bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–08–25
forty-five papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Inner membrane turns inside out to exit mitochondrial organelles.
  2. Niacin supplementation in a child with novel MTTN variant m.5670A>G causing early onset mitochondrial myopathy and NAD+ deficiency.
  3. Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
  4. The Role of Mitochondrial Pyruvate Carrier in Neurological Disorders.
  5. Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
  6. dldhcri3 zebrafish exhibited altered mitochondrial ultrastructure, morphology and dysfunction partially rescued by probucol or thiamine.
  7. BCL2L13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function.
  8. FAM210A: An emerging regulator of mitochondrial homeostasis.
  9. Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes.
  10. Editorial: Mitochondrial plasticity and quality control in health and disease.
  11. A somatic view of the genomic impact of mitochondrial endosymbiosis.
  12. Phenotyping mitochondrial glutamyl-tRNA synthetase deficiency (EARS2): A case series and systematic literature review.
  13. Restoration of defective oxidative phosphorylation to a subset of neurons prevents mitochondrial encephalopathy.
  14. Unfolded proteins in the mitochondria activate HRI and inhibit mitochondrial protein translation.
  15. Queuine ameliorates impaired mitochondrial function caused by mt-tRNAAsn variants.
  16. Targeting mitochondrial quality control: new therapeutic strategies for major diseases.
  17. Misregulation of mitochondrial 6mA promotes the propagation of mutant mtDNA and causes aging in C. elegans.
  18. AI-recognized mitochondrial phenotype enables identification of drug targets.
  19. Metabolic cycles: A unifying concept for energy transfer in the heart.
  20. MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.
  21. SLC30A9: an evolutionarily conserved mitochondrial zinc transporter essential for mammalian early embryonic development.
  22. Unraveling mitochondrial dysfunction: comprehensive perspectives on its impact on neurodegenerative diseases.
  23. Structural basis for substrate binding and selection by human mitochondrial RNA polymerase.
  24. Drosophila model to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy.
  25. Hormonal orchestra: mastering mitochondria's role in health and disease.
  26. IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency.
  27. Development of a Signal-integrating Reporter to Monitor Mitochondria-ER Contacts.
  28. Proteome-scale prediction of molecular mechanisms underlying dominant genetic diseases.
  29. 3-Nitrotyrosine shortens axons of non-dopaminergic neurons by inhibiting mitochondrial motility.
  30. Mitochondrial protein deacetylation by SIRT3 in osteoclasts promotes bone resorption with aging in female mice.
  31. NAD+ precursors prolong survival and improve cardiac phenotypes in a mouse model of Friedreich's Ataxia.
  32. Artificial targeting of autophagy components to mitochondria reveals both conventional and unconventional mitophagy pathways.
  33. Nanozymes targeting mitochondrial repair in disease treatment.
  34. Phosphoglycerate kinase is a central leverage point in Parkinson's disease-driven neuronal metabolic deficits.
  35. Glutamine supplementation as a novel metabolic therapeutic strategy for LIG3-dependent chronic intestinal pseudo-obstruction.
  36. Novel heterozygous OPA3 variant in a family with congenital cataracts, sensorineural hearing loss and neuropathy, without optic atrophy and comparison of pathogenic and population variants.
  37. Genome-scale quantification and prediction of pathogenic stop codon readthrough by small molecules.
  38. O-GlcNAc impacts mitophagy via the PINK1-dependent pathway.
  39. Reply to: The effects of ENDOG on lipid metabolism may be tissue-dependent and may not require its translocation from mitochondria.
  40. Junctophilin-2 Regulates Mitochondrial Metabolism.
  41. Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway.
  42. Accumulation of damaged mitochondria in aging astrocytes due to mitophagy dysfunction: Implications for susceptibility to mitochondrial stress.
  43. Calibration of variant effect predictors on genome-wide data masks heterogeneous performance across genes.
  44. ACAD10 and ACAD11 allow entry of 4-hydroxy fatty acids into β-oxidation.
  45. Succinate dehydrogenase-complex II regulates skeletal muscle cellular respiration and contractility but not muscle mass in genetically induced pulmonary emphysema.
  1. Nature. 2024 Aug;632(8027): 987-988
    Inner membrane turns inside out to exit mitochondrial organelles.
    David Pla-Martín, Andreas S Reichert.
      
    Keywords:  Biochemistry; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-02528-w
  2. Neuromuscul Disord. 2024 Aug 02. pii: S0960-8966(24)00146-9. [Epub ahead of print]43 14-19
    Niacin supplementation in a child with novel MTTN variant m.5670A>G causing early onset mitochondrial myopathy and NAD+ deficiency.
    Juho Aaltio, Liliya Euro, Olli Tynninen, Hieu S Vu, Min Ni, Ralph J DeBerardinis, Anu Suomalainen, Pirjo Isohanni.
      Myopathy is a common manifestation in mitochondrial disorders, but the pathomechanisms are still insufficiently studied in children. Here, we report a severe, progressive mitochondrial myopathy in a four-year-old child, who died at eight years. He developed progressive loss of muscle strength with nocturnal hypoventilation and dilated cardiomyopathy. Skeletal muscle showed ragged red fibers and severe combined respiratory chain deficiency. Mitochondrial DNA sequencing revealed a novel m.5670A>G mutation in mitochondrial tRNAAsn (MTTN) with 88 % heteroplasmy in muscle. The proband also had systemic NAD+ deficiency but rescuing this with the NAD+ precursor niacin did not stop disease progression. Targeted metabolomics revealed an overall shift of metabolism towards controls after niacin supplementation, with normalized tryptophan metabolites and lipid-metabolic markers, but most amino acids did not respond to niacin therapy. To conclude, we report a new MTTN mutation, secondary NAD+ deficiency in childhood-onset mitochondrial myopathy with metabolic but meager clinical response to niacin supplementation.
    Keywords:  MTTN; Mitochondrial myopathy; NAD+ deficiency; Niacin; Niacin supplementation; tRNA-Asn
    DOI:  https://doi.org/10.1016/j.nmd.2024.07.005
  3. Nature. 2024 Aug 21.
    Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
    Akriti Prashar, Claudio Bussi, Antony Fearns, Mariana I Capurro, Xiaodong Gao, Hiromi Sesaki, Maximiliano G Gutierrez, Nicola L Jones.
      Mitochondrial membranes define distinct structural and functional compartments. Cristae of the inner mitochondrial membrane (IMM) function as independent bioenergetic units that undergo rapid and transient remodelling, but the significance of this compartmentalized organization is unknown1. Using super-resolution microscopy, here we show that cytosolic IMM vesicles, devoid of outer mitochondrial membrane or mitochondrial matrix, are formed during resting state. These vesicles derived from the IMM (VDIMs) are formed by IMM herniation through pores formed by voltage-dependent anion channel 1 in the outer mitochondrial membrane. Live-cell imaging showed that lysosomes in proximity to mitochondria engulfed the herniating IMM and, aided by the endosomal sorting complex required for transport machinery, led to the formation of VDIMs in a microautophagy-like process, sparing the remainder of the organelle. VDIM formation was enhanced in mitochondria undergoing oxidative stress, suggesting their potential role in maintenance of mitochondrial function. Furthermore, the formation of VDIMs required calcium release by the reactive oxygen species-activated, lysosomal calcium channel, transient receptor potential mucolipin 1, showing an interorganelle communication pathway for maintenance of mitochondrial homeostasis. Thus, IMM compartmentalization could allow for the selective removal of damaged IMM sections via VDIMs, which should protect mitochondria from localized injury. Our findings show a new pathway of intramitochondrial quality control.
    DOI:  https://doi.org/10.1038/s41586-024-07835-w
  4. Mol Neurobiol. 2024 Aug 23.
    The Role of Mitochondrial Pyruvate Carrier in Neurological Disorders.
    Yue Liu, Xiying Yu, Wei Jiang.
      The mitochondrial pyruvate carrier (MPC) is a specific protein complex located in the inner mitochondrial membrane. Comprising a heterodimer of two homodimeric membrane proteins, mitochondrial pyruvate carrier 1 and mitochondrial pyruvate carrier 2, MPC connects cytoplasmic metabolism to mitochondrial metabolism by transferring pyruvate from the cytoplasm to the mitochondria. The nervous system requires substantial energy to maintain its function, and the mitochondrial energy supply is closely linked to neurological function. Mitochondrial dysfunction can induce or exacerbate intracerebral pathologies. MPC influences mitochondrial function due to its specific role as a pyruvate transporter. However, recent studies on MPC and mitochondrial dysfunction in neurological disorders have yielded controversial results, and the underlying mechanisms remain unclear. In this brief review, we provide an overview of the structure and function of MPC. We further discuss the potential mechanisms and feasibility of targeting MPC in treating Parkinson's disease, Alzheimer's disease, and cerebral ischemia/hypoxia injury. This review aims to offer insights into MPC as a target for clinical treatment.
    Keywords:  Metabolism; Mitochondrial dysfunction; Mitochondrial pyruvate carrier; Neurological disorders
    DOI:  https://doi.org/10.1007/s12035-024-04435-7
  5. Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00287-0. [Epub ahead of print]
    Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
    Traci E LaMoia, Brandon T Hubbard, Mateus T Guerra, Ali Nasiri, Ikki Sakuma, Mario Kahn, Dongyan Zhang, Russell P Goodman, Michael H Nathanson, Yasemin Sancak, Mark Perelis, Vamsi K Mootha, Gerald I Shulman.
