bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2023‒10‒01
fifty-five papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial proteome research: the road ahead.
  2. Editorial: Mitochondrial dysfunction as a target in neurodegenerative diseases.
  3. The fountain of youth of mitochondrial research: Research is targeting mitochondrial dysfunction to tackle aging and much more, but hype is an increasing concern.
  4. The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Role in Human Diseases.
  5. Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.
  6. Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease.
  7. Optimized Nutrition in Mitochondrial Diseases Correlates with Improved Muscle Fatigue, Strength, and Quality of Life: You Are What You Eat, or Are You?
  8. Mitochondrial DNA Copy Number Drives the Penetrance of Acute Intermittent Porphyria.
  9. Hearing Impairment and Neuroimaging Results in Mitochondrial Diseases.
  10. Establishing induced pluripotent stem cell lines from two dominant optic atrophy patients with distinct OPA1 mutations and clinical pathologies.
  11. Early fate decision for mitochondrially encoded proteins by a molecular triage.
  12. TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis.
  13. Possible Role of Mitochondrial Transfer RNA Gene 5816 A > G Genetic Polymorphism (m.5816A > G) in a 3-Year-Old Child with Dystonia: Report of a Case.
  14. Insights into the regulation of mitochondrial functions by PKA-mediated phosphorylation.
  15. Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5.
  16. Generation of an induced pluripotent stem cell line (BCHNCi003-A) from a patient with mitochondrial pyruvate carrier deficiency caused by biallelic MPC1 mutations.
  17. FA Sliding as the Mechanism for the ANT1-Mediated Fatty Acid Anion Transport in Lipid Bilayers.
  18. Giant mitochondria in cardiomyocytes: cellular architecture in health and disease.
  19. Multifaceted roles of mitochondrial dysfunction in diseases: from powerhouses to saboteurs.
  20. Expression of Concern: Estrogen receptor mediates a distinct mitochondrial unfolded protein response.
  21. New Acylcarnitine Ratio as a Reliable Indicator of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency.
  22. Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly.
  23. Mitochondria and Brain Disease: A Comprehensive Review of Pathological Mechanisms and Therapeutic Opportunities.
  24. Age-related changes of skeletal muscle metabolic response to contraction are also sex-dependent.
  25. Volatile anaesthetic toxicity in the genetic mitochondrial disease Leigh syndrome.
  26. Late-onset MELAS syndrome in a 46-year-old man with initial symptom of chest tightness: a case report.
  27. Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum.
  28. A novel panel of Drosophila TAFAZZIN mutants in distinct genetic backgrounds as a resource for therapeutic testing.
  29. Toward Ameliorating Insulin Resistance: Targeting a Novel PAK1 Signaling Pathway Required for Skeletal Muscle Mitochondrial Function.
  30. Two domains of Tim50 coordinate translocation of proteins across the two mitochondrial membranes.
  31. The Impact of Ketone Body Metabolism on Mitochondrial Function and Cardiovascular Diseases.
  32. Engineering RsDddA as mitochondrial base editor with wide target compatibility and enhanced activity.
  33. Protocol for measuring respiratory function of mitochondria in frozen colon tissue from rats.
  34. Iron drives anabolic metabolism through active histone demethylation and mTORC1.
  35. Reduced ER-mitochondrial contact sites and mitochondrial Ca2+ flux in PRKN-mutant patient tyrosine hydroxylase reporter iPSC lines.
  36. A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators.
  37. The variable domain from dynamin-related protein 1 promotes liquid-liquid phase separation that enhances its interaction with cardiolipin-containing membranes.
  38. Role of Lipids and Divalent Cations in Membrane Fusion Mediated by the Heptad Repeat Domain 1 of Mitofusin.
  39. Harmonizing Genetic Testing for Parkinson's Disease: Results of the PARKNET Multicentric Study.
  40. Mitochondrial Dynamics and Insulin Secretion.
  41. Multi-omics profiling reveals rhythmic liver function shaped by meal timing.
  42. Synthetic Par polarity induces cytoskeleton asymmetry in unpolarized mammalian cells.
  43. Mitochondrial PGAM5-Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses.
  44. Simulating the conformational dynamics of the ATPase complex on proteasome using its free-energy landscape.
  45. Can AI predict who will win a Nobel Prize?
  46. bamSliceR : cross-cohort variant and allelic bias analysis for rare variants and rare diseases.
  47. Most protein domains exist as variants with distinct functions across cells, tissues and diseases.
  48. Genetic Contribution to End-Stage Cardiomyopathy Requiring Heart Transplantation.
  49. An Anthracene Carboxamide-Based Fluorescent Probe for Rapid and Sensitive Detection of Mitochondrial Hypochlorite in Living Cells.
  50. The genetic underpinnings of variable penetrance and expressivity of pathogenic mutations in cardiometabolic traits.
  51. A new method for multiancestry polygenic prediction improves performance across diverse populations.
  52. mTORC1 Regulates the Metabolic Switch of Postnatal Cardiomyocytes During Regeneration.
  53. Caspase-3 cleaved tau impairs mitochondrial function through the opening of the mitochondrial permeability transition pore.
  54. Patient-specific models link neurotransmitter receptor mechanisms with motor and visuospatial axes of Parkinson's disease.
  55. Editorial: Integrative multi-modal, multi-omics analytics for the better understanding of metabolic diseases.
  1. Nat Rev Mol Cell Biol. 2023 Sep 29.
    Mitochondrial proteome research: the road ahead.
    Zakery N Baker, Patrick Forny, David J Pagliarini.
      Mitochondria are multifaceted organelles with key roles in anabolic and catabolic metabolism, bioenergetics, cellular signalling and nutrient sensing, and programmed cell death processes. Their diverse functions are enabled by a sophisticated set of protein components encoded by the nuclear and mitochondrial genomes. The extent and complexity of the mitochondrial proteome remained unclear for decades. This began to change 20 years ago when, driven by the emergence of mass spectrometry-based proteomics, the first draft mitochondrial proteomes were established. In the ensuing decades, further technological and computational advances helped to refine these 'maps', with current estimates of the core mammalian mitochondrial proteome ranging from 1,000 to 1,500 proteins. The creation of these compendia provided a systemic view of an organelle previously studied primarily in a reductionist fashion and has accelerated both basic scientific discovery and the diagnosis and treatment of human disease. Yet numerous challenges remain in understanding mitochondrial biology and translating this knowledge into the medical context. In this Roadmap, we propose a path forward for refining the mitochondrial protein map to enhance its discovery and therapeutic potential. We discuss how emerging technologies can assist the detection of new mitochondrial proteins, reveal their patterns of expression across diverse tissues and cell types, and provide key information on proteoforms. We highlight the power of an enhanced map for systematically defining the functions of its members. Finally, we examine the utility of an expanded, functionally annotated mitochondrial proteome in a translational setting for aiding both diagnosis of mitochondrial disease and targeting of mitochondria for treatment.
    DOI:  https://doi.org/10.1038/s41580-023-00650-7
  2. Front Mol Neurosci. 2023 ;16 1271175
    Editorial: Mitochondrial dysfunction as a target in neurodegenerative diseases.
    Lorena Perrone.
      
    Keywords:  DRP1; cell-specific; microglia; mitochondria; mitophagy; neurodegeneration; proteomics; sex-specific
    DOI:  https://doi.org/10.3389/fnmol.2023.1271175
  3. EMBO Rep. 2023 Sep 28. e58118
    The fountain of youth of mitochondrial research: Research is targeting mitochondrial dysfunction to tackle aging and much more, but hype is an increasing concern.
    Andrea Rinaldi.
      A new wave of studies is untangling the connection between primary genetic mitochondrial diseases and the role of mitochondria in aging: what are the implications for longevity?
    DOI:  https://doi.org/10.15252/embr.202358118
  4. Biomolecules. 2023 Aug 25. pii: 1304. [Epub ahead of print]13(9):
    The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Role in Human Diseases.
    Donato D'Angelo, Rosario Rizzuto.
      Calcium (Ca2+) ions act as a second messenger, regulating several cell functions. Mitochondria are critical organelles for the regulation of intracellular Ca2+. Mitochondrial calcium (mtCa2+) uptake is ensured by the presence in the inner mitochondrial membrane (IMM) of the mitochondrial calcium uniporter (MCU) complex, a macromolecular structure composed of pore-forming and regulatory subunits. MtCa2+ uptake plays a crucial role in the regulation of oxidative metabolism and cell death. A lot of evidence demonstrates that the dysregulation of mtCa2+ homeostasis can have serious pathological outcomes. In this review, we briefly discuss the molecular structure and the function of the MCU complex and then we focus our attention on human diseases in which a dysfunction in mtCa2+ has been shown.
    Keywords:  MCU; cancer; cardiovascular diseases; metabolic diseases; mitochondrial Ca2+ signaling; neurodegenerative disorders; skeletal muscle diseases
    DOI:  https://doi.org/10.3390/biom13091304
  5. Nat Cell Biol. 2023 Sep 28.
    Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.
    Nicholas J Kramer, Gyan Prakash, R Stefan Isaac, Karine Choquet, Iliana Soto, Boryana Petrova, Hope E Merens, Naama Kanarek, L Stirling Churchman.
      Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells requiring coordinated gene expression across organelles. To identify genes involved in dual-origin protein complex synthesis, we performed fluorescence-activated cell-sorting-based genome-wide screens analysing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of Complex IV. We identified genes involved in OXPHOS biogenesis, including two uncharacterized genes: PREPL and NME6. We found that PREPL specifically impacts Complex IV biogenesis by acting at the intersection of mitochondrial lipid metabolism and protein synthesis, whereas NME6, an uncharacterized nucleoside diphosphate kinase, controls OXPHOS biogenesis through multiple mechanisms reliant on its NDPK domain. Firstly, NME6 forms a complex with RCC1L, which together perform nucleoside diphosphate kinase activity to maintain local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Secondly, NME6 modulates the activity of mitoribosome regulatory complexes, altering mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression.
    DOI:  https://doi.org/10.1038/s41556-023-01244-3
  6. Life (Basel). 2023 Sep 03. pii: 1863. [Epub ahead of print]13(9):
    Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease.
    Paola Loguercio Polosa, Francesco Capriglia, Francesco Bruni.
      In mammalian mitochondria, the processing of primary RNA transcripts involves a coordinated series of cleavage and modification events, leading to the formation of processing intermediates and mature mt-RNAs. RNA19 is an unusually stable unprocessed precursor, physiologically polyadenylated, which includes the 16S mt-rRNA, the mt-tRNALeuUUR and the mt-ND1 mRNA. These peculiarities, together with the alteration of its steady-state levels in cellular models with defects in mitochondrial function, make RNA19 a potentially important molecule for the physiological regulation of mitochondrial molecular processes as well as for the pathogenesis of mitochondrial diseases. In this work, we quantitatively and qualitatively examined RNA19 in MELAS trans-mitochondrial cybrids carrying the mtDNA 3243A>G transition and displaying a profound mitochondrial translation defect. Through a combination of isokinetic sucrose gradient and RT-qPCR experiments, we found that RNA19 accumulated and co-sedimented with the mitoribosomal large subunit (mt-LSU) in mutant cells. Intriguingly, exogenous expression of the isolated LARS2 C-terminal domain (Cterm), which was shown to rescue defective translation in MELAS cybrids, decreased the levels of mt-LSU-associated RNA19 by relegating it to the pool of free unbound RNAs. Overall, the data reported here support a regulatory role for RNA19 in mitochondrial physiopathological processes, designating this RNA precursor as a possible molecular target in view of therapeutic strategy development.
