogenous spastin accumulates in MERCs. We demonstrated in different cellular models that downregulation of spastin enhances the number of MERCs, alters mitochondrial morphology, and impairs ER and mitochondrial calcium homeostasis. These effects are associated with reduced mitochondrial membrane potential, oxygen species levels, and oxidative metabolism. These findings extend our knowledge on the role of spastin in the ER and suggest MERCs deregulation as potential causes of SPG4-HSP disease.
    Keywords:  Biological sciences; Molecular biology; Molecular interaction
    DOI:  https://doi.org/10.1016/j.isci.2024.110683
  32. NPJ Digit Med. 2024 Sep 06. 7(1): 235
    Integrating digital gait data with metabolomics and clinical data to predict outcomes in Parkinson's disease.
    NCER-PD Consortium
      Parkinson's disease (PD) presents diverse symptoms and comorbidities, complicating its diagnosis and management. The primary objective of this cross-sectional, monocentric study was to assess digital gait sensor data's utility for monitoring and diagnosis of motor and gait impairment in PD. As a secondary objective, for the more challenging tasks of detecting comorbidities, non-motor outcomes, and disease progression subgroups, we evaluated for the first time the integration of digital markers with metabolomics and clinical data. Using shoe-attached digital sensors, we collected gait measurements from 162 patients and 129 controls in a single visit. Machine learning models showed significant diagnostic power, with AUC scores of 83-92% for PD vs. control and up to 75% for motor severity classification. Integrating gait data with metabolomics and clinical data improved predictions for challenging-to-detect comorbidities such as hallucinations. Overall, this approach using digital biomarkers and multimodal data integration can assist in objective disease monitoring, diagnosis, and comorbidity detection.
    DOI:  https://doi.org/10.1038/s41746-024-01236-z
  33. bioRxiv. 2024 Aug 28. pii: 2023.04.09.536178. [Epub ahead of print]
    Astrocytic LRRK2 Controls Synaptic Connectivity via Regulation of ERM Phosphorylation.
    Shiyi Wang, Ryan Baumert, Gabrielle Séjourné, Dhanesh Sivadasan Bindu, Kylie Dimond, Kristina Sakers, Leslie Vazquez, Jessica Moore, Christabel Xin Tan, Tetsuya Takano, Maria Pia Rodriguez, Scott H Soderling, Albert R La Spada, Cagla Eroglu.
      Astrocytes, a major glial cell type of the brain, regulate synapse numbers and function. However, whether astrocyte dysfunction can cause synaptic pathologies in neurological disorders such as Parkinson's Disease (PD) is unknown. Here, we investigated the impact of the most common PD-linked mutation in the leucine-rich repeat kinase 2 ( LRRK2 ) gene (G2019S) on the synaptic functions of astrocytes. We found that both in human and mouse cortex, the LRRK2 G2019S mutation causes astrocyte morphology deficits and enhances the phosphorylation of the ERM proteins (Ezrin, Radixin, and Moesin), which are important components of perisynaptic astrocyte processes. Reducing ERM phosphorylation in LRRK2 G2019S mouse astrocytes restored astrocyte morphology and corrected excitatory synaptic deficits. Using an in vivo BioID proteomic approach, we found Ezrin, the most abundant astrocytic ERM protein, interacts with the Autophagy-Related 7 (Atg7), a master regulator of catabolic processes. The Ezrin/Atg7 interaction is inhibited by Ezrin phosphorylation, thus diminished in the LRRK2 G2019S astrocytes. Importantly, Atg7 function is required to maintain proper astrocyte morphology. These studies reveal an astrocytic molecular mechanism that could serve as a therapeutic target in PD.
    DOI:  https://doi.org/10.1101/2023.04.09.536178
  34. Jpn J Ophthalmol. 2024 Sep 14.
    Ocular genetics in the Japanese population.
    Yoshihiro Hotta, Kaoruko Torii, Masakazu Takayama.
      In today's globalized society, ophthalmologists can examine people of different ethnicities regardless of where they live. The frequency of disease-causing genes varies according to a patient's ethnic background. We explain genetic findings for Japanese patients with inherited eye diseases. Ocular genetics has made great advances over the past 30 years. For example, detecting mutations at nucleotide position 11778 in mitochondrial DNA was useful in the genetic diagnosis of Leber's hereditary optic neuropathy (LHON). I evaluated the genotype-phenotype relationship in cases of corneal dystrophy and inherited retinal dystrophy (IRD). I identified the entire exon sequence of the eyes shut homolog (EYS) gene in patients with autosomal recessive retinitis pigmentosa (RP). EYS gene mutations are the most frequent cause of autosomal recessive RP. RPGRIP1 may be a common causative gene with early-onset severe retinal dystrophy, including Leber congenital amaurosis. However, some genes have complex structures that are difficult to analyze, including the OPN1LW/OPN1MW gene cluster in blue cone monochromacy and the IKBKG/NEMO genes in incontinentia pigmenti. This review will also present two cases with uniparental disomy, a case of IRD with double mutations, and a case with RP complicated with LHON-like neuropathy. Precise understanding of the effects of genetic variants may reveal differences in the clinical characteristics of patients with the same variant. When starting genome medicine, accurately diagnosing the patient, making accurate prediction, determining the genetic pattern, and providing genetic counseling are important. Above all, that both the doctors and patients understand genetic diseases correctly is important.