      To examine the roles of mitochondrial calcium Ca2+ ([Ca2+]mt) and cytosolic Ca2+ ([Ca2+]cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced [Ca2+]mt and increased [Ca2+]cyt content. Despite decreased [Ca2+]mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of [14C16]palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that [Ca2+]cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from [Ca2+]mt and reveal a key role for [Ca2+]cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.
    Keywords:  CAMKII; Q-Flux; calcium; fat oxidation; glucose oxidation; isocitrate dehydrogenase flux; metabolic dysfunction-associated steatotic liver disease; mitochondria; mitochondrial calcium uniporter; succinate dehydrogenase flux; tricarboxylic acid cycle; type 2 diabetes; α-ketoglutarate dehydrogenase flux
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.016
  6. JCI Insight. 2024 Aug 20. pii: e178973. [Epub ahead of print]
    dldhcri3 zebrafish exhibited altered mitochondrial ultrastructure, morphology and dysfunction partially rescued by probucol or thiamine.
    Manuela Lavorato, Donna Iadarola, Cristina Remes, Prabhjot Kaur, Chynna Broxton, Neal D Mathew, Rui Xiao, Christoph Seiler, Eiko Nakamaru-Ogiso, Vernon E Anderson, Marni J Falk.
      Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disease caused by variants in DLD, the E3 subunit of mitochondrial α-keto acid dehydrogenase complexes. DLD disease symptoms are multi-systemic, variably manifesting as Leigh syndrome, neurodevelopmental disability, seizures, cardiomyopathy, liver disease, fatigue and lactic acidemia. While most DLD disease symptoms are attributed to dysfunction of the pyruvate dehydrogenase complex, understanding the effects of other α-keto acid dehydrogenase deficiencies remain unclear. Current therapies for DLD deficiency are ineffective, with no vertebrate animal model available for preclinical study. We created a viable Danio rerio (zebrafish) KO model of DLD deficiency, dldhcri3. Detailed phenotypic characterization revealed shortened larval survival, uninflated swim bladder, hepatomegaly and fatty liver, and reduced swim activity. These animals displayed increased pyruvate and lactate levels, with severe disruption of branched-chain amino acid catabolism manifest as increased valine, leucine, isoleucine, α-ketoisovalerate, and α-ketoglutarate levels. Evaluation of mitochondrial ultrastructure revealed gross enlargement, severe cristae disruption and reduction in matrix electron density in liver, intestines, and muscle. Therapeutic modeling of candidate therapies demonstrated probucol or thiamine improved larval swim activity. Overall, this vertebrate model demonstrated characteristic phenotypic and metabolic alterations of DLD disease, offering a robust platform to screen and characterize candidate therapies.
    Keywords:  Drug therapy; Genetics; Intermediary metabolism; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.178973
  7. iScience. 2024 Aug 16. 27(8): 110510
    BCL2L13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function.
    Dogan Grepper, Cassandra Tabasso, Nadège Zanou, Axel K F Aguettaz, Mauricio Castro-Sepulveda, Dorian V Ziegler, Sylviane Lagarrigue, Yoan Arribat, Adrien Martinotti, Ammar Ebrahimi, Jean Daraspe, Lluis Fajas, Francesca Amati.
      The physical connection between mitochondria and endoplasmic reticulum (ER) is an essential signaling hub to ensure organelle and cellular functions. In skeletal muscle, ER-mitochondria calcium (Ca2+) signaling is crucial to maintain cellular homeostasis during physical activity. High expression of BCL2L13, a member of the BCL-2 family, was suggested as an adaptive response in endurance-trained human subjects. In adult zebrafish, we found that the loss of Bcl2l13 impairs skeletal muscle structure and function. Ca2+ signaling is altered in Bcl2l13 knockout animals and mitochondrial complexes activity is decreased. Organelle fractioning in mammalian cells shows BCL2L13 at mitochondria, ER, and mitochondria-associated membranes. ER-mitochondria contact sites number is not modified by BCL2L13 modulation, but knockdown of BCL2L13 in C2C12 cells changes cytosolic Ca2+ release and mitochondrial Ca2+ uptake. This suggests that BCL2L13 interaction with mitochondria and ER, and its role in Ca2+ signaling, contributes to proper skeletal muscle function.
    Keywords:  cell biology; pharmacology
    DOI:  https://doi.org/10.1016/j.isci.2024.110510
  8. Bioessays. 2024 Aug 19. e2400090
    FAM210A: An emerging regulator of mitochondrial homeostasis.
    Yubo Wang, Feng Yue.
      Mitochondrial homeostasis serves as a cornerstone of cellular function, orchestrating a delicate balance between energy production, redox status, and cellular signaling transduction. This equilibrium involves a myriad of interconnected processes, including mitochondrial dynamics, quality control mechanisms, and biogenesis and degradation. Perturbations in mitochondrial homeostasis have been implicated in a wide range of diseases, including neurodegenerative diseases, metabolic syndromes, and aging-related disorders. In the past decades, the discovery of numerous mitochondrial proteins and signaling has led to a more complete understanding of the intricate mechanisms underlying mitochondrial homeostasis. Recent studies have revealed that Family with sequence similarity 210 member A (FAM210A) is a novel nuclear-encoded mitochondrial protein involved in multiple aspects of mitochondrial homeostasis, including mitochondrial quality control, dynamics, cristae remodeling, metabolism, and proteostasis. Here, we review the function and physiological role of FAM210A in cellular and organismal health. This review discusses how FAM210A acts as a regulator on mitochondrial inner membrane to coordinate mitochondrial dynamics and metabolism.
    Keywords:  FAM210A; cristae remodeling; energy metabolism; mitochondrial dynamics; proteostasis; quality control
    DOI:  https://doi.org/10.1002/bies.202400090
  9. Elife. 2024 Aug 19. pii: e97027. [Epub ahead of print]13
    Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes.
    Sara Bitar, Timo Baumann, Christopher Weber, Majd Abusaada, Liliana Rojas-Charry, Patrick Ziegler, Thomas Schettgen, Isabella Eva Randerath, Vivek Venkataramani, Bernhard Michalke, Eva-Maria Hanschmann, Giuseppe Arena, Rejko Krueger, Li Zhang, Axel Methner.
      Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain. Familial cases of PD are often caused by mutations of PTEN-induced kinase 1 (PINK1) and the ubiquitin ligase Parkin, both pivotal in maintaining mitochondrial quality control. CISD1, a homodimeric mitochondrial iron-sulfur-binding protein, is a major target of Parkin-mediated ubiquitination. We here discovered a heightened propensity of CISD1 to form dimers in Pink1 mutant flies and in dopaminergic neurons from PINK1 mutation patients. The dimer consists of two monomers that are covalently linked by a disulfide bridge. In this conformation CISD1 cannot coordinate the iron-sulfur cofactor. Overexpressing Cisd, the Drosophila orthologue of CISD1, and a mutant Cisd incapable of binding the iron-sulfur cluster in Drosophila reduced climbing ability and lifespan. This was more pronounced with mutant Cisd and aggravated in Pink1 mutant flies. Complete loss of Cisd, in contrast, rescued all detrimental effects of Pink1 mutation on climbing ability, wing posture, dopamine levels, lifespan, and mitochondrial ultrastructure. Our results suggest that Cisd, probably iron-depleted Cisd, operates downstream of Pink1 shedding light on PD pathophysiology and implicating CISD1 as a potential therapeutic target.
    Keywords:  D. melanogaster; cell biology; human; mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.97027
  10. Front Cell Dev Biol. 2024 ;12 1468818
    Editorial: Mitochondrial plasticity and quality control in health and disease.
    Francesca Forini, Elena Levantini, Emilia Bramanti, Filippo Maria Santorelli, Azhar Ali, Vincenzo Lionetti, Milena Rizzo.
      
    Keywords:  mitochondria in development and differentiation; mitochondria quality control; mitochondrial disorders; mitochondrial dysfunction in pathologies; mitochondrial genome
    DOI:  https://doi.org/10.3389/fcell.2024.1468818
  11. PLoS Biol. 2024 Aug;22(8): e3002756
    A somatic view of the genomic impact of mitochondrial endosymbiosis.
    Rose M Doss, Martin W Breuss.
      The endosymbiosis of mitochondrial ancestors resulted in the transfer of genetic material on an evolutionary scale for eukaryotic species. A new study in PLOS Biology expands this to the genome of somatic cells within individuals and highlights its correlation with aging and disease.
    DOI:  https://doi.org/10.1371/journal.pbio.3002756
  12. Neurobiol Dis. 2024 Aug 20. pii: S0969-9961(24)00244-4. [Epub ahead of print] 106644
    Phenotyping mitochondrial glutamyl-tRNA synthetase deficiency (EARS2): A case series and systematic literature review.
    Gonçalo Pelayo, Margarida Paiva Coelho, Joana Correia, Anabela Bandeira, Célia Nogueira, Laura Vilarinho, Esmeralda Martins.