    Keywords:  Cterm; LARS2; MELAS; RNA19; mitochondrial disease; mitochondrial translation; mitoribosome; mt-RNA processing; trans-mitochondrial cybrids
    DOI:  https://doi.org/10.3390/life13091863
  7. Neurotherapeutics. 2023 Sep 28.
    Optimized Nutrition in Mitochondrial Diseases Correlates with Improved Muscle Fatigue, Strength, and Quality of Life: You Are What You Eat, or Are You?
    Russell P Saneto, Amel Karaa.
      
    Keywords:  Mitochondrial activity factor; Muscle fatigue; Myopathy; Nutrition; Primary mitochondrial disease
    DOI:  https://doi.org/10.1007/s13311-023-01445-6
  8. Life (Basel). 2023 Sep 15. pii: 1923. [Epub ahead of print]13(9):
    Mitochondrial DNA Copy Number Drives the Penetrance of Acute Intermittent Porphyria.
    Elena Di Pierro, Miriana Perrone, Milena Franco, Francesca Granata, Lorena Duca, Debora Lattuada, Giacomo De Luca, Giovanna Graziadei.
      No published study has investigated the mitochondrial count in patients suffering from acute intermittent porphyria (AIP). In order to determine whether mitochondrial content can influence the pathogenesis of porphyria, we measured the mitochondrial DNA (mtDNA) copy number in the peripheral blood cells of 34 patients and 37 healthy individuals. We found that all AIP patients had a low number of mitochondria, likely as a result of a protective mechanism against an inherited heme synthesis deficiency. Furthermore, we identified a close correlation between disease penetrance and decreases in the mitochondrial content and serum levels of PERM1, a marker of mitochondrial biogenesis. In a healthy individual, mitochondrial count is usually modulated to fit its ability to respond to various environmental stressors and bioenergetic demands. In AIP patients, coincidentally, the phenotype only manifests in response to endogenous and exogenous triggers factors. Therefore, these new findings suggest that a deficiency in mitochondrial proliferation could affect the individual responsiveness to stimuli, providing a new explanation for the variability in the clinical manifestations of porphyria. However, the metabolic and/or genetic factors responsible for this impairment remain to be identified. In conclusion, both mtDNA copy number per cell and mitochondrial biogenesis seem to play a role in either inhibiting or promoting disease expression. They could serve as two novel biomarkers for porphyria.
    Keywords:  PERM1; acute intermittent porphyria; heme; incomplete penetrance; mitochondrial biogenesis; mtDNA copy number
    DOI:  https://doi.org/10.3390/life13091923
  9. J Pers Med. 2023 Aug 29. pii: 1329. [Epub ahead of print]13(9):
    Hearing Impairment and Neuroimaging Results in Mitochondrial Diseases.
    Gabriella Cadoni, Guido Primiano, Pasqualina M Picciotti, Rosalinda Calandrelli, Jacopo Galli, Serenella Servidei, Guido Conti.
      Mitochondrial diseases (MDs) are heterogeneous genetic disorders characterized by mitochondrial DNA (mtDNA) defects, involving tissues highly dependent on oxidative metabolism: the inner ear, brain, eye, skeletal muscle, and heart. We describe adult patients with genetically defined MDs, characterizing hearing function and neuroimaging results. We enrolled 34 patients (mean age: 50.02 ± 15 years, range: 18-75 years; 20 females and 14 males) classified in four groups: MELAS, MIDD, PEO, and Encephalopathy/Polyneuropathy. Audiological evaluations included psychoacoustical tests (pure-tone and speech audiometry), electrophysiological tests (Auditory Brainstem Responses, ABRs), and Impedenzometry. Neuroimaging evaluations considered global MRI abnormalities or structural brain changes. In total, 19/34 patients carried the m.3243A > G mutation (6 affected by MELAS, 12 affected by MIDD, and 1 affected by PEO); 11 had an mtDNA deletion (all affected by PEO); 3 had nuclear genes associated with MDs (POLG1 and OPA1); and 1 patient had an mtDNA deletion without an identified nuclear gene defect (affected by PEO). Sensory neural, bilateral, and symmetrical hearing loss was present in 25 patients (73.5%) to different degrees: 9 mild, 9 moderate, 5 severe, and 2 profound. The severe/profound and mild hearing losses were associated with pantonal and high-frequency audiograms, respectively. Instead, moderate hearing losses were associated with both high-frequency (five cases) and pantonal (five cases) audiogram shapes. In addition, 21/25 patients showed a cochlear site of lesion (84%), and 4/25 (16%) showed a retrocochlear site. We found global MRI abnormalities or structural brain changes in 26/30 subjects (86.6%): 21 had white matter abnormalities, 15 had cortical atrophy, 10 had subcortical atrophy, 8 had basal nuclei involvement or cerebellar atrophy, 4 had stroke-like lesions or laminar necrosis, and 1 had cysts or vacuolated lesions. We concluded that genetic alterations are associated with different clinical presentations for both auditory function and neuroradiological findings. There is no fixed relationship between genotype and phenotype for the clinical conditions analyzed.
    Keywords:  MRI; brain changes; cochlear; deafness; mitochondrial diseases; mtDNA; retrocochlear
    DOI:  https://doi.org/10.3390/jpm13091329
  10. Front Genet. 2023 ;14 1251216
    Establishing induced pluripotent stem cell lines from two dominant optic atrophy patients with distinct OPA1 mutations and clinical pathologies.
    Katherine A Pohl, Xiangmei Zhang, Anh H Pham, Jane W Chan, Alfredo A Sadun, Xian-Jie Yang.
      Dominant optic atrophy (DOA) is an inherited disease that leads to the loss of retinal ganglion cells (RGCs), the projection neurons that relay visual information from the retina to the brain through the optic nerve. The majority of DOA cases can be attributed to mutations in optic atrophy 1 (OPA1), a nuclear gene encoding a mitochondrial-targeted protein that plays important roles in maintaining mitochondrial structure, dynamics, and bioenergetics. Although OPA1 is ubiquitously expressed in all human tissues, RGCs appear to be the primary cell type affected by OPA1 mutations. DOA has not been extensively studied in human RGCs due to the general unavailability of retinal tissues. However, recent advances in stem cell biology have made it possible to produce human RGCs from pluripotent stem cells (PSCs). To aid in establishing DOA disease models based on human PSC-derived RGCs, we have generated iPSC lines from two DOA patients who carry distinct OPA1 mutations and present very different disease symptoms. Studies using these OPA1 mutant RGCs can be correlated with clinical features in the patients to provide insights into DOA disease mechanisms.
    Keywords:  DOA; OPA1; RGC; dominant optic atrophy; induced pluripotent stem cells (iPSC); retinal ganglion cell
    DOI:  https://doi.org/10.3389/fgene.2023.1251216
  11. Mol Cell. 2023 Sep 21. pii: S1097-2765(23)00696-2. [Epub ahead of print]
    Early fate decision for mitochondrially encoded proteins by a molecular triage.
    Andreas Kohler, Andreas Carlström, Hendrik Nolte, Verena Kohler, Sung-Jun Jung, Sagar Sridhara, Takashi Tatsuta, Jens Berndtsson, Thomas Langer, Martin Ott.
      Folding of newly synthesized proteins poses challenges for a functional proteome. Dedicated protein quality control (PQC) systems either promote the folding of nascent polypeptides at ribosomes or, if this fails, ensure their degradation. Although well studied for cytosolic protein biogenesis, it is not understood how these processes work for mitochondrially encoded proteins, key subunits of the oxidative phosphorylation (OXPHOS) system. Here, we identify dedicated hubs in proximity to mitoribosomal tunnel exits coordinating mitochondrial protein biogenesis and quality control. Conserved prohibitin (PHB)/m-AAA protease supercomplexes and the availability of assembly chaperones determine the fate of newly synthesized proteins by molecular triaging. The localization of these competing activities in the vicinity of the mitoribosomal tunnel exit allows for a prompt decision on whether newly synthesized proteins are fed into OXPHOS assembly or are degraded.
    Keywords:  assembly factors; complex assembly; m-AAA protease; mitochondria; mitoribosome; prohibitin; protein biogenesis; protein quality control; respiratory chain; translation
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.001
  12. Nat Commun. 2023 Sep 29. 14(1): 6099
    TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis.
    Donghua Hu, Min Tan, Dongliang Lu, Brian Kleiboeker, Xuejing Liu, Hongsuk Park, Alexxai V Kravitz, Kooresh I Shoghi, Yu-Hua Tseng, Babak Razani, Akihiro Ikeda, Irfan J Lodhi.
      Mitochondrial morphology, which is controlled by mitochondrial fission and fusion, is an important regulator of the thermogenic capacity of brown adipocytes. Adipose-specific peroxisome deficiency impairs thermogenesis by inhibiting cold-induced mitochondrial fission due to decreased mitochondrial membrane content of the peroxisome-derived lipids called plasmalogens. Here, we identify TMEM135 as a critical mediator of the peroxisomal regulation of mitochondrial fission and thermogenesis. Adipose-specific TMEM135 knockout in mice blocks mitochondrial fission, impairs thermogenesis, and increases diet-induced obesity and insulin resistance. Conversely, TMEM135 overexpression promotes mitochondrial division, counteracts obesity and insulin resistance, and rescues thermogenesis in peroxisome-deficient mice. Mechanistically, thermogenic stimuli promote association between peroxisomes and mitochondria and plasmalogen-dependent localization of TMEM135 in mitochondria, where it mediates PKA-dependent phosphorylation and mitochondrial retention of the fission factor Drp1. Together, these results reveal a previously unrecognized inter-organelle communication regulating mitochondrial fission and energy homeostasis and identify TMEM135 as a potential target for therapeutic activation of BAT.
    DOI:  https://doi.org/10.1038/s41467-023-41849-8
  13. Glob Med Genet. 2023 Sep;10(3): 263-270
    Possible Role of Mitochondrial Transfer RNA Gene 5816 A > G Genetic Polymorphism (m.5816A > G) in a 3-Year-Old Child with Dystonia: Report of a Case.
    Sumei Wang, Minglu Liang, Jiehui Ma, Sheng Huang, Lili Fan, Feng Zhu, Dan Sun.
      Background  Mutations in the mitochondrial transfer RNA (mt-tRNA) gene are a hotspot for mitochondrial DNA (mtDNA) mutations and are most common in mitochondrial diseases. Methods  We identified the mt-tRNA gene 5816 A > G (m.5816 A > G) mutation in a 3-year-old child with dystonia who died. We performed clinical evaluation, genetic analysis, and biochemical investigation with mitochondrial function testing. Results  Our patient was found to have dystonia with hyperlactatemia. Electroencephalogram findings were abnormal in children with numerous multifocal spikes, multispike, spikes and slow waves, slow waves and low amplitude fast waves, more pronounced in the occipital region bilaterally, and occurring continuously during sleep. One year later, the preexisting patient had seizures lasting 1 to 2 hours and subsequently died. mtDNA sequencing revealed that the proband, her mother, and her grandmother all carried the m.5816A > G mutation. Oxygen consumption rate (OCR) assays revealed that the proband's basal resting OCR, adenosine triphosphate production, proton leak, maximal respiration, and spare capacity OCR were all significantly lower compared with healthy children of the same age. Conclusion  The present case demonstrates a childhood dystonia caused by a mt-tRNA gene 5816 A > G mutation, which has never been reported before. Our findings provide valuable new insights into the pathogenic mechanism and function of the m.5816A > G mutation.