    Keywords:  Early-onset severe retinal dystrophy (EOSRD); Genetic counseling; Hereditary eye disease; Inherited retinal dystrophy; Retinitis pigmentosa
    DOI:  https://doi.org/10.1007/s10384-024-01109-8
  35. Nat Cell Biol. 2024 Sep 11.
    Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells.
    Huafeng Zhang, Jincheng Liu, Wu Yuan, Qian Zhang, Xiao Luo, Yonggang Li, Yue'e Peng, Jingyu Feng, Xiaoyu Liu, Jie Chen, Yabo Zhou, Jiadi Lv, Nannan Zhou, Jingwei Ma, Ke Tang, Bo Huang.
      Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms.
    DOI:  https://doi.org/10.1038/s41556-024-01503-x
  36. Exp Neurol. 2024 Sep 09. pii: S0014-4886(24)00271-1. [Epub ahead of print] 114945
    CHCHD10P80L knock-in zebrafish display a mild ALS-like phenotype.
    Virginie Petel Légaré, Ziyaan A Harji, Christian J Rampal, Hana Antonicka, Tyler J N Gurberg, Olivia Persia, Esteban C Rodríguez, E A Shoubridge, Gary A B Armstrong.
      Mutations in the nuclear-encoded mitochondrial gene CHCHD10 have been observed in patients with a spectrum of diseases that include amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathogenic nature of disease-associated variants of CHCHD10 we generated a zebrafish knock-in (KI) model expressing the orthologous ALS-associated CHCHD10P80L variant (zebrafish: Chchd10P83L). Larval chchd10P83L/P83L fish displayed reduced Chchd10 protein expression levels, motor impairment, reduced survival and abnormal neuromuscular junctions (NMJ). These deficits were not accompanied by changes in transcripts involved in the integrated stress response (ISR), phenocopying previous findings in our knockout (chchd10-/-). Adult, 11-month old chchd10P83L/P83L zebrafish, displayed smaller slow- and fast-twitch muscle cell cross-sectional areas compared to wild type zebrafish muscle cells. Motoneurons in the spinal cord of chchd10P83L/P83L zebrafish displayed similar cross-sectional areas to that of wild type motor neurons and significantly fewer motor neurons were observed when compared to chchd2-/- adult spinal cords. Bulk RNA sequencing using whole spinal cords of 7-month old fish revealed transcriptional changes associated with neuroinflammation, apoptosis, amino acid metabolism and mt-DNA inflammatory response in our chchd10P83L/P83L model. The findings presented here, suggest that the CHCHD10P80L variant confers an ALS-like phenotype when expressed in zebrafish.
    Keywords:  Als; CHCHD10; Knock-in mutation; Mitochondria; Motor neuron; Neurodegeneration; Zebrafish
    DOI:  https://doi.org/10.1016/j.expneurol.2024.114945
  37. Commun Biol. 2024 Sep 11. 7(1): 1116
    Haplotype variability in mitochondrial rRNA predisposes to metabolic syndrome.
    Petr Pecina, Kristýna Čunátová, Vilma Kaplanová, Guillermo Puertas-Frias, Jan Šilhavý, Kateřina Tauchmannová, Marek Vrbacký, Tomáš Čajka, Ondřej Gahura, Markéta Hlaváčková, Viktor Stránecký, Stanislav Kmoch, Michal Pravenec, Josef Houštěk, Tomáš Mráček, Alena Pecinová.
      Metabolic syndrome is a growing concern in developed societies and due to its polygenic nature, the genetic component is only slowly being elucidated. Common mitochondrial DNA sequence variants have been associated with symptoms of metabolic syndrome and may, therefore, be relevant players in the genetics of metabolic syndrome. We investigate the effect of mitochondrial sequence variation on the metabolic phenotype in conplastic rat strains with identical nuclear but unique mitochondrial genomes, challenged by high-fat diet. We find that the variation in mitochondrial rRNA sequence represents risk factor in the insulin resistance development, which is associated with diacylglycerols accumulation, induced by tissue-specific reduction of the oxidative capacity. These metabolic perturbations stem from the 12S rRNA sequence variation affecting mitochondrial ribosome assembly and translation. Our work demonstrates that physiological variation in mitochondrial rRNA might represent a relevant underlying factor in the progression of metabolic syndrome.
    DOI:  https://doi.org/10.1038/s42003-024-06819-w
  38. Nature. 2024 Sep 11.
    Cell-to-cell tunnels rescue neurons from degeneration.
    Julia F Riley, Erika L F Holzbaur.