      Mitochondrial glutamyl-aminoacyl tRNA synthetase deficiency, stemming from biallelic mutations in the EARS2 gene, was first described in 2012. With <50 cases reported globally, this condition exhibits a distinct phenotype of neonatal or childhood-onset, often referred to as leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). It has also been one of the few reversible mitochondrial disorders described. The natural history of these patients is poorly documented, ranging from clinical and radiological improvement to early death. Herein, we detail three cases from our centre, including follow-up on the Portuguese patient reported by Steenweg et al., These cases illustrate the phenotypic spectrum: i) rapidly progressive neonatal presentation with lactic acidemia and corpus callosum agenesis, leading to early death; ii) early onset with a severe, slowly progressive course; iii) early onset with a milder phenotype, showing some improvement and mild neurological symptoms. Additionally, we conducted a systematic literature review on cases of EARS2-deficient patients, focusing on clinical manifestations, laboratory findings, radiological aspects, and disease progression over time, along with respective data analysis. "Patients with EARS2 deficiency typically present within the first year of life with a well-defined neurometabolic disorder picture, often including hypotonia and/or spasticity, along with neurodevelopmental delay or regression. There are no pathognomonic features specific to EARS2 deficiency, and no genotype-phenotype correlation has been identified." Comparing to initial characterization by Steenweg et al., this analysis reveals an expanded disease spectrum. We propose a novel strategy for clustering phenotypes into severe, moderate, or mild disease based on initial presentation, seemingly correlating with disease progression. The paucity of data on the disease's natural history highlights the need for a multicentric approach to enhance understanding and management. TAKE-HOME MESSAGE: Analysis of all cases published with EARS2 deficiency allows for establish disease spectrum and a novel strategy for clustering phenotypes which correlate to disease progression.
    Keywords:  EARS2 protein; Glutamyl-tRNA synthetase 2; Human; Mitochondrial; Mitochondrial diseases
    DOI:  https://doi.org/10.1016/j.nbd.2024.106644
  13. EMBO Mol Med. 2024 Aug 21.
    Restoration of defective oxidative phosphorylation to a subset of neurons prevents mitochondrial encephalopathy.
    Brittni R Walker, Lise-Michelle Theard, Milena Pinto, Monica Rodriguez-Silva, Sandra R Bacman, Carlos T Moraes.
      Oxidative Phosphorylation (OXPHOS) defects can cause severe encephalopathies and no effective treatment exists for these disorders. To assess the ability of gene replacement to prevent disease progression, we subjected two different CNS-deficient mouse models (Ndufs3/complex I or Cox10/complex IV conditional knockouts) to gene therapy. We used retro-orbitally injected AAV-PHP.eB to deliver the missing gene to the CNS of these mice. In both cases, we observed survival extension from 5-6 to more than 15 months, with no detectable disease phenotypes. Likewise, molecular and cellular phenotypes were mostly recovered in the treated mice. Surprisingly, these remarkable phenotypic improvements were achieved with only ~30% of neurons expressing the transgene from the AAV-PHP.eB vector in the conditions used. These findings suggest that neurons lacking OXPHOS are protected by the surrounding neuronal environment and that partial compensation for neuronal OXPHOS loss can have disproportionately positive effects.
    Keywords:  Gene Therapy; Mitochondria; Mitochondrial Disease; Oxidative Phosphorylation
    DOI:  https://doi.org/10.1038/s44321-024-00111-4
  14. Cell Signal. 2024 Aug 19. pii: S0898-6568(24)00321-8. [Epub ahead of print] 111353
    Unfolded proteins in the mitochondria activate HRI and inhibit mitochondrial protein translation.
    Yongshu Wu, Yang Yang, Xiaodong Qin, Zhixiong Zhang, Munib Ullah, Yanmin Li, Zhidong Zhang.
      The mitochondrial unfolded protein response (UPRmt) is triggered through eIF2α phosphorylation in mammals. However, the mechanisms of UPRmt activation and the influence of eIF2α phosphorylation on mitochondrial protein translation remain unclear. In this study, we confirmed that the UPRmt is a rapid and specific stress response that occurs through pharmacological induction of eIF2α phosphorylation, along with the phosphorylation of eIF2α, ATF4, and CHOP. Moreover, with the upregulation of the expression of some chaperones, cytochrome P450 enzymes, and DDIT4, as determined by RNA-Seq and ribosome profiling, eIF2α phosphorylation was found to be essential for the expression of ATF4 and CHOP, after which ATF4 trafficked into the nucleus and initiated CHOP expression. In addition, the generation of ROS and mitochondrial morphology were not affected by the GTPP-induced UPRmt. Furthermore, we investigated the mechanism by which HRI kinase-mediated UPRmt is induced by mitochondrial unfolded proteins via CRISPR-Cas9 technology, mitochondrial recruitment of HRI and interactions with other proteins. Moreover, we confirmed that mitochondrial protein translation and mitochondrial protein import were inhibited through eIF2α phosphorylation with the accumulation of unfolded mitochondrial proteins. These findings reveal the molecular mechanism of the UPRmt and its impact on cellular protein translation, which will offer novel insights into the functions of the UPRmt, including its implications for human disease and pathobiology.
    Keywords:  Heme-regulated inhibitor; Mitochondrial proteostasis; Mitochondrial unfolded protein response; eIF2α phosphorylation
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111353
  15. J Transl Med. 2024 Aug 22. 22(1): 780
    Queuine ameliorates impaired mitochondrial function caused by mt-tRNAAsn variants.
    Yan Lin, Jiayin Wang, Xingyu Zhuang, Ying Zhao, Wei Wang, Dongdong Wang, Yuying Zhao, Chuanzhu Yan, Kunqian Ji.
       BACKGROUND: Mitochondrial tRNA (mt-tRNA) variants have been found to cause disease. Post-transcriptional queuosine (Q) modifications of mt-tRNA can promote efficient mitochondrial mRNA translation. Q modifications of mt-tRNAAsn have recently been identified. Here, the therapeutic effectiveness of queuine was investigated in cells from patients with mt-tRNAAsn variants.
    METHODS: Six patients (from four families) carrying mt-tRNAAsn variants were included in the study. Queuine levels were quantified by mass spectrometry. Clinical, genetic, histochemical, biochemical, and molecular analysis was performed on muscle tissues and lymphoblastoid cell lines (LCLs) from patients to investigate the pathogenicity of the novel m.5708 C > T variant. The use of queuine in mitigating mitochondrial dysfunction resulting from the mt-tRNAAsn variants was evaluated.
    RESULTS: The variants included the m.5701 delA, m.5708 C > T, m.5709 C > T, and m.5698 G > A variants in mt-tRNAAsn. The pathogenicity of the novel m.5708 C > T variant was confirmed, as demonstrated by a decreased steady-state level of mt-tRNAAsn, mtDNA-encoded protein levels, oxygen consumption rate (OCR), and the respiratory complex activity. Notably, the serum queuine level was significantly reduced in these patients and in vitro queuine supplementation was found to restore the reductions in mitochondrial protein activities, mitochondrial membrane potential, OCR, and increases in reactive oxygen species.
    CONCLUSIONS: The study not only confirmed the pathogenicity of the m.5708 C > T variant but also explored the therapeutic potential of queuine in individuals with mt-tRNAAsn variants. The recognition of the novel m.5708 C > T variant's pathogenic nature contributes to our comprehension of mitochondrial disorders. Furthermore, the results emphasize queuine supplementation as a promising approach to enhance the stability of mt-tRNAAsn and rescue mitochondrial dysfunction caused by mt-tRNAAsn variants, indicating potential implications for the development of targeted therapies for patients with mt-tRNAAsn variants.
    Keywords:  Mitochondrial disease; Queuine; Therapy; m.5708C > T; mt-tRNAAsn
    DOI:  https://doi.org/10.1186/s12967-024-05574-0
  16. Mil Med Res. 2024 Aug 21. 11(1): 59
    Targeting mitochondrial quality control: new therapeutic strategies for major diseases.
    Wei-Long Hong, He Huang, Xue Zeng, Chen-Yang Duan.
      Mitochondria play a crucial role in maintaining the normal physiological state of cells. Hence, ensuring mitochondrial quality control is imperative for the prevention and treatment of numerous diseases. Previous reviews on this topic have however been inconsistencies and lack of systematic organization. Therefore, this review aims to provide a comprehensive and systematic overview of mitochondrial quality control and explore the possibility of targeting the same for the treatment of major diseases. This review systematically summarizes three fundamental characteristics of mitochondrial quality control, including mitochondrial morphology and dynamics, function and metabolism, and protein expression and regulation. It also extensively examines how imbalances in mitochondrial quality are linked to major diseases, such as ischemia-hypoxia, inflammatory disorders, viral infections, metabolic dysregulations, degenerative conditions, and tumors. Additionally, the review explores innovative approaches to target mitochondrial quality control, including using small molecule drugs that regulate critical steps in maintaining mitochondrial quality, nanomolecular materials designed for precise targeting of mitochondria, and novel cellular therapies, such as vesicle therapy and mitochondrial transplantation. This review offers a novel perspective on comprehending the shared mechanisms underlying the occurrence and progression of major diseases and provides theoretical support and practical guidance for the clinical implementation of innovative therapeutic strategies that target mitochondrial quality control for treating major diseases.
    Keywords:  Major diseases; Mitochondrial quality control; Mitochondrial targeted therapy
    DOI:  https://doi.org/10.1186/s40779-024-00556-1
  17. Cell Metab. 2024 Aug 16. pii: S1550-4131(24)00291-2. [Epub ahead of print]
    Misregulation of mitochondrial 6mA promotes the propagation of mutant mtDNA and causes aging in C. elegans.
    Anne Hahn, Grace Ching Ching Hung, Arnaud Ahier, Chuan-Yang Dai, Ina Kirmes, Brian M Forde, Daniel Campbell, Rachel Shin Yie Lee, Josiah Sucic, Tessa Onraet, Steven Zuryn.