    Keywords:  dystonia; epilepsy; mitochondrial DNA mutation; mitochondrial diseases
    DOI:  https://doi.org/10.1055/s-0043-1774708
  14. J Biochem. 2023 Sep 29. pii: mvad075. [Epub ahead of print]
    Insights into the regulation of mitochondrial functions by PKA-mediated phosphorylation.
    Shiori Akabane, Toshihiko Oka.
      Cyclic AMP (cAMP) - protein kinase A (PKA) signaling is a highly conserved pathway in eukaryotes and plays a central role in cell signaling cascades in response to environmental changes. Elevated cAMP levels promote the activation of PKA, which phosphorylates various downstream proteins. Many cytosolic and nuclear proteins, such as metabolic enzymes and transcriptional factors, have been identified as substrates for PKA, suggesting that PKA-mediated regulation occurs predominantly in the cytosol. Mitochondrial proteins are also phosphorylated by PKA, and PKA-mediated phosphorylation of mitochondrial proteins is considered to control a variety of mitochondrial functions, including oxidative phosphorylation, protein import, morphology, and quality control. In this review, we outline PKA mitochondrial substrates and summarize the regulation of mitochondrial functions through PKA-mediated phosphorylation.
    Keywords:  PKA; cAMP; mitochondria; phosphorylation
    DOI:  https://doi.org/10.1093/jb/mvad075
  15. Mov Disord. 2023 Sep 27.
    Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5.
    Pin-Shiuan Chen, Ni-Chung Lee, Chieh-Ju Sung, Ya-Wen Liu, Wen-Chin Weng, Pi-Chuan Fan, Wang-Tso Lee, Yin-Hsiu Chien, Chao-Szu Wu, Yueh-Feng Sung, Ming-Chen Tsai, Yi-Chung Lee, Hsueh-Wen Hsueh, Sabrina Mai-Yi Fan, Meng-Chen Wu, Hsun Li, Huan-Yun Chen, Han-I Lin, Chih-Hsin Ou-Yang, Wuh-Liang Hwuh, Chin-Hsien Lin.
      BACKGROUND: Rare mutations in NADH:ubiquinone oxidoreductase complex assembly factor 5 (NDUFAF5) are linked to Leigh syndrome.OBJECTIVE: We aimed to describe clinical characteristics and functional findings in a patient cohort with NDUFAF5 mutations.
    METHODS: Patients with biallelic NDUFAF5 mutations were recruited from multi-centers in Taiwan. Clinical, laboratory, radiological, and follow-up features were recorded and mitochondrial assays were performed in patients' skin fibroblasts.
    RESULTS: Nine patients from seven unrelated pedigrees were enrolled, eight homozygous for c.836 T > G (p.Met279Arg) in NDUFAF5 and one compound heterozygous for p.Met279Arg. Onset age had a bimodal distribution. The early-onset group (age <3 years) presented with psychomotor delay, seizure, respiratory failure, and hyponatremia. The late-onset group (age ≥5 years) presented with normal development, but slowly progressive dystonia. Combing 25 previously described patients, the p.Met279Arg variant was exclusively identified in Chinese ancestry. Compared with other groups, patients with late-onset homozygous p.Met279Arg were older at onset (P = 0.008), had less developmental delay (P = 0.01), less hyponatremia (P = 0.01), and better prognosis with preserved ambulatory function into early adulthood (P = 0.01). Bilateral basal ganglia necrosis was a common radiological feature, but brainstem and spinal cord involvement was more common with early-onset patients (P = 0.02). A modifier gene analysis showed higher concomitant mutation burden in early-versus late-onset p.Met279Arg homozygous cases (P = 0.04), consistent with more impaired mitochondrial function in fibroblasts from an early-onset case than a late-onset patient.
    CONCLUSIONS: The p.Met279Arg variant is a common mutation in our population with phenotypic heterogeneity and divergent prognosis based on age at onset. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  Leigh syndrome; NDUFAF5; dystonia; mitochondria; mitochondrial complex I deficiency; striatal necrosis
    DOI:  https://doi.org/10.1002/mds.29604
  16. Stem Cell Res. 2023 Sep 21. pii: S1873-5061(23)00192-7. [Epub ahead of print]72 103206
    Generation of an induced pluripotent stem cell line (BCHNCi003-A) from a patient with mitochondrial pyruvate carrier deficiency caused by biallelic MPC1 mutations.
    Huafang Jiang, Chaolong Xu, Wenyan Li, Ling Zhou, Fang Fang.
      Mitochondrial pyruvate carrier deficiency (MPYCD) is a rare mitochondrial disease characterized by developmental delay, microcephaly, growth failure, increased serum lactate with a normal lactate/pyruvate ratio. Mutations in the MPC1 gene have been identified to cause MPYCD. Herein, we generated an induced pluripotent stem cell (iPSC) line from the skin fibroblasts of a patient with MPYCD, carrying biallelic mutations, c.208G>A (p.Ala70Thr) and c.290G>A (p.Arg97Gln) in MPC1. These iPSCs showed the expression of pluripotency markers, the ability to differentiate into three germ layers, and MPC1 mutations with normal karyotype.
    DOI:  https://doi.org/10.1016/j.scr.2023.103206
  17. Int J Mol Sci. 2023 Sep 05. pii: 13701. [Epub ahead of print]24(18):
    FA Sliding as the Mechanism for the ANT1-Mediated Fatty Acid Anion Transport in Lipid Bilayers.
    Jürgen Kreiter, Sanja Škulj, Zlatko Brkljača, Sarah Bardakji, Mario Vazdar, Elena E Pohl.
      Mitochondrial adenine nucleotide translocase (ANT) exchanges ADP for ATP to maintain energy production in the cell. Its protonophoric function in the presence of long-chain fatty acids (FA) is also recognized. Our previous results imply that proton/FA transport can be best described with the FA cycling model, in which protonated FA transports the proton to the mitochondrial matrix. The mechanism by which ANT1 transports FA anions back to the intermembrane space remains unclear. Using a combined approach involving measurements of the current through the planar lipid bilayers reconstituted with ANT1, site-directed mutagenesis and molecular dynamics simulations, we show that the FA anion is first attracted by positively charged arginines or lysines on the matrix side of ANT1 before moving along the positively charged protein-lipid interface and binding to R79, where it is protonated. We show that R79 is also critical for the competitive binding of ANT1 substrates (ADP and ATP) and inhibitors (carboxyatractyloside and bongkrekic acid). The binding sites are well conserved in mitochondrial SLC25 members, suggesting a general mechanism for transporting FA anions across the inner mitochondrial membrane.
    Keywords:  AAC; ADP/ATP carrier; arachidonic acid; fatty acid cycling hypothesis; fatty acids anion transport; proton transport; uncoupling proteins
    DOI:  https://doi.org/10.3390/ijms241813701
  18. Basic Res Cardiol. 2023 Sep 29. 118(1): 39
    Giant mitochondria in cardiomyocytes: cellular architecture in health and disease.
    Amy Li, Gerald J Shami, Lisa Griffiths, Sean Lal, Helen Irving, Filip Braet.
      Giant mitochondria are frequently observed in different disease models within the brain, kidney, and liver. In cardiac muscle, these enlarged organelles are present across diverse physiological and pathophysiological conditions including in ageing and exercise, and clinically in alcohol-induced heart disease and various cardiomyopathies. This mitochondrial aberration is widely considered an early structural hallmark of disease leading to adverse organ function. In this thematic paper, we discuss the current state-of-knowledge on the presence, structure and functional implications of giant mitochondria in heart muscle. Despite its demonstrated reoccurrence in different heart diseases, the literature on this pathophysiological phenomenon remains relatively sparse since its initial observations in the early 60s. We review historical and contemporary investigations from cultured cardiomyocytes to human tissue samples to address the role of giant mitochondria in cardiac health and disease. Finally, we discuss their significance for the future development of novel mitochondria-targeted therapies to improve cardiac metabolism and functionality.
    Keywords:  Cardiomyopathy; Giant and megamitochondria; Histopathological marker; Mitochondrial aberrations; Mitochondrion pathophysiology; Muscle disease
    DOI:  https://doi.org/10.1007/s00395-023-01011-3
  19. Arch Pharm Res. 2023 Sep 26.
    Multifaceted roles of mitochondrial dysfunction in diseases: from powerhouses to saboteurs.
    Surapriya Surendranath Prabhu, Aathira Sujathan Nair, Saiprabha Vijayakumar Nirmala.
      The fact that mitochondria play a crucial part in energy generation has led to the nickname "powerhouses" of the cell being applied to them. They also play a significant role in many other cellular functions, including calcium signalling, apoptosis, and the creation of vital biomolecules. As a result, cellular function and health as a whole can be significantly impacted by mitochondrial malfunction. Indeed, malignancies frequently have increased levels of mitochondrial biogenesis and quality control. Adverse selection exists for harmful mitochondrial genome mutations, even though certain malignancies include modifications in the nuclear-encoded tricarboxylic acid cycle enzymes that generate carcinogenic metabolites. Since rare human cancers with mutated mitochondrial genomes are often benign, removing mitochondrial DNA reduces carcinogenesis. Therefore, targeting mitochondria offers therapeutic options since they serve several functions and are crucial to developing malignant tumors. Here, we discuss the various steps involved in the mechanism of cancer for which mitochondria plays a significant role, as well as the role of mitochondria in diseases other than cancer. It is crucial to understand mitochondrial malfunction to target these organelles for therapeutic reasons. This highlights the significance of investigating mitochondrial dysfunction in cancer and other disease research.
    Keywords:  Apoptosis; Carcinogenesis; Genome mutations; Mitochondrial dysfunction; Oncogenic signaling
    DOI:  https://doi.org/10.1007/s12272-023-01465-y
  20. J Cell Sci. 2023 09 15. pii: jcs261591. [Epub ahead of print]136(18):
    Expression of Concern: Estrogen receptor mediates a distinct mitochondrial unfolded protein response.
    Luena Papa, Doris Germain.
      
    DOI:  https://doi.org/10.1242/jcs.261591
  21. Int J Neonatal Screen. 2023 Aug 25. pii: 48. [Epub ahead of print]9(3):
    New Acylcarnitine Ratio as a Reliable Indicator of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency.
    Galina V Baydakova, Polina G Tsygankova, Natalia L Pechatnikova, Olga A Bazhanova, Yana D Nazarenko, Ekaterina Y Zakharova.
      Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiencies are rare fatal disorders of fatty acid β-oxidation with no apparent genotype-phenotype correlation. The measurement of acylcarnitines by MS/MS is a current diagnostic workup in these disorders. Nevertheless, false-positive and false-negative results have been reported, highlighting a necessity for more sensitive and specific biomarkers. This study included 54 patients with LCHAD/MTP deficiency that has been confirmed by biochemical and molecular methods. The analysis of acylcarnitines in dried blood spots was performed using ESI-MS/MS. The established "HADHA ratio" = (C16OH + C18OH + C18:1OH)/C0 was significantly elevated in all 54 affected individuals in comparison to the control group. Apart from 54 LCHAD deficiency patients, the "HADHA ratio" was calculated in 19 patients with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. As VLCAD-deficient patients did not show increased "HADHA ratio", the results emphasized the high specificity of this new ratio. Therefore, the "HADHA ratio" was shown to be instrumental in improving the overall performance of MS/MS-based analysis of acylcarnitine levels in the diagnostics of LCHAD/MTP deficiencies. The ratio was demonstrated to increase the sensitivity and specificity of this method and reduce the chances of false-negative results.
    Keywords:  HADHA; acylcarnitines; biochemical marker; inherited metabolic diseases; long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency
    DOI:  https://doi.org/10.3390/ijns9030048
  22. Int J Mol Sci. 2023 Sep 08. pii: 13835. [Epub ahead of print]24(18):
    Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly.
    Anna Picca, Flora Guerra, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi, Cecilia Bucci, Emanuele Marzetti.
      Mitophagy is crucial for maintaining mitochondrial quality. However, its assessment in vivo is challenging. The endosomal-lysosomal system is a more accessible pathway through which subtypes of extracellular vesicles (EVs), which also contain mitochondrial constituents, are released for disposal. The inclusion of mitochondrial components into EVs occurs in the setting of mild mitochondrial damage and during impairment of lysosomal function. By releasing mitochondrial-derived vesicles (MDVs), cells limit the unload of mitochondrial damage-associated molecular patterns with proinflammatory activity. Both positive and negative effects of EVs on recipient cells have been described. Whether this is due to the production of EVs other than those containing mitochondria, such as MDVs, holding specific biological functions is currently unknown. Evidence on the existence of different MDV subtypes has been produced. However, their characterization is not always pursued, which would be relevant to exploring the dynamics of mitochondrial quality control in health and disease. Furthermore, MDV classification may be instrumental in understanding their biological roles and promoting their implementation as biomarkers in clinical studies.
    Keywords:  damage-associated molecular patterns (DAMPs); endosomal–lysosomal system; exosomes; extracellular vesicles; inflammation; mitochondrial DNA; mitochondrial quality control; mitophagy; mitovesicles; oxidative stress
    DOI:  https://doi.org/10.3390/ijms241813835
  23. Biomedicines. 2023 Sep 07. pii: 2488. [Epub ahead of print]11(9):
    Mitochondria and Brain Disease: A Comprehensive Review of Pathological Mechanisms and Therapeutic Opportunities.
    Vicente Javier Clemente-Suárez, Laura Redondo-Flórez, Ana Isabel Beltrán-Velasco, Domingo Jesús Ramos-Campo, Pedro Belinchón-deMiguel, Ismael Martinez-Guardado, Athanasios A Dalamitros, Rodrigo Yáñez-Sepúlveda, Alexandra Martín-Rodríguez, José Francisco Tornero-Aguilera.
      Mitochondria play a vital role in maintaining cellular energy homeostasis, regulating apoptosis, and controlling redox signaling. Dysfunction of mitochondria has been implicated in the pathogenesis of various brain diseases, including neurodegenerative disorders, stroke, and psychiatric illnesses. This review paper provides a comprehensive overview of the intricate relationship between mitochondria and brain disease, focusing on the underlying pathological mechanisms and exploring potential therapeutic opportunities. The review covers key topics such as mitochondrial DNA mutations, impaired oxidative phosphorylation, mitochondrial dynamics, calcium dysregulation, and reactive oxygen species generation in the context of brain disease. Additionally, it discusses emerging strategies targeting mitochondrial dysfunction, including mitochondrial protective agents, metabolic modulators, and gene therapy approaches. By critically analysing the existing literature and recent advancements, this review aims to enhance our understanding of the multifaceted role of mitochondria in brain disease and shed light on novel therapeutic interventions.
    Keywords:  brain disease; mitochondria; mitochondrial DNA mutations; mitochondrial dynamics; mitochondrial protective agents; neurodegenerative disorders; oxidative phosphorylation; reactive oxygen species
    DOI:  https://doi.org/10.3390/biomedicines11092488
  24. J Physiol. 2023 Sep 23.
    Age-related changes of skeletal muscle metabolic response to contraction are also sex-dependent.
    Matthew D Campbell, Danijel Djukovic, Daniel Raftery, David J Marcinek.
      Mitochondria adapt to increased energy demands during muscle contraction by acutely altering metabolite fluxes and substrate oxidation. With age, an impaired mitochondrial metabolic response may contribute to reduced exercise tolerance and decreased skeletal muscle mass, specific force, increased overall fatty depositions in the skeletal muscle, frailty and depressed energy maintenance. We hypothesized that elevated energy stress in mitochondria with age alters the capacity of mitochondria to utilize different substrates following muscle contraction. To test this hypothesis, we used in vivo electrical stimulation to simulate high-intensity intervals (HII) or low intensity steady-state (LISS) exercise in young (5-7 months) and aged (27-29 months) male and female mice to characterize effects of age and sex on mitochondrial substrate utilization in skeletal muscle following contraction. Mitochondrial respiration using glutamate decreased in aged males following HII and glutamate oxidation was inhibited following HII in both the contracted and non-stimulated muscle of aged female muscle. Analyses of the muscle metabolome of female mice indicated that changes in metabolic pathways induced by HII and LISS contractions in young muscle are absent in aged muscle. To test improved mitochondrial function on substrate utilization following HII, we treated aged females with elamipretide (ELAM), a mitochondrially-targeted peptide shown to improve mitochondrial bioenergetics and restore redox status in aged muscle. ELAM removed inhibition of glutamate oxidation and showed increased metabolic pathway changes following HII, suggesting rescuing redox status and improving bioenergetic function in mitochondria from aged muscle increases glutamate utilization and enhances the metabolic response to muscle contraction in aged muscle. KEY POINTS: Acute local contraction of gastrocnemius can systemically alter mitochondrial respiration in non-stimulated muscle. Age-related changes in mitochondrial respiration using glutamate or palmitoyl carnitine following contraction are sex-dependent. Respiration using glutamate after high-intensity contraction is inhibited in aged female muscle. Metabolite level and pathway changes following muscle contraction decrease with age in female mice. Treatment with the mitochondrially-targeted peptide elamipretide can partially rescue metabolite response to muscle contraction.
    Keywords:  age; high-intensity intervals; low-intensity steady-state; metabolism; mitochondrial adaptation; sarcopenia; sex specific effects
    DOI:  https://doi.org/10.1113/JP285124
  25. Br J Anaesth. 2023 Sep 26. pii: S0007-0912(23)00442-7. [Epub ahead of print]
    Volatile anaesthetic toxicity in the genetic mitochondrial disease Leigh syndrome.
    Kira A Spencer, Michael Mulholland, John Snell, Miranda Howe, Katerina James, Allison R Hanaford, Philip G Morgan, Margaret Sedensky, Simon C Johnson.
      BACKGROUND: Volatile anaesthetics are widely used in human medicine. Although generally safe, hypersensitivity and toxicity can occur in rare cases, such as in certain genetic disorders. Anaesthesia hypersensitivity is well-documented in a subset of mitochondrial diseases, but whether volatile anaesthetics are toxic in this setting has not been explored.METHODS: We exposed Ndufs4(-/-) mice, a model of Leigh syndrome, to isoflurane (0.2-0.6%), oxygen 100%, or air. Cardiorespiratory function, weight, blood metabolites, and survival were assessed. We exposed post-symptom onset and pre-symptom onset animals and animals treated with the macrophage depleting drug PLX3397/pexidartinib to define the role of overt neuroinflammation in volatile anaesthetic toxicities.
    RESULTS: Isoflurane induced hyperlactataemia, weight loss, and mortality in a concentration- and duration-dependent manner from 0.2% to 0.6% compared with carrier gas (O2 100%) or mock (air) exposures (lifespan after 30-min exposures ∗P<0.05 for isoflurane 0.4% vs air or vs O2, ∗∗P<0.005 for isoflurane 0.6% vs air or O2; 60-min exposures ∗∗P<0.005 for isoflurane 0.2% vs air, ∗P<0.05 for isoflurane 0.2% vs O2). Isoflurane toxicity was significantly reduced in Ndufs4(-/-) exposed before CNS disease onset, and the macrophage depleting drug pexidartinib attenuated sequelae of isoflurane toxicity (survival ∗∗∗P=0.0008 isoflurane 0.4% vs pexidartinib plus isoflurane 0.4%). Finally, the laboratory animal standard of care of 100% O2 as a carrier gas contributed significantly to weight loss and reduced survival, but not to metabolic changes, and increased acute mortality.
    CONCLUSIONS: Isoflurane is toxic in the Ndufs4(-/-) model of Leigh syndrome. Toxic effects are dependent on the status of underlying neurologic disease, largely prevented by the CSF1R inhibitor pexidartinib, and influenced by oxygen concentration in the carrier gas.
    Keywords:  electron transport chain complex I; mitochondrial disease; neurodegenerative disease; paediatric disease; toxicity
    DOI:  https://doi.org/10.1016/j.bja.2023.08.009
  26. Eur Heart J Case Rep. 2023 Sep;7(9): ytad441
    Late-onset MELAS syndrome in a 46-year-old man with initial symptom of chest tightness: a case report.
    Ai Wang, Ji Zhao, Yun Zhao, Yan Yan.
      Background: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder caused by mutations in mitochondrial DNA, resulting in impaired energy production and affecting multiple organs. We present a suspected MELAS syndrome case with the initial symptom of chest tightness.Case summary: A 46-year-old man sought medical attention due to progressively worsening chest tightness during physical activity. He had been receiving treatment for type 2 diabetes for 15 years. One year ago, he presented with symptoms of hearing impairment. Transthoracic echocardiography revealed increased thickness of the left ventricular wall. Serum protein electrophoresis showed no evidence of light-chain amyloidosis, and the 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scan showed no definite uptake in the heart muscle. The patient's head magnetic resonance imaging (MRI) indicated lacunar infarcts. The lactate threshold test was positive. The biopsy of the skeletal muscle showed broken red fibre infiltration on modified Gomori trichrome staining, and electron microscopy revealed signs of mitochondrial cardiomyopathy, including mild mitochondrial swelling, lipid accumulation, and myofibril damage. A whole-exome genetic test was used to detect the m.3243A>G mutation in the MT-TL1 gene. Based on these findings, MELAS syndrome was the most probable diagnosis.
    Discussion: The patient presented with chest tightness in adulthood, without any accompanying psychoneurological symptoms. However, the patient presented with other symptoms, including diabetes mellitus, hearing loss, abnormal lactate levels, ischaemic lesions on head MRI, and left ventricular hypertrophy. By identifying a mutation in the MT-TL1 gene and conducting a muscle biopsy, the diagnosis of MELAS syndrome was definitively confirmed.
    Keywords:  Cardiomyopathy; Case report; MELAS syndrome; Mitochondrial disease
    DOI:  https://doi.org/10.1093/ehjcr/ytad441
  27. J Neurol. 2023 Sep 26.
    Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum.