      
    Keywords:  Cell biology; Neurodegeneration
    DOI:  https://doi.org/10.1038/d41586-024-02862-z
  39. FEBS Lett. 2024 Sep 11.
    Quinone chemistry in respiratory complex I involves protonation of a conserved aspartic acid residue.
    Caroline Harter, Frédéric Melin, Franziska Hoeser, Petra Hellwig, Daniel Wohlwend, Thorsten Friedrich.
      Respiratory complex I is a central metabolic enzyme coupling NADH oxidation and quinone reduction with proton translocation. Despite the knowledge of the structure of the complex, the coupling of both processes is not entirely understood. Here, we use a combination of site-directed mutagenesis, biochemical assays, and redox-induced FTIR spectroscopy to demonstrate that the quinone chemistry includes the protonation and deprotonation of a specific, conserved aspartic acid residue in the quinone binding site (D325 on subunit NuoCD in Escherichia coli). Our experimental data support a proposal derived from theoretical considerations that deprotonation of this residue is involved in triggering proton translocation in respiratory complex I.
    Keywords:  Escherichia coli; NADH dehydrogenase; NADH:quinone oxidoreductase; iron–sulfur cluster; proton‐coupled electron transfer; quinone reduction; redox‐induced FTIR spectroscopy; site‐directed mutagenesis
    DOI:  https://doi.org/10.1002/1873-3468.15013
  40. Mol Cell Neurosci. 2024 Sep 10. pii: S1044-7431(24)00054-X. [Epub ahead of print]131 103969
    SUMOylation modulates mitochondrial dynamics in an in vitro rotenone model of Parkinson's disease.
    Ericks Sousa Soares, Letícia Yoshitome Queiroz, Ellen Gerhardt, Rui Daniel S Prediger, Tiago Fleming Outeiro, Helena Iturvides Cimarosti.
      SUMOylation is a post-translational modification essential for various biological processes. SUMO proteins bind to target substrates in a three-step enzymatic pathway, which is rapidly reversible by the action of specific proteases, known as SENPs. Studies have shown that SUMOylation is dysregulated in several human disorders, including neurodegenerative diseases that are characterized by the progressive loss of neurons, mitochondrial dysfunction, deficits in autophagy, and oxidative stress. Considering the potential neuroprotective roles of SUMOylation, the aim of this study was to investigate the effects of SENP3 knockdown in H4 neuroglioma cells exposed to rotenone, an in vitro model of cytotoxicity that mimics dopaminergic loss in Parkinson's disease (PD). The current data show that SENP3 knockdown increases SUMO-2/3 conjugates, which is accompanied by reduced levels of the mitochondrial fission protein Drp1 and increased levels of the mitochondrial fusion protein OPA1. Of high interest, SENP3 knockdown prevented rotenone-induced superoxide production and cellular death. Taken together, these findings highlight the importance of SUMOylation in maintaining mitochondrial homeostasis and the neuroprotective potential of this modification in PD.
    Keywords:  Mitochondria; Parkinson's disease; SENP3 knockdown; SUMOylation
    DOI:  https://doi.org/10.1016/j.mcn.2024.103969
  41. Front Cardiovasc Med. 2024 ;11 1446055
    Case Report: Lethal mitochondrial cardiomyopathy linked to a compound heterozygous variant of PARS2.
    Siyuan Jing, Qiuyan Yao, Mei Wu, Yifei Li.
       Introduction: Variants in the PARS2 gene have been previously associated with developmental and epileptic encephalopathy. PARS2 deficiency was characterized as a neurodevelopmental and neurodegenerative disorder with early-onset seizures and global developmental delay. Herein, we reported the first case with severe heart failure due to lethal mitochondrial cardiomyopathy with PARS2 compound heterozygous variants.
    Case presentation: This patient demonstrated fatigue, chest tightness, and shortness of breath. An acute major illness had been identified at the initial evaluation, which was characterized by severe diaphoresis, dizziness, and fatigue. Blood-urine tandem mass spectrometry found multiple disorders in acid metabolism, characterized as increased homovanillic acid (130.39 mmol/L) and 2-hydroxyisovaleric acid (1.70 mmol/L), which are associated with myocardial injuries. Therefore, an inherited metabolic disorder was suspected and whole-exome sequencing was performed, revealing a novel compound heterozygous variant of c.953C>T and c.283G>A on PARS2. Echocardiography confirmed the findings from the MRI, which presented an increased left ventricular diameter at the end of the diastolic stage. The molecular structure of SYPM was established as AF-Q7L3T8-F1, and the identified mutant sites were located in the proline-tRNA ligase domain. However, the patient died due to severe heart failure.
    Conclusion: This is the first case to reveal a novel compound heterozygous variant of PARS2-induced lethal cardiomyopathy with unreversed heart failure. Thus, this report enhances our understanding of mitochondrial tRNA function in maintaining heart function.
    Keywords:  PARS2; WES; dilated cardiomyopathy; heart failure; mitochondrial disorder
    DOI:  https://doi.org/10.3389/fcvm.2024.1446055
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