      In virtually all eukaryotes, the mitochondrial DNA (mtDNA) encodes proteins necessary for oxidative phosphorylation (OXPHOS) and RNAs required for their synthesis. The mechanisms of regulation of mtDNA copy number and expression are not completely understood but crucially ensure the correct stoichiometric assembly of OXPHOS complexes from nuclear- and mtDNA-encoded subunits. Here, we detect adenosine N6-methylation (6mA) on the mtDNA of diverse animal and plant species. This modification is regulated in C. elegans by the DNA methyltransferase DAMT-1 and demethylase ALKB-1. Misregulation of mtDNA 6mA through targeted modulation of these activities inappropriately alters mtDNA copy number and transcript levels, impairing OXPHOS function, elevating oxidative stress, and shortening lifespan. Compounding these defects, mtDNA 6mA hypomethylation promotes the cross-generational propagation of a deleterious mtDNA. Together, these results reveal that mtDNA 6mA is highly conserved among eukaryotes and regulates lifespan by influencing mtDNA copy number, expression, and heritable mutation levels in vivo.
    Keywords:  6mA; ROS; aging; epigenetics; heteroplasmy; lifespan; mitochondria; mitochondrial genome; mtDNA; oxidative stress
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.020
  18. Nat Comput Sci. 2024 Aug 22.
    AI-recognized mitochondrial phenotype enables identification of drug targets.
      
    DOI:  https://doi.org/10.1038/s43588-024-00682-9
  19. J Mol Cell Cardiol. 2024 Aug 21. pii: S0022-2828(24)00135-4. [Epub ahead of print]195 103-109
    Metabolic cycles: A unifying concept for energy transfer in the heart.
    Mitchell Beito, Heinrich Taegtmeyer.
      It is still debated whether changes in metabolic flux are cause or consequence of contractile dysfunction in non-ischemic heart disease. We have previously proposed a model of cardiac metabolism grounded in a series of six moiety-conserved, interconnected cycles. In view of a recent interest to augment oxygen availability in heart failure through iron supplementation, we integrated this intervention in terms of moiety conservation. Examining published work from both human and murine models, we argue this strategy restores a mitochondrial cycle of energy transfer by enhancing mitochondrial pyruvate carrier (MPC) expression and providing pyruvate as a substrate for carboxylation and anaplerosis. Metabolomic data from failing heart muscle reveal elevated pyruvate levels with a concomitant decrease in the levels of Krebs cycle intermediates. Additionally, MPC is downregulated in the same failing hearts, as well as under hypoxic conditions. MPC expression increases upon mechanical unloading in the failing human heart, as does contractile function. We note that MPC deficiency also alters expression of enzymes involved in pyruvate carboxylation and decarboxylation, increases intermediates of biosynthetic pathways, and eventually leads to cardiac hypertrophy and dilated cardiomyopathy. Collectively, we propose that an unbroken chain of moiety-conserved cycles facilitates energy transfer in the heart. We refer to the transport and subsequent carboxylation of pyruvate in the mitochondrial matrix as an example and a proposed target for metabolic support to reverse impaired contractile function.
    Keywords:  Cardiac metabolism; Energy transfer; Heart failure; Metabolic cycles
    DOI:  https://doi.org/10.1016/j.yjmcc.2024.08.002
  20. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2402491121
    MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.
    Prottoy Hasan, Elena Berezhnaya, Macarena Rodríguez-Prados, David Weaver, Carmen Bekeova, Benjamin Cartes-Saavedra, Erin Birch, Andreas M Beyer, Janine H Santos, Erin L Seifert, John W Elrod, György Hajnóczky.
      Activating Ca2+-sensitive enzymes of oxidative metabolism while preventing calcium overload that leads to mitochondrial and cellular injury requires dynamic control of mitochondrial Ca2+ uptake. This is ensured by the mitochondrial calcium uptake (MICU)1/2 proteins that gate the pore of the mitochondrial calcium uniporter (mtCU). MICU1 is relatively sparse in the heart, and recent studies claimed the mammalian heart lacks MICU1 gating of mtCU. However, genetic models have not been tested. We find that MICU1 is present in a complex with MCU in nonfailing human hearts. Furthermore, using murine genetic models and pharmacology, we show that MICU1 and MICU2 control cardiac mitochondrial Ca2+ influx, and that MICU1 deletion alters cardiomyocyte mitochondrial calcium signaling and energy metabolism. MICU1 loss causes substantial compensatory changes in the mtCU composition and abundance, increased turnover of essential MCU regulator (EMRE) early on and, later, of MCU, that limit mitochondrial Ca2+ uptake and allow cell survival. Thus, both the primary consequences of MICU1 loss and the ensuing robust compensation highlight MICU1's relevance in the beating heart.
    Keywords:  MICU1; MICU2; calcium; cardiomyocyte; mitochondrial calcium uniporter gating
    DOI:  https://doi.org/10.1073/pnas.2402491121
  21. Cell Mol Life Sci. 2024 Aug 19. 81(1): 357
    SLC30A9: an evolutionarily conserved mitochondrial zinc transporter essential for mammalian early embryonic development.
    Jing Ge, Huihui Li, Xin Liang, Bing Zhou.
      SLC30A9 (ZnT9) is a mitochondria-resident zinc transporter. Mutations in SLC30A9 have been reported in human patients with a novel cerebro-renal syndrome. Here, we show that ZnT9 is an evolutionarily highly conserved protein, with many regions extremely preserved among evolutionarily distant organisms. In Drosophila melanogaster (the fly), ZnT9 (ZnT49B) knockdown results in acutely impaired movement and drastic mitochondrial deformation. Severe Drosophila ZnT9 (dZnT9) reduction and ZnT9-null mutant flies are pupal lethal. The phenotype of dZnT9 knockdown can be partially rescued by mouse ZnT9 expression or zinc chelator TPEN, indicating the defect of dZnT9 loss is indeed a result of zinc dyshomeostasis. Interestingly, in the mouse, germline loss of Znt9 produces even more extreme phenotypes: the mutant embryos exhibit midgestational lethality with severe development abnormalities. Targeted mutagenesis of Znt9 in the mouse brain leads to serious dwarfism and physical incapacitation, followed by death shortly. Strikingly, the GH/IGF-1 signals are almost non-existent in these tissue-specific knockout mice, consistent with the medical finding in some human patients with severe mitochondrial deficiecny. ZnT9 mutations cause mitochondrial zinc dyshomeostasis, and we demonstrate mechanistically that mitochondrial zinc elevation quickly and potently inhibits the activities of respiration complexes. These results reveal the critical role of ZnT9 and mitochondrial zinc homeostasis in mammalian development. Based on our functional analyses, we finally discussed the possible nature of the so far identified human SLC30A9 mutations.
    Keywords:  CG8632; Electron transport chain; GH/IGF; ZnT49B; ZnT9
    DOI:  https://doi.org/10.1007/s00018-024-05377-y
  22. Rev Neurosci. 2024 Aug 20.
    Unraveling mitochondrial dysfunction: comprehensive perspectives on its impact on neurodegenerative diseases.
    Abdul Aziz Mohamed Yusoff, Siti Zulaikha Nashwa Mohd Khair.
      Neurodegenerative diseases represent a significant challenge to modern medicine, with their complex etiology and progressive nature posing hurdles to effective treatment strategies. Among the various contributing factors, mitochondrial dysfunction has emerged as a pivotal player in the pathogenesis of several neurodegenerative disorders. This review paper provides a comprehensive overview of how mitochondrial impairment contributes to the development of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, driven by bioenergetic defects, biogenesis impairment, alterations in mitochondrial dynamics (such as fusion or fission), disruptions in calcium buffering, lipid metabolism dysregulation and mitophagy dysfunction. It also covers current therapeutic interventions targeting mitochondrial dysfunction in these diseases.
    Keywords:  mitochondrial bioenergetics and biogenesis; mitochondrial dynamics and mitophagy; mitochondrial dysfunctions; neurodegenerative diseases; therapy
    DOI:  https://doi.org/10.1515/revneuro-2024-0080
  23. Nat Commun. 2024 Aug 20. 15(1): 7134
    Structural basis for substrate binding and selection by human mitochondrial RNA polymerase.
    Karl Herbine, Ashok R Nayak, Dmitry Temiakov.
      The mechanism by which RNAP selects cognate substrates and discriminates between deoxy and ribonucleotides is of fundamental importance to the fidelity of transcription. Here, we present cryo-EM structures of human mitochondrial transcription elongation complexes that reveal substrate ATP bound in Entry and Insertion Sites. In the Entry Site, the substrate binds along the O helix of the fingers domain of mtRNAP but does not interact with the templating DNA base. Interactions between RNAP and the triphosphate moiety of the NTP in the Entry Site ensure discrimination against nucleosides and their diphosphate and monophosphate derivatives but not against non-cognate rNTPs and dNTPs. Closing of the fingers domain over the catalytic site results in delivery of both the templating DNA base and the substrate into the Insertion Site and recruitment of the catalytic magnesium ions. The cryo-EM data also reveal a conformation adopted by mtRNAP to reject a non-cognate substrate from its active site. Our findings establish a structural basis for substrate binding and suggest a unified mechanism of NTP selection for single-subunit RNAPs.
    DOI:  https://doi.org/10.1038/s41467-024-50817-9
  24. Elife. 2024 Aug 23. pii: RP87880. [Epub ahead of print]12
    Drosophila model to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy.
    Yohei Nitta, Jiro Osaka, Ryuto Maki, Satoko Hakeda-Suzuki, Emiko Suzuki, Satoshi Ueki, Takashi Suzuki, Atsushi Sugie.