    Yujiro Higuchi, Masahiro Ando, Fumikazu Kojima, Junhui Yuan, Akihiro Hashiguchi, Akiko Yoshimura, Yu Hiramatsu, Satoshi Nozuma, Shinobu Fukumura, Hiroyuki Yahikozawa, Erika Abe, Itaru Toyoshima, Masashiro Sugawara, Yuji Okamoto, Eiji Matsuura, Hiroshi Takashima.
      BACKGROUND AND OBJECTIVE: Biallelic mutations in the COA7 gene have been associated with spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3), and a notable clinical diversity has been observed. We aim to identify the genetic and phenotypic spectrum of COA7-related disorders.METHODS: We conducted comprehensive genetic analyses on the COA7 gene within a large group of Japanese patients clinically diagnosed with inherited peripheral neuropathy or cerebellar ataxia.
    RESULTS: In addition to our original report, which involved four patients until 2018, we identified biallelic variants of the COA7 gene in another three unrelated patients, and the variants were c.17A > G (p.D6G), c.115C > T (p.R39W), and c.449G > A (p.C150Y; novel). Patient 1 presented with an infantile-onset generalized dystonia without cerebellar ataxia. Despite experiencing an initial transient positive response to levodopa and deep brain stimulation, he became bedridden by the age of 19. Patient 2 presented with cerebellar ataxia, neuropathy, as well as parkinsonism, and showed a slight improvement upon levodopa administration. Dopamine transporter SPECT showed decreased uptake in the bilateral putamen in both patients. Patient 3 exhibited severe muscle weakness, respiratory failure, and feeding difficulties. A haplotype analysis of the mutation hotspot in Japan, c.17A > G (p.D6G), uncovered a common haplotype block.
    CONCLUSION: COA7-related disorders typically encompass a spectrum of conditions characterized by a variety of major (cerebellar ataxia and axonal polyneuropathy) and minor (leukoencephalopathy, dystonia, and parkinsonism) symptoms, but may also display a dystonia-predominant phenotype. We propose that COA7 should be considered as a new causative gene for infancy-onset generalized dystonia, and COA7 gene screening is recommended for patients with unexplained dysfunctions of the central and peripheral nervous systems.
    Keywords:  COA7; Dystonia; Mitochondrial disease; Parkinsonism; Spinocerebellar ataxia with axonal neuropathy
    DOI:  https://doi.org/10.1007/s00415-023-11998-3
  28. PLoS One. 2023 ;18(9): e0286380
    A novel panel of Drosophila TAFAZZIN mutants in distinct genetic backgrounds as a resource for therapeutic testing.
    Kristin Richardson, Robert Wessells.
      Barth Syndrome is a rare, X-linked disorder caused by mutation of the gene TAFAZZIN (TAZ). The corresponding Tafazzin protein is involved in the remodeling of cardiolipin, a phospholipid with critical roles in mitochondrial function. While recent clinical trials have been promising, there is still no cure for Barth Syndrome. Because TAZ is highly conserved, multiple animal and cell culture models exist for pre-clinical testing of therapeutics. However, since the same mutation in different patients can lead to different symptoms and responses to treatment, isogenized experimental models can't fully account for human disease conditions. On the other hand, isogenized animal models allow for sufficient numbers to thoroughly establish efficacy for a given genetic background. Therefore, a combined method for testing treatments in a panel of isogenized cohorts that are genetically distinct from each other would be transformative for testing emerging pre-clinical therapies. To aid in this effort, we've created a novel panel of 10 Drosophila lines, each with the same TAZ mutation in highly diverse genetic backgrounds, to serve as a helpful resource to represent natural variation in background genetics in pre-clinical studies. As a proof of principle, we test our panel here using nicotinamide riboside (NR), a treatment with established therapeutic value, to evaluate how robust this therapy is across the 10 genetic backgrounds in this novel reference panel. We find substantial variation in the response to NR across backgrounds. We expect this resource will be valuable in pre-clinical testing of emerging therapies for Barth Syndrome.
    DOI:  https://doi.org/10.1371/journal.pone.0286380
  29. Antioxidants (Basel). 2023 Aug 22. pii: 1658. [Epub ahead of print]12(9):
    Toward Ameliorating Insulin Resistance: Targeting a Novel PAK1 Signaling Pathway Required for Skeletal Muscle Mitochondrial Function.
    Rekha Balakrishnan, Pablo A Garcia, Rajakrishnan Veluthakal, Janice M Huss, Joseph M Hoolachan, Debbie C Thurmond.
      The p21-activated kinase 1 (PAK1) is required for insulin-stimulated glucose uptake in skeletal muscle cells. However, whether PAK1 regulates skeletal muscle mitochondrial function, which is a central determinant of insulin sensitivity, is unknown. Here, the effect of modulating PAK1 levels (knockdown via siRNA, overexpression via adenoviral transduction, and/or inhibition of activation via IPA3) on mitochondrial function was assessed in normal and/or insulin-resistant rat L6.GLUT4myc and human muscle (LHCN-M2) myotubes. Human type 2 diabetes (T2D) and non-diabetic (ND) skeletal muscle samples were also used for validation of the identified signaling elements. PAK1 depletion in myotubes decreased mitochondrial copy number, respiration, altered mitochondrial structure, downregulated PGC1α (a core regulator of mitochondrial biogenesis and oxidative metabolism) and PGC1α activators, p38 mitogen-activated protein kinase (p38MAPK) and activating transcription factor 2 (ATF2). PAK1 enrichment in insulin-resistant myotubes improved mitochondrial function and rescued PGC1α expression levels. Activated PAK1 was localized to the cytoplasm, and PAK1 enrichment concurrent with p38MAPK inhibition did not increase PGC1α levels. PAK1 inhibition and enrichment also modified nuclear phosphorylated-ATF2 levels. T2D human samples showed a deficit for PGC1α, and PAK1 depletion in LHCN-M2 cells led to reduced mitochondrial respiration. Overall, the results suggest that PAK1 regulates muscle mitochondrial function upstream of the p38MAPK/ATF2/PGC1α-axis pathway.
    Keywords:  PAK1; insulin resistance; mitochondria; skeletal muscle; type 2 diabetes
    DOI:  https://doi.org/10.3390/antiox12091658
  30. Life Sci Alliance. 2023 Dec;pii: e202302122. [Epub ahead of print]6(12):
    Two domains of Tim50 coordinate translocation of proteins across the two mitochondrial membranes.
    Marcel G Genge, Shalini Roy Chowdhury, Vít Dohnálek, Kaori Yunoki, Takashi Hirashima, Toshiya Endo, Pavel Doležal, Dejana Mokranjac.
      Hundreds of mitochondrial proteins with N-terminal presequences are translocated across the outer and inner mitochondrial membranes via the TOM and TIM23 complexes, respectively. How translocation of proteins across two mitochondrial membranes is coordinated is largely unknown. Here, we show that the two domains of Tim50 in the intermembrane space, named core and PBD, both have essential roles in this process. Building upon the surprising observation that the two domains of Tim50 can complement each other in trans, we establish that the core domain contains the main presequence-binding site and serves as the main recruitment point to the TIM23 complex. On the other hand, the PBD plays, directly or indirectly, a critical role in cooperation of the TOM and TIM23 complexes and supports the receptor function of Tim50. Thus, the two domains of Tim50 both have essential but distinct roles and together coordinate translocation of proteins across two mitochondrial membranes.
    DOI:  https://doi.org/10.26508/lsa.202302122
  31. J Atheroscler Thromb. 2023 Sep 28.
    The Impact of Ketone Body Metabolism on Mitochondrial Function and Cardiovascular Diseases.
    Yuichiro Arima.
      Ketone bodies, consisting of beta-hydroxybutyrate, acetoacetate, and acetone, are metabolic byproducts known as energy substrates during fasting. Recent advancements have shed light on the multifaceted effects of ketone body metabolism, which led to increased interest in therapeutic interventions aimed at elevating ketone body levels. However, excessive elevation of ketone body concentration can lead to ketoacidosis, which may have fatal consequences. Therefore, in this review, we aimed to focus on the latest insights on ketone body metabolism, particularly emphasizing its association with mitochondria as the primary site of interaction. Given the distinct separation between ketone body synthesis and breakdown pathways, we provide an overview of each metabolic pathway. Additionally, we discuss the relevance of ketone bodies to conditions such as nonalcoholic fatty liver disease or nonalcoholic steatohepatitis and cardiovascular diseases. Moreover, we explore the utilization of ketone body metabolism, including dietary interventions, in the context of aging, where mitochondrial dysfunction plays a crucial role. Through this review, we aim to present a comprehensive understanding of ketone body metabolism and its intricate relationship with mitochondrial function, spanning the potential implications in various health conditions and the aging process.
    Keywords:  Aging; Cardiovascular diseases; Ketone body metabolism; Mitochondria
    DOI:  https://doi.org/10.5551/jat.RV22011
  32. Mol Ther Nucleic Acids. 2023 Dec 12. 34 102028
    Engineering RsDddA as mitochondrial base editor with wide target compatibility and enhanced activity.
    Kai Cheng, Cao Li, Jiachuan Jin, Xuezhen Qian, Jiayin Guo, Limini Shen, YiChen Dai, Xue Zhang, Zhanwei Li, Yichun Guan, Fei Zhou, Jin Tang, Jun Zhang, Bin Shen, Xin Lou.
      Double-stranded DNA-specific cytidine deaminase (DddA) base editors hold great promise for applications in bio-medical research, medicine, and biotechnology. Strict sequence preference on spacing region presents a challenge for DddA editors to reach their full potential. To overcome this sequence-context constraint, we analyzed a protein dataset and identified a novel DddAtox homolog from Ruminococcus sp. AF17-6 (RsDddA). We engineered RsDddA for mitochondrial base editing in a mammalian cell line and demonstrated RsDddA-derived cytosine base editors (RsDdCBE) offered a broadened NC sequence compatibility and exhibited robust editing efficiency. Moreover, our results suggest the average frequencies of mitochondrial genome-wide off-target editing arising from RsDdCBE are comparable to canonical DdCBE and its variants.
    Keywords:  DdCBE; MT: RNA/DNA Editing; base editing; mitochondrial disease; mtDNA engineering; target compatibility
    DOI:  https://doi.org/10.1016/j.omtn.2023.09.005
  33. STAR Protoc. 2023 Sep 23. pii: S2666-1667(23)00527-0. [Epub ahead of print]4(4): 102560
    Protocol for measuring respiratory function of mitochondria in frozen colon tissue from rats.
    Chunlong Mu, Jane Shearer.
      Mitochondrial respirometry allows for the comprehensive study of oxygen consumption within the electron transport system in tissues. However, limited techniques exist for analyzing frozen or biobanked intestinal tissues. Here, we present a protocol to evaluate the respiratory function of mitochondria in colonic tissues after cryopreservation at -80°C. We describe steps for rat dissection, respirometry calibration, and tissue preparation. We then detail measurement of oxygen respiration and protein concentration. This protocol facilitates the retrospective analysis of mitochondrial respiration in frozen tissue.
    Keywords:  Health Sciences; Metabolism; Model Organisms; Molecular Biology
    DOI:  https://doi.org/10.1016/j.xpro.2023.102560
  34. Nat Cell Biol. 2023 Sep 25.
    Iron drives anabolic metabolism through active histone demethylation and mTORC1.
    Jason S Shapiro, Hsiang-Chun Chang, Yuki Tatekoshi, Zibo Zhao, Zohra Sattar Waxali, Bong Jin Hong, Haimei Chen, Justin A Geier, Elizabeth T Bartom, Adam De Jesus, Farnaz K Nejad, Amir Mahmoodzadeh, Tatsuya Sato, Lucia Ramos-Alonso, Antonia Maria Romero, Maria Teresa Martinez-Pastor, Shang-Chuan Jiang, Shiv K Sah-Teli, Liming Li, David Bentrem, Gary Lopaschuk, Issam Ben-Sahra, Thomas V O'Halloran, Ali Shilatifard, Sergi Puig, Joy Bergelson, Peppi Koivunen, Hossein Ardehali.
      All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here we report a previously undescribed eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of a high-affinity leucine transporter, LAT3, and RPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency supersedes other nutrient inputs into mTORC1. This process occurs in vivo and is not an indirect effect by canonical iron-utilizing pathways. Because ancestral eukaryotes share homologues of KDMs and mTORC1 core components, this pathway probably pre-dated the emergence of the other kingdom-specific nutrient sensors for mTORC1.
    DOI:  https://doi.org/10.1038/s41556-023-01225-6
  35. Front Cell Dev Biol. 2023 ;11 1171440
    Reduced ER-mitochondrial contact sites and mitochondrial Ca2+ flux in PRKN-mutant patient tyrosine hydroxylase reporter iPSC lines.
    Mutsumi Yokota, Yutaro Yoshino, Mitsuko Hosoi, Ryota Hashimoto, Soichiro Kakuta, Takahiro Shiga, Kei-Ichi Ishikawa, Hideyuki Okano, Nobutaka Hattori, Wado Akamatsu, Masato Koike.
      Endoplasmic reticulum-mitochondrial contact sites (ERMCS) play an important role in mitochondrial dynamics, calcium signaling, and autophagy. Disruption of the ERMCS has been linked to several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, the etiological role of ERMCS in these diseases remains unclear. We previously established tyrosine hydroxylase reporter (TH-GFP) iPSC lines from a PD patient with a PRKN mutation to perform correlative light-electron microscopy (CLEM) analysis and live cell imaging in GFP-expressing dopaminergic neurons. Here, we analyzed ERMCS in GFP-expressing PRKN-mutant dopaminergic neurons from patients using CLEM and a proximity ligation assay (PLA). The PLA showed that the ERMCS were significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control under normal conditions. The reduction of the ERMCS in PRKN-mutant patient dopaminergic neurons was further enhanced by treatment with a mitochondrial uncoupler. In addition, mitochondrial calcium imaging showed that mitochondrial Ca2+ flux was significantly reduced in PRKN-mutant patient dopaminergic neurons compared to the control. These results suggest a defect in calcium flux from ER to mitochondria is due to the decreased ERMCS in PRKN-mutant patient dopaminergic neurons. Our study of ERMCS using TH-GFP iPSC lines would contribute to further understanding of the mechanisms of dopaminergic neuron degeneration in patients with PRKN mutations.
    Keywords:  ER-mitochondrial contact sites; PRKN; dopaminergic neurons; iPSC; tyrosine hydroxylase reporter
    DOI:  https://doi.org/10.3389/fcell.2023.1171440
  36. Nat Commun. 2023 Sep 25. 14(1): 5971
    A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators.
    Yi-Cheng Chang, Hsiao-Lin Lee, Wenjin Yang, Meng-Lun Hsieh, Cai-Cin Liu, Tung-Yuan Lee, Jing-Yong Huang, Jiun-Yi Nong, Fu-An Li, Hsiao-Li Chuang, Zhi-Zhong Ding, Wei-Lun Su, Li-Yun Chueh, Yi-Ting Tsai, Che-Hong Chen, Daria Mochly-Rosen, Lee-Ming Chuang.
      Obesity and type 2 diabetes have reached pandemic proportion. ALDH2 (acetaldehyde dehydrogenase 2, mitochondrial) is the key metabolizing enzyme of acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal. A missense Glu504Lys mutation of the ALDH2 gene is prevalent in 560 million East Asians, resulting in reduced ALDH2 enzymatic activity. We find that male Aldh2 knock-in mice mimicking human Glu504Lys mutation were prone to develop diet-induced obesity, glucose intolerance, insulin resistance, and fatty liver due to reduced adaptive thermogenesis and energy expenditure. We find reduced activity of ALDH2 of the brown adipose tissue from the male Aldh2 homozygous knock-in mice. Proteomic analyses of the brown adipose tissue from the male Aldh2 knock-in mice identifies increased 4-hydroxynonenal-adducted proteins involved in mitochondrial fatty acid oxidation and electron transport chain, leading to markedly decreased fatty acid oxidation rate and mitochondrial respiration of brown adipose tissue, which is essential for adaptive thermogenesis and energy expenditure. AD-9308 is a water-soluble, potent, and highly selective ALDH2 activator. AD-9308 treatment ameliorates diet-induced obesity and fatty liver, and improves glucose homeostasis in both male Aldh2 wild-type and knock-in mice. Our data highlight the therapeutic potential of reducing toxic aldehyde levels by activating ALDH2 for metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-023-41570-6
  37. Protein Sci. 2023 Sep 24. e4787
    The variable domain from dynamin-related protein 1 promotes liquid-liquid phase separation that enhances its interaction with cardiolipin-containing membranes.
    Ammon E Posey, Kyle A Ross, Mehran Bagheri, Elizabeth N Lanum, Misha A Khan, Christine E Jennings, Megan C Harwig, Nolan W Kennedy, Vincent J Hilser, James L Harden, R Blake Hill.
      Dynamins are an essential superfamily of mechanoenzymes that remodel membranes and often contain a "variable domain" important for regulation. For the mitochondrial fission dynamin, dynamin-related protein 1, a regulatory role for the variable domain is demonstrated by gain- and loss-of-function mutations, yet the basis for this is unclear. Here, the isolated variable domain is shown to be intrinsically disordered and undergo a cooperative transition in the stabilizing osmolyte trimethylamine N-oxide. However, the osmolyte-induced state is not folded and surprisingly appears as a condensed state. Other co-solutes including known molecular crowder Ficoll PM 70, also induce a condensed state. Fluorescence recovery after photobleaching experiments reveal this state to be liquid-like indicating the variable domain undergoes a liquid-liquid phase separation under crowding conditions. These crowding conditions also enhance binding to cardiolipin, a mitochondrial lipid, which appears to promote phase separation. Since dynamin-related protein 1 is found assembled into discrete punctate structures on the mitochondrial surface, the inference from the present work is that these structures might arise from a condensed state involving the variable domain that may enable rapid tuning of mechanoenzyme assembly necessary for fission. This article is protected by copyright. All rights reserved.
    Keywords:  NMR; dynamin; fluorescence; intrinsically disordered protein; mitochondria; mitochondrial fission; phase separation; protein folding
    DOI:  https://doi.org/10.1002/pro.4787
  38. Biomolecules. 2023 Sep 02. pii: 1341. [Epub ahead of print]13(9):
    Role of Lipids and Divalent Cations in Membrane Fusion Mediated by the Heptad Repeat Domain 1 of Mitofusin.
    Anaïs Vlieghe, Kristina Niort, Hugo Fumat, Jean-Michel Guigner, Mickaël M Cohen, David Tareste.
      Mitochondria are highly dynamic organelles that constantly undergo fusion and fission events to maintain their shape, distribution and cellular function. Mitofusin 1 and 2 proteins are two dynamin-like GTPases involved in the fusion of outer mitochondrial membranes (OMM). Mitofusins are anchored to the OMM through their transmembrane domain and possess two heptad repeat domains (HR1 and HR2) in addition to their N-terminal GTPase domain. The HR1 domain was found to induce fusion via its amphipathic helix, which interacts with the lipid bilayer structure. The lipid composition of mitochondrial membranes can also impact fusion. However, the precise mode of action of lipids in mitochondrial fusion is not fully understood. In this study, we examined the role of the mitochondrial lipids phosphatidylethanolamine (PE), cardiolipin (CL) and phosphatidic acid (PA) in membrane fusion induced by the HR1 domain, both in the presence and absence of divalent cations (Ca2+ or Mg2+). Our results showed that PE, as well as PA in the presence of Ca2+, effectively stimulated HR1-mediated fusion, while CL had a slight inhibitory effect. By considering the biophysical properties of these lipids in the absence or presence of divalent cations, we inferred that the interplay between divalent cations and specific cone-shaped lipids creates regions with packing defects in the membrane, which provides a favorable environment for the amphipathic helix of HR1 to bind to the membrane and initiate fusion.
    Keywords:  Mitofusin; amphipathic helix; divalent cations; fusion; lipid packing defects; membrane; mitochondria
    DOI:  https://doi.org/10.3390/biom13091341
  39. Mov Disord. 2023 Sep 26.
    Harmonizing Genetic Testing for Parkinson's Disease: Results of the PARKNET Multicentric Study.
    PARKNET study group
      BACKGROUND AND OBJECTIVE: Early-onset Parkinson's disease (EOPD) commonly recognizes a genetic basis; thus, patients with EOPD are often addressed to diagnostic testing based on next-generation sequencing (NGS) of PD-associated multigene panels. However, NGS interpretation can be challenging in a diagnostic setting, and few studies have addressed this issue so far.METHODS: We retrospectively collected data from 648 patients with PD with age at onset younger than 55 years who underwent NGS of a minimal shared panel of 15 PD-related genes, as well as PD-multiplex ligation-dependent probe amplification in eight Italian diagnostic laboratories. Data included a minimal clinical dataset, the complete list of variants included in the diagnostic report, and final interpretation (positive/negative/inconclusive). Patients were further stratified based on age at onset ≤40 years (very EOPD, n = 157). All variants were reclassified according to the latest American College of Medical Genetics and Genomics criteria. For classification purposes, PD-associated GBA1 variants were considered diagnostic.
    RESULTS: In 186 of 648 (29%) patients, the diagnostic report listed at least one variant, and the outcome was considered diagnostic (positive) in 105 (16%). After reanalysis, diagnosis changed in 18 of 186 (10%) patients, with 5 shifting from inconclusive to positive and 13 former positive being reclassified as inconclusive. A definite diagnosis was eventually reached in 97 (15%) patients, of whom the majority carried GBA1 variants or, less frequently, biallelic PRKN variants. In 89 (14%) cases, the genetic report was inconclusive.
    CONCLUSIONS: This study attempts to harmonize reporting of PD genetic testing across several diagnostic labs and highlights current difficulties in interpreting genetic variants emerging from NGS-multigene panels, with relevant implications for counseling. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  EOPD; Parkinson's disease; gene panel; next-generation sequencing; variant classification
    DOI:  https://doi.org/10.1002/mds.29617
  40. Int J Mol Sci. 2023 Sep 07. pii: 13782. [Epub ahead of print]24(18):
    Mitochondrial Dynamics and Insulin Secretion.
    Uma D Kabra, Martin Jastroch.