      Autosomal dominant optic atrophy (DOA) is a progressive form of blindness caused by degeneration of retinal ganglion cells and their axons, mainly caused by mutations in the OPA1 mitochondrial dynamin like GTPase (OPA1) gene. OPA1 encodes a dynamin-like GTPase present in the mitochondrial inner membrane. When associated with OPA1 mutations, DOA can present not only ocular symptoms but also multi-organ symptoms (DOA plus). DOA plus often results from point mutations in the GTPase domain, which are assumed to have dominant-negative effects. However, the presence of mutations in the GTPase domain does not always result in DOA plus. Therefore, an experimental system to distinguish between DOA and DOA plus is needed. In this study, we found that loss-of-function mutations of the dOPA1 gene in Drosophila can imitate the pathology of optic nerve degeneration observed in DOA. We successfully rescued this degeneration by expressing the human OPA1 (hOPA1) gene, indicating that hOPA1 is functionally interchangeable with dOPA1 in the fly system. However, mutations previously identified did not ameliorate the dOPA1 deficiency phenotype. By expressing both WT and DOA plus mutant hOPA1 forms in the optic nerve of dOPA1 mutants, we observed that DOA plus mutations suppressed the rescue, facilitating the distinction between loss-of-function and dominant-negative mutations in hOPA1. This fly model aids in distinguishing DOA from DOA plus and guides initial hOPA1 mutation treatment strategies.
    Keywords:  D. melanogaster; Drosophila; OPA1; axonal degeneration; dominant optic atrophy; medicine
    DOI:  https://doi.org/10.7554/eLife.87880
  25. Endocrine. 2024 Aug 22.
    Hormonal orchestra: mastering mitochondria's role in health and disease.
    Ebtesam Al-Suhaimi, Rahaf AlQuwaie, Reem AlSaqabi, Dwi Winarni, Firli Rahmah Primula Dewi, Abdullah A AlRubaish, Adeeb Shehzad, Abdelhamid Elaissari.
      Mitochondria is a subcellular organelle involved in the pathogenesis of cellular stress, immune responses, differentiation, metabolic disorders, aging, and death by regulating process of fission, fusion, mitophagy, and transport. However, an increased interest in mitochondria as powerhouse for ATP production, the mechanisms of mitochondria-mediated cellular dysfunction in response to hormonal interaction remains unknown. Mitochondrial matrix contains chaperones and proteases that regulate intrinsic apoptosis pathway through pro-apoptotic Bcl-2 family's proteins Bax/Bak, and Cyt C release, and induces caspase-dependent and independent cells death. Energy and growth regulators such as thyroid hormones have profound effect on mitochondrial inner membrane protein and lipid compositions, ATP production by regulating oxidative phosphorylation system. Mitochondria contain cholesterol side-chain cleavage enzyme, P450scc, ferredoxin, and ferredoxin reductase providing an essential site for steroid hormones biosynthesis. In line with this, neurohormones such as oxytocin, vasopressin, and melatonin are correlated with mitochondrial integrity, displaying therapeutic implications for inflammatory and immune responses. Melatonin's also displayed protective role against oxidative stress and mitochondrial synthesis of ROS, suggesting a defense mechanism against aging-related diseases. An imbalance in mitochondrial bioenergetics can cause neurodegenerative disorders, cardiovascular diseases, and cancers. Hormone-induced PGC-1α stimulates mitochondrial biogenesis via activation of NRF1 and NRF2, which in turn triggers mtTFA in brown adipose and cardiac myocytes. Mitochondria can be transferred through cells merging, exosome-mediated transfer, and tunneling through nanotubes. By delineating the underlying molecular mechanism of hormonal mitochondrial interaction, this study reviews the dynamics mechanisms of mitochondria and its effects on cellular level, health, diseases, and therapeutic strategies targeting mitochondrial diseases.
    Keywords:  Bioenergetics; Brain Disease; Hormones; Mitochondria; Pathophysiology
    DOI:  https://doi.org/10.1007/s12020-024-03967-1
  26. Orphanet J Rare Dis. 2024 Aug 21. 19(1): 305
    IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency.
    Qiyu Dong, Xiaojie Yin, Shuanglong Fan, Sheng Zhong, Wenxin Yang, Keer Chen, Qian Wang, Xue Ma, Refiloe Laurentinah Mahlatsi, Yanling Yang, Jianxin Lyu, Hezhi Fang, Ya Wang.
       BACKGROUND: Leigh syndrome (LS) is a common mitochondrial disease caused by mutations in both mitochondrial and nuclear genes. Isoleucyl-tRNA synthetase 2 (IARS2) encodes mitochondrial isoleucine-tRNA synthetase, and variants in IARS2 have been reported to cause LS. However, the pathogenic mechanism of IARS2 variants is still unclear.
    METHODS: Two unrelated patients, a 4-year-old boy and a 5-year-old boy diagnosed with LS, were recruited, and detailed clinical data were collected. The DNA of the patients and their parents was isolated from the peripheral blood for the identification of pathogenic variants using next-generation sequencing and Sanger sequencing. The ClustalW program, allele frequency analysis databases (gnomAD and ExAc), and pathogenicity prediction databases (Clinvar, Mutation Taster and PolyPhen2) were used to predict the conservation and pathogenicity of the variants. The gene expression level, oxygen consumption rate (OCR), respiratory chain complex activity, cellular adenosine triphosphate (ATP) production, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (ROS) levels were measured in patient-derived lymphocytes and IARS2-knockdown HEK293T cells to evaluate the pathogenicity of the variants.
    RESULTS: We reported 2 unrelated Chinese patients manifested with LS who carried biallelic IARS2 variants (c.1_390del and c.2450G > A from a 4-year-old boy, and c.2090G > A and c.2122G > A from a 5-year-old boy), of which c.1_390del and c.2090G > A were novel. Functional studies revealed that the patient-derived lymphocytes carrying c.1_390del and c.2450G > A variants exhibited impaired mitochondrial function due to severe mitochondrial complexes I and III deficiencies, which was also found in IARS2-knockdown HEK293T cells. The compensatory experiments in vitro cell models confirmed the pathogenicity of IARS2 variants since re-expression of wild-type IARS2 rather than mutant IARS2 could rescue complexes I and III deficiency, oxygen consumption, and cellular ATP content in IARS2 knockdown cells.
    CONCLUSION: Our results not only expand the gene mutation spectrum of LS, but also reveal for the first time the pathogenic mechanism of IARS2 variants due to a combined deficiency of mitochondrial complexes I and III, which is helpful for the clinical diagnosis of IARS2 mutation-related diseases.
    Keywords:   IARS2 ; Leigh syndrome; Mitochondrial disease; OXPHOS
    DOI:  https://doi.org/10.1186/s13023-024-03310-x
  27. ACS Synth Biol. 2024 Aug 20.
    Development of a Signal-integrating Reporter to Monitor Mitochondria-ER Contacts.
    Zheng Yang, David C Chan.
      Mitochondria-endoplasmic reticulum contact sites (MERCS) serve as hotspots for important cellular processes, including calcium homeostasis, phospholipid homeostasis, mitochondria dynamics, and mitochondrial quality control. MERCS reporters based on complementation of green fluorescent proteins (GFP) fragments have been designed to visualize MERCS in real-time, but we find that they do not accurately respond to changes in MERCS content. Here, we utilize split LacZ complementing fragments to develop the first MERCS reporter system (termed SpLacZ-MERCS) that continuously integrates the MERCS information within a cell and generates a fluorescent output. Our system exhibits good organelle targeting, no artifactual tethering, and effective, dynamic tracking of the MERCS level in single cells. The SpLacZ-MERCS reporter was validated by drug treatments and genetic perturbations known to affect mitochondria-ER contacts. The signal-integrating nature of SpLacZ-MERCS may enable systematic identification of genes and drugs that regulate mitochondria-ER interactions. Our successful application of the split LacZ complementation strategy to study MERCS may be extended to study other forms of interorganellar crosstalk.
    Keywords:  contact sites; endoplasmic reticulum; mitochondria; organelle interactions
    DOI:  https://doi.org/10.1021/acssynbio.4c00098
  28. PLoS One. 2024 ;19(8): e0307312
    Proteome-scale prediction of molecular mechanisms underlying dominant genetic diseases.
    Mihaly Badonyi, Joseph A Marsh.
      Many dominant genetic disorders result from protein-altering mutations, acting primarily through dominant-negative (DN), gain-of-function (GOF), and loss-of-function (LOF) mechanisms. Deciphering the mechanisms by which dominant diseases exert their effects is often experimentally challenging and resource intensive, but is essential for developing appropriate therapeutic approaches. Diseases that arise via a LOF mechanism are more amenable to be treated by conventional gene therapy, whereas DN and GOF mechanisms may require gene editing or targeting by small molecules. Moreover, pathogenic missense mutations that act via DN and GOF mechanisms are more difficult to identify than those that act via LOF using nearly all currently available variant effect predictors. Here, we introduce a tripartite statistical model made up of support vector machine binary classifiers trained to predict whether human protein coding genes are likely to be associated with DN, GOF, or LOF molecular disease mechanisms. We test the utility of the predictions by examining biologically and clinically meaningful properties known to be associated with the mechanisms. Our results strongly support that the models are able to generalise on unseen data and offer insight into the functional attributes of proteins associated with different mechanisms. We hope that our predictions will serve as a springboard for researchers studying novel variants and those of uncertain clinical significance, guiding variant interpretation strategies and experimental characterisation. Predictions for the human UniProt reference proteome are available at https://osf.io/z4dcp/.
    DOI:  https://doi.org/10.1371/journal.pone.0307312
  29. Neurochem Int. 2024 Aug 16. pii: S0197-0186(24)00159-1. [Epub ahead of print]179 105832
    3-Nitrotyrosine shortens axons of non-dopaminergic neurons by inhibiting mitochondrial motility.
    Masahiro Hirai, Kohei Suzuki, Yusuke Kassai, Yoshiyuki Konishi.
      3-Nitrotyrosine (3-NT), a byproduct of oxidative and nitrosative stress, is implicated in age-related neurodegenerative disorders. Current literature suggests that free 3-NT becomes integrated into the carboxy-terminal domain of α-tubulin via the tyrosination/detyrosination cycle. Independently of this integration, 3-NT has been associated with the cell death of dopaminergic neurons. Given the critical role of tyrosination/detyrosination in governing axonal morphology and function, the substitution of tyrosine with 3-NT in this process may potentially disrupt axonal homeostasis, although this aspect remains underexplored. In this study, we examined the impact of 3-NT on the axons of cerebellar granule neurons, which is used as a model for non-dopaminergic neurons. Our observations revealed axonal shortening, which correlated with the incorporation of 3-NT into α-tubulin. Importantly, this axonal effect was observed prior to the onset of cellular death. Furthermore, 3-NT was found to diminish mitochondrial motility within the axon, leading to a subsequent reduction in mitochondrial membrane potential. The suppression of syntaphilin, a protein responsible for anchoring mitochondria to microtubules, restored the mitochondrial motility and axonal elongation that were inhibited by 3-NT. These findings underscore the inhibitory role of 3-NT in axonal elongation by impeding mitochondrial movement, suggesting its potential involvement in axonal dysfunction within non-dopaminergic neurons.
    Keywords:  3-Nitrotyrosine; Axonal growth; Cerebellar granule neurons; Microtubules; Mitochondria; Tubulin tyrosine ligase
    DOI:  https://doi.org/10.1016/j.neuint.2024.105832
  30. Mol Metab. 2024 Aug 16. pii: S2212-8778(24)00143-1. [Epub ahead of print] 102012
    Mitochondrial protein deacetylation by SIRT3 in osteoclasts promotes bone resorption with aging in female mice.
    Kimberly K Richardson, Gareeballah Osman Adam, Wen Ling, Aaron Warren, Adriana Marques-Carvalho, Jeff D Thostenson, Kimberly Krager, Nukhet Aykin-Burns, Stephanie D Byrum, Maria Almeida, Ha-Neui Kim.
       OBJECTIVES: The mitochondrial deacetylase sirtuin-3 (SIRT3) is necessary for the increased bone resorption and enhanced function of mitochondria in osteoclasts that occur with advancing age; how SIRT3 drives bone resorption remains elusive.
    METHODS: To determine the role of SIRT3 in osteoclast mitochondria, we used mice with conditional loss of Sirt3 in osteoclast lineage and mice with germline deletion of either Sirt3 or its known target Pink1.
    RESULTS: SIRT3 stimulates mitochondrial quality in osteoclasts in a PINK1-independent manner, promoting mitochondrial activity and osteoclast maturation and function, thereby contributing to bone loss in female but not male mice. Quantitative analyses of global proteomes and acetylomes revealed that deletion of Sirt3 dramatically increased acetylation of osteoclast mitochondrial proteins, particularly ATPase inhibitory factor 1 (ATPIF1), an essential protein for mitophagy. Inhibition of mitophagy via mdivi-1 recapitulated the effect of deletion of Sirt3 or Atpif1 in osteoclast formation and mitochondrial function.
    CONCLUSIONS: Decreasing mitophagic flux in osteoclasts may be a promising pharmacotherapeutic approach to treat osteoporosis in older adults.
    Keywords:  Acetylation; Aging; Mitochondria; Osteoclasts; Proteomics; SIRT3
    DOI:  https://doi.org/10.1016/j.molmet.2024.102012
  31. JCI Insight. 2024 Jul 18. pii: e177152. [Epub ahead of print]9(16):
    NAD+ precursors prolong survival and improve cardiac phenotypes in a mouse model of Friedreich's Ataxia.
    Caroline E Perry, Sarah M Halawani, Sarmistha Mukherjee, Lucie V Ngaba, Melissa Lieu, Won Dong Lee, James G Davis, Gabriel K Adzika, Alyssa N Bebenek, Daniel D Bazianos, Beishan Chen, Elizabeth Mercado-Ayon, Liam P Flatley, Arjun P Suryawanshi, Isabelle Ho, Joshua D Rabinowitz, Suraj D Serai, David M Biko, Jaclyn Tamaroff, Anna DeDio, Kristin Wade, Kimberly Y Lin, David J Livingston, Shana E McCormack, David R Lynch, Joseph A Baur.
      Friedreich's ataxia (FRDA) is a progressive disorder caused by insufficient expression of frataxin, which plays a critical role in assembly of iron-sulfur centers in mitochondria. Individuals are cognitively normal but display a loss of motor coordination and cardiac abnormalities. Many ultimately develop heart failure. Administration of nicotinamide adenine dinucleotide-positive (NAD+) precursors has shown promise in human mitochondrial myopathy and rodent models of heart failure, including mice lacking frataxin in cardiomyocytes. We studied mice with systemic knockdown of frataxin (shFxn), which display motor deficits and early mortality with cardiac hypertrophy. Hearts in these mice do not "fail" per se but become hyperdynamic with small chamber sizes. Data from an ongoing natural history study indicate that hyperdynamic hearts are observed in young individuals with FRDA, suggesting that the mouse model could reflect early pathology. Administering nicotinamide mononucleotide or riboside to shFxn mice increases survival, modestly improves cardiac hypertrophy, and limits increases in ejection fraction. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown are insensitive to NAD+ precursor administration, but glutathione levels are increased, suggesting improved antioxidant capacity. Overall, our findings indicate that NAD+ precursors are modestly cardioprotective in this model of FRDA and warrant further investigation.
    Keywords:  Cardiology; Metabolism; Mitochondria; Neurological disorders
    DOI:  https://doi.org/10.1172/jci.insight.177152
  32. Autophagy. 2024 Aug 23.
    Artificial targeting of autophagy components to mitochondria reveals both conventional and unconventional mitophagy pathways.
    Katharina C Lorentzen, Alan R Prescott, Ian G Ganley.
      Macroautophagy/autophagy enables lysosomal degradation of a diverse array of intracellular material. This process is essential for normal cellular function and its dysregulation is implicated in many diseases. Given this, there is much interest in understanding autophagic mechanisms of action in order to determine how it can be best targeted therapeutically. In mitophagy, the selective degradation of mitochondria via autophagy, mitochondria first need to be primed with signals that allow the recruitment of the core autophagy machinery to drive the local formation of an autophagosome around the target mitochondrion. To determine how the recruitment of different core autophagy components can drive mitophagy, we took advantage of the mito-QC mitophagy assay (an outer mitochondrial membrane-localized tandem mCherry-GFP tag). By tagging autophagy proteins with an anti-mCherry (or anti-GFP) nanobody, we could recruit them to mitochondria and simultaneously monitor levels of mitophagy. We found that targeting ULK1, ATG16L1 and the different Atg8-family proteins was sufficient to induce mitophagy. Mitochondrial recruitment of ULK1 and the Atg8-family proteins induced a conventional mitophagy pathway, requiring RB1CC1/FIP200, PIK3C3/VPS34 activity and ATG5. Surprisingly, the mitophagy pathway upon recruitment of ATG16L1 proceeded independently of ATG5, although it still required RB1CC1 and PIK3C3/VPS34 activity. In this latter pathway, mitochondria were alternatively delivered to lysosomes via uptake into early endosomes.
    Keywords:  ATG16L1; Atg8; ULK1; nanobody; targeted organelle degradation
    DOI:  https://doi.org/10.1080/15548627.2024.2395149
  33. J Biotechnol. 2024 Aug 17. pii: S0168-1656(24)00225-6. [Epub ahead of print]394 57-72
    Nanozymes targeting mitochondrial repair in disease treatment.
    Yuan Zhang, Shuxian Ma, Wenguang Chang, Wanpeng Yu, Lei Zhang.
      Mitochondria are crucial sites for biological oxidation and substance metabolism and plays a vital role in maintaining intracellular homeostasis. When mitochondria undergo oxidative damage or dysfunction, they can harm the organism, leading to various reactive oxygen species (ROS)-related diseases. Therefore, therapies targeting mitochondria are a strategy for treating multiple diseases. Many nanozymes can mimic antioxidant enzymes, which enables them to eliminate ROS to mitigate mitochondrial dysfunction. The therapeutic approaches and drugs targeting the mitochondrial electron transport chain (ETC) have emerged as effective treatments for oxidative stress-related diseases resulting from mitochondrial respiratory chain disorders. Therefore, nanozymes that can regulate homeostasis in the mitochondrial ETC have emerged as effective therapeutic agents for treating oxidative stress-related diseases. In addition, benefit from the controllability and modifiability of nanozymes, their modification with TPP, SS-31 peptide, and mitochondrial permeability membrane peptide to eliminate ROS and repair mitochondrial function. The nanozymes that specifically target mitochondria are powerful tools for the treatment of ROS-associated disorders. We discussed the design strategies pertaining to mitochondrion-targeted nanozymes to treat various diseases to develop more efficacious nanozyme tools for the treatment of ROS-related diseases in the future.
    Keywords:  Diseases; Mitochondria; Nanozymes; Reactive oxygen species; Therapeutics
    DOI:  https://doi.org/10.1016/j.jbiotec.2024.08.008
  34. Sci Adv. 2024 Aug 23. 10(34): eadn6016
    Phosphoglycerate kinase is a central leverage point in Parkinson's disease-driven neuronal metabolic deficits.
    Alexandros C Kokotos, Aldana M Antoniazzi, Santiago R Unda, Myung Soo Ko, Daehun Park, David Eliezer, Michael G Kaplitt, Pietro De Camilli, Timothy A Ryan.