      Mitochondria are involved in the regulation of cellular energy metabolism, calcium homeostasis, and apoptosis. For mitochondrial quality control, dynamic processes, such as mitochondrial fission and fusion, are necessary to maintain shape and function. Disturbances of mitochondrial dynamics lead to dysfunctional mitochondria, which contribute to the development and progression of numerous diseases, including Type 2 Diabetes (T2D). Compelling evidence has been put forward that mitochondrial dynamics play a significant role in the metabolism-secretion coupling of pancreatic β cells. The disruption of mitochondrial dynamics is linked to defects in energy production and increased apoptosis, ultimately impairing insulin secretion and β cell death. This review provides an overview of molecular mechanisms controlling mitochondrial dynamics, their dysfunction in pancreatic β cells, and pharmaceutical agents targeting mitochondrial dynamic proteins, such as mitochondrial division inhibitor-1 (mdivi-1), dynasore, P110, and 15-oxospiramilactone (S3).
    Keywords:  diabetes; fission; fusion; glucose-stimulated insulin secretion; mitochondrial dynamics; pancreatic beta cell
    DOI:  https://doi.org/10.3390/ijms241813782
  41. Nat Commun. 2023 Sep 29. 14(1): 6086
    Multi-omics profiling reveals rhythmic liver function shaped by meal timing.
    Rongfeng Huang, Jianghui Chen, Meiyu Zhou, Haoran Xin, Sin Man Lam, Xiaoqing Jiang, Jie Li, Fang Deng, Guanghou Shui, Zhihui Zhang, Min-Dian Li.
      Post-translational modifications (PTMs) couple feed-fast cycles to diurnal rhythms. However, it remains largely uncharacterized whether and how meal timing organizes diurnal rhythms beyond the transcriptome. Here, we systematically profile the daily rhythms of the proteome, four PTMs (phosphorylation, ubiquitylation, succinylation and N-glycosylation) and the lipidome in the liver from young female mice subjected to either day/sleep time-restricted feeding (DRF) or night/wake time-restricted feeding (NRF). We detect robust daily rhythms among different layers of omics with phosphorylation the most nutrient-responsive and succinylation the least. Integrative analyses reveal that clock regulation of fatty acid metabolism represents a key diurnal feature that is reset by meal timing, as indicated by the rhythmic phosphorylation of the circadian repressor PERIOD2 at Ser971 (PER2-pSer971). We confirm that PER2-pSer971 is activated by nutrient availability in vivo. Together, this dataset represents a comprehensive resource detailing the proteomic and lipidomic responses by the liver to alterations in meal timing.
    DOI:  https://doi.org/10.1038/s41467-023-41759-9
  42. Cell. 2023 Sep 20. pii: S0092-8674(23)00968-6. [Epub ahead of print]
    Synthetic Par polarity induces cytoskeleton asymmetry in unpolarized mammalian cells.
    Joseph L Watson, Lara K Krüger, Ariel J Ben-Sasson, Alice Bittleston, Marta N Shahbazi, Vicente Jose Planelles-Herrero, Joseph E Chambers, James D Manton, David Baker, Emmanuel Derivery.
      Polarized cells rely on a polarized cytoskeleton to function. Yet, how cortical polarity cues induce cytoskeleton polarization remains elusive. Here, we capitalized on recently established designed 2D protein arrays to ectopically engineer cortical polarity of virtually any protein of interest during mitosis in various cell types. This enables direct manipulation of polarity signaling and the identification of the cortical cues sufficient for cytoskeleton polarization. Using this assay, we dissected the logic of the Par complex pathway, a key regulator of cytoskeleton polarity during asymmetric cell division. We show that cortical clustering of any Par complex subunit is sufficient to trigger complex assembly and that the primary kinetic barrier to complex assembly is the relief of Par6 autoinhibition. Further, we found that inducing cortical Par complex polarity induces two hallmarks of asymmetric cell division in unpolarized mammalian cells: spindle orientation, occurring via Par3, and central spindle asymmetry, depending on aPKC activity.
    Keywords:  asymmetric cell division; cytoskeleton; polarity; protein design; synthetic biology
    DOI:  https://doi.org/10.1016/j.cell.2023.08.034
  43. Front Immunol. 2023 ;14 1243548
    Mitochondrial PGAM5-Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses.
    Bo-Ram Bang, Haruka Miki, Young Jun Kang.
      Macrophages play a critical role in the regulation of inflammation and tissue homeostasis. In addition to their vital functions for cell survival and physiology, mitochondria play a crucial role in innate immunity as a platform for the induction of inflammatory responses by regulating cell signaling and dynamics. Dynamin-related protein 1 (Drp1) plays a role in the induction of inflammatory responses and the subsequent development of various diseases. PGAM5 (phosphoglycerate mutase member 5) is a mitochondrial outer membrane phosphatase that dephosphorylates its substrate, Drp1. Previous studies showed that PGAM5 regulates the phosphorylation of Drp1 for the activation of NKT cells and T cells. However, it is not clear how PGAM5 regulates Drp1 activity for the induction of inflammation in macrophages. Here, we demonstrate that PGAM5 activity regulates the dephosphorylation of Drp1 in macrophages, leading to the induction of proinflammatory responses in macrophages. In TLR signaling, PGAM5 regulates the expression and production of inflammatory cytokines by regulating the activation of downstream signaling pathways, including the NF-κB and MAPK pathways. Upon LPS stimulation, PGAM5 interacts with Drp1 to form a complex, leading to the production of mtROS. Furthermore, PGAM5-Drp1 signaling promotes the polarization of macrophages toward a proinflammatory phenotype. Our study further demonstrates that PGAM5-Drp1 signaling promotes metabolic reprogramming by upregulating glycolysis and mitochondrial metabolism in macrophages. Altogether, PGAM5 signaling is a linker between alterations in Drp1-mediated mitochondrial dynamics and inflammatory responses in macrophages and may be a target for the treatment of inflammatory diseases.
    Keywords:  inflammatory response; innate immunity; macrophages; metabolism; mitochondria; signaling/signaling pathways
    DOI:  https://doi.org/10.3389/fimmu.2023.1243548
  44. STAR Protoc. 2023 Sep 26. pii: S2666-1667(23)00140-5. [Epub ahead of print]4(4): 102182
    Simulating the conformational dynamics of the ATPase complex on proteasome using its free-energy landscape.
    Rui Fang, Ying Lu.
      The AAA+ ATPase complex on proteasome powers its functions through a series of intricate conformational transitions. Here, we describe a procedure to simulate the conformational dynamics of the proteasomal ATPase complex. We first empirically determined the free-energy landscape (FEL) of proteasome and then simulated proteasome's conformational changes as stochastic transitions on its FEL. We compared the FEL-predicted proteasomal behaviors with experimental measurements and analyzed the map of the ATPase's global dynamics to gain mechanistic insights into proteasomal degradation. For complete details on the use and execution of this protocol, please refer to Fang et al. (2022).1.
    Keywords:  Biophysics; Computer Sciences; Protein Biochemistry; Structural Biology; Systems Biology
    DOI:  https://doi.org/10.1016/j.xpro.2023.102182
  45. Nature. 2023 Sep 28.
    Can AI predict who will win a Nobel Prize?
    Gemma Conroy.
      
    Keywords:  Machine learning; Scientific community; Software
    DOI:  https://doi.org/10.1038/d41586-023-03074-7
  46. bioRxiv. 2023 Sep 17. pii: 2023.09.15.558026. [Epub ahead of print]
    bamSliceR : cross-cohort variant and allelic bias analysis for rare variants and rare diseases.
    Yizhou Peter Huang, Lauren Harmon, Eve Gardner, Xiaotu Ma, Josiah Harsh, Zhaoyu Xue, Hong Wen, Marcel Ramos, Sean Davis, Timothy J Triche.
      Rare diseases and conditions create unique challenges for genetic epidemiologists precisely because cases and samples are scarce. In recent years, whole-genome and whole-transcriptome sequencing (WGS /WTS) have eased the study of rare genetic variants. Paired WGS and WTS data are ideal, but logistical and financial constraints often preclude generating paired WGS and WTS data. Thus, many databases contain a patchwork of specimens with either WGS or WTS data, but only a minority of samples have both. The NCI Genomic Data Commons facilitates controlled access to genomic and transcriptomic data for thousands of subjects, many with unpaired sequencing results. Local reanalysis of expressed variants across whole transcriptomes requires significant data storage, compute, and expertise. We developed the bamSliceR package to facilitate swift transition from aligned sequence reads to expressed variant characterization. bamSliceR leverages the NCI Genomic Data Commons API to query genomic sub-regions of aligned sequence reads from specimens identified through the robust Bioconductor ecosystem. We demonstrate how population-scale targeted genomic analysis can be completed using orders of magnitude fewer resources in this fashion, with minimal compute burden. We demonstrate pilot results from bamSliceR for the TARGET pediatric AML and BEAT-AML projects, where identification of rare but recurrent somatic variants directly yields biologically testable hypotheses. bamSliceR and its documentation are freely available on GitHub at https://github.com/trichelab/bamSliceR .
    DOI:  https://doi.org/10.1101/2023.09.15.558026
  47. NAR Genom Bioinform. 2023 Sep;5(3): lqad084
    Most protein domains exist as variants with distinct functions across cells, tissues and diseases.
    Kristoffer Vitting-Seerup.
      Protein domains are the active subunits that provide proteins with specific functions through precise three-dimensional structures. Such domains facilitate most protein functions, including molecular interactions and signal transduction. Currently, these protein domains are described and analyzed as invariable molecular building blocks with fixed functions. Here, I show that most human protein domains exist as multiple distinct variants termed 'domain isotypes'. Domain isotypes are used in a cell, tissue and disease-specific manner and have surprisingly different 3D structures. Accordingly, domain isotypes, compared to each other, modulate or abolish the functionality of protein domains. These results challenge the current view of protein domains as invariable building blocks and have significant implications for both wet- and dry-lab workflows. The extensive use of protein domain isotypes within protein isoforms adds to the literature indicating we need to transition to an isoform-centric research paradigm.
    DOI:  https://doi.org/10.1093/nargab/lqad084
  48. Circ Genom Precis Med. 2023 Sep 28. e004062
    Genetic Contribution to End-Stage Cardiomyopathy Requiring Heart Transplantation.
    Yuri Kim, Oddný Brattberg Gunnarsdóttir, Anissa Viveiros, Daniel Reichart, Daniel Quiat, Jon A L Willcox, Hao Zhang, Huachen Chen, Justin J Curran, Daniel H Kim, Simon Urschel, Barbara McDonough, Joshua Gorham, Steven R DePalma, Jonathan G Seidman, Christine E Seidman, Gavin Y Oudit.
      BACKGROUND: Many cardiovascular disorders propel the development of advanced heart failure that necessitates cardiac transplantation. When treatable causes are excluded, studies to define causes are often abandoned, resulting in a diagnosis of end-stage idiopathic cardiomyopathy. We studied whether DNA sequence analyses could identify unrecognized causes of end-stage nonischemic cardiomyopathy requiring heart transplantation and whether the prevalence of genetic causes differed from ambulatory cardiomyopathy cases.METHODS: We performed whole exome and genome sequencing of 122 explanted hearts from 101 adult and 21 pediatric patients with idiopathic cardiomyopathy from a single center. Data were analyzed for pathogenic/likely pathogenic variants in nuclear and mitochondrial genomes and assessed for nonhuman microbial sequences. The frequency of damaging genetic variants was compared among cardiomyopathy cohorts with different clinical severity.
    RESULTS: Fifty-four samples (44.3%) had pathogenic/likely pathogenic cardiomyopathy gene variants. The frequency of pathogenic variants was similar in pediatric (42.9%) and adult (43.6%) samples, but the distribution of mutated genes differed (P=8.30×10-4). The prevalence of causal genetic variants was significantly higher in end-stage than in previously reported ambulatory adult dilated cardiomyopathy cases (P<0.001). Among remaining samples with unexplained causes, no damaging mitochondrial variants were identified, but 28 samples contained parvovirus genome sequences, including 2 samples with 6- to 9-fold higher levels than the overall mean levels in other samples.
    CONCLUSIONS: Pathogenic variants and viral myocarditis were identified in 45.9% of patients with unexplained end-stage cardiomyopathy. Damaging gene variants are significantly more frequent among transplant compared with patients with ambulatory cardiomyopathy. Genetic analyses can help define cause of end-stage cardiomyopathy guide management and risk stratification of patients and family members.
    Keywords:  cardiomyopathies; heart failure; patients; risk; transplantation
    DOI:  https://doi.org/10.1161/CIRCGEN.123.004062
  49. Biosensors (Basel). 2023 Sep 12. pii: 883. [Epub ahead of print]13(9):
    An Anthracene Carboxamide-Based Fluorescent Probe for Rapid and Sensitive Detection of Mitochondrial Hypochlorite in Living Cells.
    Xueling Liu, Yali Wang, Guangshuai Zhou, Wenzhou Zhang.
      Mitochondrial hypochlorite (ClO-) plays important and often contradictory roles in maintaining the redox balance of mitochondria. Abnormal ClO- levels can induce mitochondrial inactivation and further cause cell apoptosis. Herein, we have developed an anthracene carboxyimide-based fluorescent probe mito-ACS for imaging mitochondrial ClO- in living cells. This probe exhibits some distinctive features as excellent resistance to photobleaching, high selectivity and sensitivity, as well as good water solubility. Mito-ACS showed a noticeable fluorescence response toward ClO- with a fast response (within 6 s) and a low detection limit (23 nM). Moreover, the introduction of triphenylphosphonium makes the probe soluble in water and selectively localizes to mitochondria. Furthermore, mito-ACS was successfully applied to image mitochondria ClO- in living cells with low toxicity. Remarkably. the less used fluorophore anthracene carboxyimide exhibiting excellent photostability and desirable optical properties provides a promising application prospect in biological systems.
    Keywords:  anthracene carboxyimide; fluorescent probe; hypochlorite; mitochondria
    DOI:  https://doi.org/10.3390/bios13090883
  50. medRxiv. 2023 Sep 18. pii: 2023.09.14.23295564. [Epub ahead of print]
    The genetic underpinnings of variable penetrance and expressivity of pathogenic mutations in cardiometabolic traits.
    Angela Wei, Richard Border, Boyang Fu, Sinéad Cullina, Nadav Brandes, Sriram Sankararaman, Eimear E Kenny, Miriam S Udler, Vasilis Ntranos, Noah Zaitlen, Valerie A Arboleda.
      Over three percent of people carry a dominant pathogenic mutation, yet only a fraction of carriers develop disease (incomplete penetrance), and phenotypes from mutations in the same gene range from mild to severe (variable expressivity). Here, we investigate underlying mechanisms for this heterogeneity: variable variant effect sizes, carrier polygenic backgrounds, and modulation of carrier effect by genetic background (epistasis). We leveraged exomes and clinical phenotypes from the UK Biobank and the Mt. Sinai Bio Me Biobank to identify carriers of pathogenic variants affecting cardiometabolic traits. We employed recently developed methods to study these cohorts, observing strong statistical support and clinical translational potential for all three mechanisms of variable penetrance and expressivity. For example, scores from our recent model of variant pathogenicity were tightly correlated with phenotype amongst clinical variant carriers, they predicted effects of variants of unknown significance, and they distinguished gain- from loss-of-function variants. We also found that polygenic scores predicted phenotypes amongst pathogenic carriers and that epistatic effects can exceed main carrier effects by an order of magnitude.
    DOI:  https://doi.org/10.1101/2023.09.14.23295564
  51. Nat Genet. 2023 Sep 25.
    A new method for multiancestry polygenic prediction improves performance across diverse populations.
    23andMe Research Team
      Polygenic risk scores (PRSs) increasingly predict complex traits; however, suboptimal performance in non-European populations raise concerns about clinical applications and health inequities. We developed CT-SLEB, a powerful and scalable method to calculate PRSs, using ancestry-specific genome-wide association study summary statistics from multiancestry training samples, integrating clumping and thresholding, empirical Bayes and superlearning. We evaluated CT-SLEB and nine alternative methods with large-scale simulated genome-wide association studies (~19 million common variants) and datasets from 23andMe, Inc., the Global Lipids Genetics Consortium, All of Us and UK Biobank, involving 5.1 million individuals of diverse ancestry, with 1.18 million individuals from four non-European populations across 13 complex traits. Results demonstrated that CT-SLEB significantly improves PRS performance in non-European populations compared with simple alternatives, with comparable or superior performance to a recent, computationally intensive method. Moreover, our simulation studies offered insights into sample size requirements and SNP density effects on multiancestry risk prediction.
    DOI:  https://doi.org/10.1038/s41588-023-01501-z
  52. bioRxiv. 2023 Sep 13. pii: 2023.09.12.557400. [Epub ahead of print]
    mTORC1 Regulates the Metabolic Switch of Postnatal Cardiomyocytes During Regeneration.
    Wyatt G Paltzer, Timothy J Aballo, Jiyoung Bae, Katharine A Hubert, Dakota J Nuttall, Cassidy Perry, Kayla N Wanless, Raya Nahlawi, Ying Ge, Ahmed I Mahmoud.
      The metabolic switch from glycolysis to fatty acid oxidation in postnatal cardiomyocytes contributes to the loss of the cardiac regenerative potential of the mammalian heart. However, the mechanisms that regulate this metabolic switch remain unclear. The protein kinase complex mechanistic target of rapamycin complex 1 (mTORC1) is a central signaling hub that regulates cellular metabolism and protein synthesis, yet its role during mammalian heart regeneration and postnatal metabolic maturation is undefined. Here, we use immunoblotting, rapamycin treatment, myocardial infarction, and global proteomics to define the role of mTORC1 in postnatal heart development and regeneration. Our results demonstrate that the activity of mTORC1 is dynamically regulated between the regenerating and the non-regenerating hearts. Acute inhibition of mTORC1 by rapamycin or everolimus reduces cardiomyocyte proliferation and inhibits neonatal heart regeneration following injury. Our quantitative proteomic analysis demonstrates that transient inhibition of mTORC1 during neonatal heart injury did not reduce protein synthesis, but rather shifts the cardiac proteome of the neonatal injured heart from glycolysis towards fatty acid oxidation. This indicates that mTORC1 inhibition following injury accelerates the postnatal metabolic switch, which promotes metabolic maturation and impedes cardiomyocyte proliferation and heart regeneration. Taken together, our results define an important role for mTORC1 in regulating postnatal cardiac metabolism and may represent a novel target to modulate cardiac metabolism and promote heart regeneration.
    DOI:  https://doi.org/10.1101/2023.09.12.557400
  53. Biochim Biophys Acta Mol Basis Dis. 2023 Sep 27. pii: S0925-4439(23)00264-8. [Epub ahead of print] 166898
    Caspase-3 cleaved tau impairs mitochondrial function through the opening of the mitochondrial permeability transition pore.
    María José Pérez, Rodrigo Ibarra-García-Padilla, Maoping Tang, George A Porter, Gail V W Johnson, Rodrigo A Quintanilla.
      Mitochondrial dysfunction is a significant factor in the development of Alzheimer's disease (AD). Previous studies have demonstrated that the expression of tau cleaved at Asp421 by caspase-3 leads to mitochondrial abnormalities and bioenergetic impairment. However, the underlying mechanism behind these alterations and their impact on neuronal function remains unknown. To investigate the mechanism behind mitochondrial dysfunction caused by this tau form, we used transient transfection and pharmacological approaches in immortalized cortical neurons and mouse primary hippocampal neurons. We assessed mitochondrial morphology and bioenergetics function after expression of full-length tau and caspase-3-cleaved tau. We also evaluated the mitochondrial permeability transition pore (mPTP) opening and its conformation as a possible mechanism to explain mitochondrial impairment induced by caspase-3 cleaved tau. Our studies showed that pharmacological inhibition of mPTP by cyclosporine A (CsA) prevented all mitochondrial length and bioenergetics abnormalities in neuronal cells expressing caspase-3 cleaved tau. Neuronal cells expressing caspase-3-cleaved tau showed sustained mPTP opening which is mostly dependent on cyclophilin D (CypD) protein expression. Moreover, the impairment of mitochondrial length and bioenergetics induced by caspase-3-cleaved tau were prevented in hippocampal neurons obtained from CypD knock-out mice. Interestingly, previous studies using these mice showed a prevention of mPTP opening and a reduction of mitochondrial failure and neurodegeneration induced by AD. Therefore, our findings showed that caspase-3-cleaved tau negatively impacts mitochondrial bioenergetics through mPTP activation, highlighting the importance of this channel and its regulatory protein, CypD, in the neuronal damage induced by tau pathology in AD.
    Keywords:  Alzheimer's disease; Cyclophilin D; Mitochondria; Mitochondrial permeability pore; Tau
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166898
  54. Nat Commun. 2023 Sep 26. 14(1): 6009
    Patient-specific models link neurotransmitter receptor mechanisms with motor and visuospatial axes of Parkinson's disease.
    Ahmed Faraz Khan, Quadri Adewale, Sue-Jin Lin, Tobias R Baumeister, Yashar Zeighami, Felix Carbonell, Nicola Palomero-Gallagher, Yasser Iturria-Medina.
      Parkinson's disease involves multiple neurotransmitter systems beyond the classical dopaminergic circuit, but their influence on structural and functional alterations is not well understood. Here, we use patient-specific causal brain modeling to identify latent neurotransmitter receptor-mediated mechanisms contributing to Parkinson's disease progression. Combining the spatial distribution of 15 receptors from post-mortem autoradiography with 6 neuroimaging-derived pathological factors, we detect a diverse set of receptors influencing gray matter atrophy, functional activity dysregulation, microstructural degeneration, and dendrite and dopaminergic transporter loss. Inter-individual variability in receptor mechanisms correlates with symptom severity along two distinct axes, representing motor and psychomotor symptoms with large GABAergic and glutamatergic contributions, and cholinergically-dominant visuospatial, psychiatric and memory dysfunction. Our work demonstrates that receptor architecture helps explain multi-factorial brain re-organization, and suggests that distinct, co-existing receptor-mediated processes underlie Parkinson's disease.
    DOI:  https://doi.org/10.1038/s41467-023-41677-w
  55. Front Endocrinol (Lausanne). 2023 ;14 1266557
    Editorial: Integrative multi-modal, multi-omics analytics for the better understanding of metabolic diseases.
    Animesh Acharjee, Prasoon Agarwal, Georgios V Gkoutos.
      
    Keywords:  biomarker; diagnostic; metabolic disease; omics; therapeutic
    DOI:  https://doi.org/10.3389/fendo.2023.1266557
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