      Although certain drivers of familial Parkinson's disease (PD) compromise mitochondrial integrity, whether metabolic deficits underly other idiopathic or genetic origins of PD is unclear. Here, we demonstrate that phosphoglycerate kinase 1 (PGK1), a gene in the PARK12 susceptibility locus, is rate limiting in neuronal glycolysis and that modestly increasing PGK1 expression boosts neuronal adenosine 5'-triphosphate production kinetics that is sufficient to suppress PARK20-driven synaptic dysfunction. We found that this activity enhancement depends on the molecular chaperone PARK7/DJ-1, whose loss of function significantly disrupts axonal bioenergetics. In vivo, viral expression of PGK1 confers protection of striatal dopamine axons against metabolic lesions. These data support the notion that bioenergetic deficits may underpin PD-associated pathologies and point to improving neuronal adenosine 5'-triphosphate production kinetics as a promising path forward in PD therapeutics.
    DOI:  https://doi.org/10.1126/sciadv.adn6016
  35. Gastroenterology. 2024 Aug 20. pii: S0016-5085(24)05350-2. [Epub ahead of print]
    Glutamine supplementation as a novel metabolic therapeutic strategy for LIG3-dependent chronic intestinal pseudo-obstruction.
    Chiara Diquigiovanni, Nicola Rizzardi, Erica Cataldi-Stagetti, Livia Gozzellino, Federica Isidori, Francesca Valenti, Arianna Orsini, Annalisa Astolfi, Tania Giangregorio, Loris Pironi, Elisa Boschetti, Serena Arrigo, Alessandra Maresca, Penelope Magnoni, Anna Costanzini, Valerio Carelli, Mariko Taniguchi-Ikeda, Romana Fato, Christian Bergamini, Roberto De Giorgio, Elena Bonora.
       BACKGROUND AND AIMS: We recently identified a recessive syndrome due to LIG3 mutations in patients with chronic intestinal pseudo-obstruction, leukoencephalopathy and neurogenic bladder. LIG3 mutations affect mitochondrial DNA (mtDNA) maintenance, leading to defective energy production. We aimed at identifying altered molecular pathways and develop possible targeted treatments to revert / ameliorate the cellular energy impairment.
    METHODS: Whole transcriptome analysis was performed on patients' derived fibroblasts total RNA and controls. Mitochondrial function, mitophagy, L-Glutamine (L-Gln) supplementation effects were analyzed by live cell analysis, immunostaining and western blot. Patients were treated with Dipeptiven according to standard protocols. Patients' symptoms were analyzed by the Gastrointestinal Symptom Rating Scale questionnaire.
    RESULTS: We identified deregulated transcripts in mutant fibroblasts vs. controls, including overexpression of genes involved in extracellular matrix development and remodeling and mitochondrial functions. Gut biopsies of LIG3-mutant patients documented collagen and elastic fiber accumulation. Mutant fibroblasts exhibited impaired mitochondrial mitophagy indicative of dysfunctional turnover and altered Ca2+ homeostasis. L-Gln supplementation (6 mM), previously shown to increase mtDNA-defective cell survival, improved growth rate and ATP production in LIG3-mutant fibroblasts. These data led us to provide parenterally a dipeptide containing L-Gln to three siblings carrying biallelic LIG3 mutations. Compared to baseline, gastrointestinal and extra-gastrointestinal symptoms significantly improved after 8 months of treatment.
    CONCLUSIONS: LIG3 deficiency leads to mitochondrial dysfunction. High levels L-Gln supplementation was beneficial in LIG3-mutant cells and improved symptom severity without noticeable side effects. Our results provide a proof-of-concept to design ad hoc clinical trials with L-Gln in LIG3-mutant patients.
    Keywords:  Chronic Intestinal Pseudo-Obstruction; L-Glutamine; LIG3; Mitochondria
    DOI:  https://doi.org/10.1053/j.gastro.2024.08.009
  36. Am J Med Genet A. 2024 Aug 21. e63846
    Novel heterozygous OPA3 variant in a family with congenital cataracts, sensorineural hearing loss and neuropathy, without optic atrophy and comparison of pathogenic and population variants.
    Monica Penon-Portmann, Kendyl Naugle, Frank Brodie, Julie Schallhorn, Paul Griggs, Joyce So.
      Heterozygous mutations in the OPA3 gene are associated with autosomal dominant optic atrophy-3 (OPA3), whereas biallelic mutations cause autosomal recessive 3-methylglutaconic aciduria type III. To date, all cases with pathogenic variants in the gene OPA3 have presented with optic atrophy. We report a large family with congenital cataracts, hearing loss and neuropathy, with a likely pathogenic novel missense variant in OPA3, c.30G>C; p.(Lys10Asn) that segregates with disease in the family pedigree. The family's clinical presentation has significant phenotypic overlap with previously reported cases of OPA3, except for a notable lack of optic atrophy. The analysis of all known disease-associated variants in OPA3 revealed an enrichment in missense variants in patients with OPA3 phenotype compared with loss-of-function variants, which are more likely to be observed in individuals with 3-methylglutaconic aciduria type III, supporting different mechanisms of disease. This case broadens the clinical and genetic spectrum associated with OPA3 mutations and highlights that optic atrophy is not an obligate feature of OPA3-related disorders.
    Keywords:  OPA3; congenital cataracts; mitochondrial; neuropathy; optic atrophy; sensorineural hearing loss
    DOI:  https://doi.org/10.1002/ajmg.a.63846
  37. Nat Genet. 2024 Aug 22.
    Genome-scale quantification and prediction of pathogenic stop codon readthrough by small molecules.
    Ignasi Toledano, Fran Supek, Ben Lehner.
      Premature termination codons (PTCs) cause ~10-20% of inherited diseases and are a major mechanism of tumor suppressor gene inactivation in cancer. A general strategy to alleviate the effects of PTCs would be to promote translational readthrough. Nonsense suppression by small molecules has proven effective in diverse disease models, but translation into the clinic is hampered by ineffective readthrough of many PTCs. Here we directly tackle the challenge of defining drug efficacy by quantifying the readthrough of ~5,800 human pathogenic stop codons by eight drugs. We find that different drugs promote the readthrough of complementary subsets of PTCs defined by local sequence context. This allows us to build interpretable models that accurately predict drug-induced readthrough genome-wide, and we validate these models by quantifying endogenous stop codon readthrough. Accurate readthrough quantification and prediction will empower clinical trial design and the development of personalized nonsense suppression therapies.
    DOI:  https://doi.org/10.1038/s41588-024-01878-5
  38. Front Aging Neurosci. 2024 ;16 1387931
    O-GlcNAc impacts mitophagy via the PINK1-dependent pathway.
    Ibtihal M Alghusen, Marisa S Carman, Heather M Wilkins, Taylor A Strope, Caleb Gimore, Halyna Fedosyuk, Jad Shawa, Sophiya John Ephrame, Aspin R Denson, Xiaowan Wang, Russell H Swerdlow, Chad Slawson.
       Background: The accumulation of dysfunctional mitochondria is an early feature of Alzheimer's disease (AD). The impaired turnover of damaged mitochondria increases reactive oxygen species production and lowers ATP generation, leading to cellular toxicity and neurodegeneration. Interestingly, AD exhibits a disruption in the global post-translational modification β-N-acetylglucosamine (O-GlcNAc). O-GlcNAc is a ubiquitous single sugar modification found in the nuclear, cytoplasmic, and mitochondrial proteins. Cells maintain a homeostatic level of O-GlcNAc by cycling the addition and removal of the sugar by O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA), respectively.
    Methods: We used patient-derived induced pluripotent stem cells, a transgenic mouse model of AD, SH-SY5Y neuroblastoma cell lines to examine the effect of sustained O-GlcNAcase inhibition by Thiamet-G (TMG) or OGT deficiency on mitophagy using biochemical analyses.
    Results: Here, we established an essential role for O-GlcNAc in regulating mitophagy (mitochondria-selective autophagy). Stimulating mitophagy using urolithin A (UA) decreases cellular O-GlcNAc and elevates mitochondrial O-GlcNAc. Sustained elevation in O-GlcNAcylation via pharmacologically inhibiting OGA using Thiamet-G (TMG) increases the mitochondrial level of mitophagy protein PTEN-induced kinase 1 (PINK1) and autophagy-related protein light chain 3 (LC3). Moreover, we detected O-GlcNAc on PINK1 and TMG increases its O-GlcNAcylation level. Conversely, decreasing cellular O-GlcNAcylation by knocking down OGT decreases both PINK1 protein expression and LC3 protein expression. Mitochondria isolated from CAMKII-OGT-KO mice also had decreased PINK1 and LC3. Moreover, human brain organoids treated with TMG showed significant elevation in LC3 compared to control. However, TMG-treated AD organoids showed no changes in LC3 expression.
    Conclusion: Collectively, these data demonstrate that O-GlcNAc plays a crucial role in the activation and progression of mitophagy, and this activation is disrupted in AD.
    Keywords:  Alzheimer’s disease; O-GlcNAc; OGT; PTEN-induced kinase-1; mitophagy
    DOI:  https://doi.org/10.3389/fnagi.2024.1387931
  39. Nat Commun. 2024 Aug 21. 15(1): 7122
    Reply to: The effects of ENDOG on lipid metabolism may be tissue-dependent and may not require its translocation from mitochondria.
    Wenjun Wang, Qinghua Zhou.
      
    DOI:  https://doi.org/10.1038/s41467-024-51448-w
  40. Circulation. 2024 Aug 20. 150(8): 657-660
    Junctophilin-2 Regulates Mitochondrial Metabolism.
    Sasha Z Prisco, Lynn M Hartweck, Felipe Kazmirczak, Jenna B Mendelson, Stephanie L Deng, Madelyn Blake, Satadru K Lahiri, Xander H T Wehrens, Kurt W Prins.
      
    Keywords:  metabolism; mitochondria; ventricular dysfunction, right
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.064343
  41. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2322755121
    Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway.
    Max L Valenstein, Pranav V Lalgudi, Xin Gu, Jibril F Kedir, Martin S Taylor, Raghu R Chivukula, David M Sabatini.
      The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth and metabolism in response to many environmental cues, including nutrients. Amino acids signal to mTORC1 by modulating the guanine nucleotide loading states of the heterodimeric Rag GTPases, which bind and recruit mTORC1 to the lysosomal surface, its site of activation. The Rag GTPases are tethered to the lysosome by the Ragulator complex and regulated by the GATOR1, GATOR2, and KICSTOR multiprotein complexes that localize to the lysosomal surface through an unknown mechanism(s). Here, we show that mTORC1 is completely insensitive to amino acids in cells lacking the Rag GTPases or the Ragulator component p18. Moreover, not only are the Rag GTPases and Ragulator required for amino acids to regulate mTORC1, they are also essential for the lysosomal recruitment of the GATOR1, GATOR2, and KICSTOR complexes, which stably associate and traffic to the lysosome as the "GATOR" supercomplex. The nucleotide state of RagA/B controls the lysosomal association of GATOR, in a fashion competitively antagonized by the N terminus of the amino acid transporter SLC38A9. Targeting of Ragulator to the surface of mitochondria is sufficient to relocalize the Rags and GATOR to this organelle, but not to enable the nutrient-regulated recruitment of mTORC1 to mitochondria. Thus, our results reveal that the Rag-Ragulator complex is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway and underscore that mTORC1 activation requires signal transduction on the lysosomal surface.
    Keywords:  biochemistry; mTOR signaling; nutrient sensing
    DOI:  https://doi.org/10.1073/pnas.2322755121
  42. Biochim Biophys Acta Mol Basis Dis. 2024 Aug 15. pii: S0925-4439(24)00463-0. [Epub ahead of print]1870(8): 167470
    Accumulation of damaged mitochondria in aging astrocytes due to mitophagy dysfunction: Implications for susceptibility to mitochondrial stress.
    Luan Pereira Diniz, Ana Paula Bergamo Araujo, Clara Fernandes Carvalho, Isadora Matias, Lívia de Sá Hayashide, Mariana Marques, Bruna Pessoa, Cherley Borba Vieira Andrade, Gabriele Vargas, Daniela Dias Queiroz, Jorge José de Carvalho, Antonio Galina, Flávia Carvalho Alcantara Gomes.
      Aging disrupts brain function, leading to cognitive decline and neurodegenerative diseases. Senescent astrocytes, a hallmark of aging, contribute to this process through unknown mechanisms. This study investigates how senescence impacts astrocytic mitochondrial dynamics, which are critical for brain health. Our research, conducted using aged mouse brains, represents the first evidence of morphologically damaged mitochondria in astrocytes, along with functional alterations in mitochondrial respiration. In vitro experiments revealed that senescent astrocytes exhibit an increase in mitochondrial fragmentation and impaired mitophagy. Concurrently, there was an upregulation of mitochondrial biogenesis, indicating a compensatory response to mitochondrial damage. Importantly, these senescent astrocytes were more susceptible to mitochondrial stress, a vulnerability reversed by rapamycin treatment. These findings suggest a potential link between senescence, impaired mitochondrial quality control, and increased susceptibility to mitochondrial stress in astrocytes. Overall, our study highlights the importance of addressing mitochondrial dysfunction and senescence-related changes in astrocytes as a promising approach for developing therapies to counter age-related neurodegeneration and improve brain health.
    Keywords:  Aging; Astrocytes; Mitochondria and senescence
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167470
  43. Am J Hum Genet. 2024 Aug 20. pii: S0002-9297(24)00262-3. [Epub ahead of print]
    Calibration of variant effect predictors on genome-wide data masks heterogeneous performance across genes.
    Malvika Tejura, Shawn Fayer, Abbye E McEwen, Jake Flynn, Lea M Starita, Douglas M Fowler.
      In silico variant effect predictions are available for nearly all missense variants but played a minimal role in clinical variant classification because they were deemed to provide only supporting evidence. Recently, the ClinGen Sequence Variant Interpretation (SVI) Working Group updated recommendations for variant effect prediction use. By analyzing control pathogenic and benign variants across all genes, they were able to compute evidence strength for predictor score intervals with some intervals generating moderate, strong, or even very strong evidence. However, this genome-wide approach could obscure heterogeneous predictor performance in different genes. We quantified the gene-by-gene performance of two top predictors, REVEL and BayesDel, by analyzing control variants in each predictor score interval in 3,668 disease-relevant genes. Approximately 10% of intervals had sufficient control variants for analysis, and ∼70% of these intervals exceeded the maximum number of incorrect predictions implied by the SVI recommendations. These trending discordant intervals arose owing to the divergence of the gene-specific distribution of predictions from the genome-wide distribution, suggesting that gene-specific calibration is needed in many cases. Approximately 22% of ClinVar missense variants of uncertain significance in genes we analyzed (REVEL = 100,629, BayesDel = 71,928) had predictions in trending discordant intervals. Thus, genome-wide calibrations could result in many variants receiving inappropriate evidence strength. To facilitate a review of the SVI's calibrations, we developed a web application enabling visualization of gene-specific predictions and trending concordant and discordant intervals.
    Keywords:  calibrations; variant effect predictors; variant interpretation
    DOI:  https://doi.org/10.1016/j.ajhg.2024.07.018
  44. Cell Mol Life Sci. 2024 Aug 22. 81(1): 367
    ACAD10 and ACAD11 allow entry of 4-hydroxy fatty acids into β-oxidation.
    Stéphanie Paquay, Julia Duraffourd, Marina Bury, Isaac P Heremans, Francesco Caligiore, Isabelle Gerin, Vincent Stroobant, Jean Jacobs, Aymeric Pinon, Julie Graff, Didier Vertommen, Emile Van Schaftingen, Joseph P Dewulf, Guido T Bommer.
      Hydroxylated fatty acids are important intermediates in lipid metabolism and signaling. Surprisingly, the metabolism of 4-hydroxy fatty acids remains largely unexplored. We found that both ACAD10 and ACAD11 unite two enzymatic activities to introduce these metabolites into mitochondrial and peroxisomal β-oxidation, respectively. First, they phosphorylate 4-hydroxyacyl-CoAs via a kinase domain, followed by an elimination of the phosphate to form enoyl-CoAs catalyzed by an acyl-CoA dehydrogenase (ACAD) domain. Studies in knockout cell lines revealed that ACAD10 preferentially metabolizes shorter chain 4-hydroxy fatty acids than ACAD11 (i.e. 6 carbons versus 10 carbons). Yet, recombinant proteins showed comparable activity on the corresponding 4-hydroxyacyl-CoAs. This suggests that the localization of ACAD10 and ACAD11 to mitochondria and peroxisomes, respectively, might influence their physiological substrate spectrum. Interestingly, we observed that ACAD10 is cleaved internally during its maturation generating a C-terminal part consisting of the ACAD domain, and an N-terminal part comprising the kinase domain and a haloacid dehalogenase (HAD) domain. HAD domains often exhibit phosphatase activity, but negligible activity was observed in the case of ACAD10. Yet, inactivation of a presumptive key residue in this domain significantly increased the kinase activity, suggesting that this domain might have acquired a regulatory function to prevent accumulation of the phospho-hydroxyacyl-CoA intermediate. Taken together, our work reveals that 4-hydroxy fatty acids enter mitochondrial and peroxisomal fatty acid β-oxidation via two enzymes with an overlapping substrate repertoire.
    Keywords:  4-hydroxy fatty acids; ACAD10; ACAD11; Beta-oxidation; Haloacid dehalogenase domain; Phosphohydroxyacyl-CoA
    DOI:  https://doi.org/10.1007/s00018-024-05397-8
  45. Sci Adv. 2024 Aug 23. 10(34): eado8549
    Succinate dehydrogenase-complex II regulates skeletal muscle cellular respiration and contractility but not muscle mass in genetically induced pulmonary emphysema.
    Joseph Balnis, Ankita Tufts, Emily L Jackson, Lisa A Drake, Diane V Singer, David Lacomis, Chun Geun Lee, Jack A Elias, Jason D Doles, L James Maher, Annie Jen, Joshua J Coon, David Jourd'heuil, Harold A Singer, Catherine E Vincent, Ariel Jaitovich.
      Reduced skeletal muscle mass and oxidative capacity coexist in patients with pulmonary emphysema and are independently associated with higher mortality. If reduced cellular respiration contributes to muscle atrophy in that setting remains unknown. Using a mouse with genetically induced pulmonary emphysema that recapitulates muscle dysfunction, we found that reduced activity of succinate dehydrogenase (SDH) is a hallmark of its myopathic changes. We generated an inducible, muscle-specific SDH knockout mouse that demonstrates lower mitochondrial oxygen consumption, myofiber contractility, and exercise endurance. Respirometry analyses show that in vitro complex I respiration is unaffected by loss of SDH subunit C in muscle mitochondria, which is consistent with the pulmonary emphysema animal data. SDH knockout initially causes succinate accumulation associated with a down-regulated transcriptome but modest proteome effects. Muscle mass, myofiber type composition, and overall body mass constituents remain unaltered in the transgenic mice. Thus, while SDH regulates myofiber respiration in experimental pulmonary emphysema, it does not control muscle mass or other body constituents.
    DOI:  https://doi.org/10.1126/sciadv.ado8549
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