bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–05–19
forty-six papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth Syndrome.
  2. Increased Diagnostic Yield by Reanalysis of Whole Exome Sequencing Data in Mitochondrial Disease.
  3. A novel MT-ATP6 variant associated with complicated ataxia in two unrelated Italian patients: case report and functional studies.
  4. Editorial: Molecular links between mitochondrial damage and human neurodegenerative disorders, volume II.
  5. Mitochondrial Biomarkers in the Omics Era: A Clinical-Pathophysiological Perspective.
  6. Digenic Inheritance in Rare Disorders and Mitochondrial Disease-Crossing the Frontier to a More Comprehensive Understanding of Etiology.
  7. Mitochondrial cardiomyopathy: a puzzle for the final diagnosis.
  8. Leber's hereditary optic neuropathy like disease in MT-ATP6 variant m.8969G>A.
  9. The Blood-Brain Barrier Is Unaffected in the Ndufs4-/- Mouse Model of Leigh Syndrome.
  10. SIN-3 transcriptional coregulator maintains mitochondrial homeostasis and polyamine flux.
  11. Mitochondrial heterogeneity and adaptations to cellular needs.
  12. Heme allocation in eukaryotic cells relies on mitochondrial heme export through FLVCR1b to cytosolic GAPDH.
  13. The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration.
  14. Shwachman-Diamond syndrome mimicking mitochondrial hepatopathy.
  15. Mitophagy in health and disease. Molecular mechanisms, regulatory pathways, and therapeutic implications.
  16. Clinical and genetic analysis of methylmalonic aciduria in 60 patients from Southern China: a single center retrospective study.
  17. Co-occurrence of glial fibrillary acidic protein astrocytopathy in a patient with Leber's hereditary optic neuropathy due to DNAJC30 mutations.
  18. Mitochondrial dysfunction: mechanisms and advances in therapy.
  19. Neurotransmitter accumulation and Parkinson's disease-like phenotype caused by anion channelrhodopsin opto-controlled astrocytic mitochondrial depolarization in substantia nigra pars compacta.
  20. Mitochondrial citrate transporters Ctp1-Yhm2 and respiratory chain: A coordinated functional connection in Saccharomyces cerevisiae metabolism.
  21. Requirements for the biogenesis of [2Fe-2S] proteins in the human and yeast cytosol.
  22. Deoxyguanosine kinase deficiency: natural history and liver transplant outcome.
  23. Metabolic regulation of single synaptic vesicle exo- and endocytosis in hippocampal synapses.
  24. Emerging Roles of Vitamin B12 in Aging and Inflammation.
  25. Alterations of PINK1-PRKN signaling in mice during normal aging.
  26. Matrix stiffening promotes perinuclear clustering of mitochondria.
  27. MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy.
  28. Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay.
  29. Two residues in the DNA binding site of Pif1 helicase are essential for nuclear functions but dispensable for mitochondrial respiratory growth.
  30. Genetics of inherited peripheral neuropathies and the next frontier: looking backwards to progress forwards.
  31. D-Bifunctional Protein Deficiency Diagnosis-A Challenge in Low Resource Settings: Case Report and Review of the Literature.
  32. Novel Mutations in the ND5 Gene Associated With Leber Hereditary Optic Neuropathy.
  33. Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission.
  34. Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE.
  35. Subcellular imaging of lipids and sugars using genetically encoded proximity sensors.
  36. The mutation R107Q alters mtSSB ssDNA compaction ability and binding dynamics.
  37. The Role of Structural Variants in the Genetic Architecture of Parkinson's Disease.
  38. Integrating population genetics, stem cell biology and cellular genomics to study complex human diseases.
  39. Mitochondrial GPX4 acetylation is involved in cadmium-induced renal cell ferroptosis.
  40. Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling.
  41. Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.
  42. Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions.
  43. mRNA therapy is safe for treating the inherited metabolic condition propionic acidaemia.
  44. Multi-omics integration of scRNA-seq time series data predicts new intervention points for Parkinson's disease.
  45. A metabolic atlas of mouse aging.
  46. Serine synthesis controls mitochondrial biogenesis in macrophages.
  1. bioRxiv. 2024 Apr 29. pii: 2024.04.28.591534. [Epub ahead of print]
    Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth Syndrome.
    Olivia Sniezek Carney, Kodi William Harris, Yvonne Wohlfarter, Kyuna Lee, Grant Butschek, Arianna Anzmann, Steven M Claypool, Anne Hamacher-Brady, Markus Keller, Hilary J Vernon.
      Barth syndrome (BTHS) is a rare mitochondrial disease caused by pathogenic variants in the gene TAFAZZIN, which leads to abnormal cardiolipin (CL) metabolism on the inner mitochondrial membrane. Although TAFAZZIN is ubiquitously expressed, BTHS involves a complex combination of tissue specific phenotypes including cardiomyopathy, neutropenia, skeletal myopathy, and growth delays, with a relatively minimal neurological burden. To understand both the developmental and functional effects of TAZ-deficiency in different tissues, we generated isogenic TAZ knockout (TAZ- KO) and WT cardiomyocytes (CMs) and neural progenitor cells (NPCs) from CRISPR-edited induced pluripotent stem cells (iPSCs). In TAZ-KO CMs we discovered evidence of dysregulated mitophagy including dysmorphic mitochondria and mitochondrial cristae, differential expression of key autophagy-associated genes, and an inability of TAZ-deficient CMs to properly initiate stress-induced mitophagy. In TAZ-deficient NPCs we identified novel phenotypes including a reduction in CIV abundance and CIV activity in the CIII2&CIV2 intermediate complex. Interestingly, while CL acyl chain manipulation was unable to alter mitophagy defects in TAZ-KO CMs, we found that linoleic acid or oleic acid supplementation was able to partially restore CIV abundance in TAZ-deficient NPCs. Taken together, our results have implications for understanding the tissue-specific pathology of BTHS and potential for tissue-specific therapeutic targeting. Moreover, our results highlight an emerging role for mitophagy in the cardiac pathophysiology of BTHS and reveal a potential neuron-specific bioenergetic phenotype.
    DOI:  https://doi.org/10.1101/2024.04.28.591534
  2. J Neuromuscul Dis. 2024 May 13.
    Increased Diagnostic Yield by Reanalysis of Whole Exome Sequencing Data in Mitochondrial Disease.
    Catarina Olimpio, Ida Paramonov, Leslie Matalonga, Steven Laurie, Katherine Schon, Kiran Polavarapu, Janbernd Kirschner, Ulrike Schara-Schmidt, Hanns Lochmüller, Patrick F Chinnery, Rita Horvath.
       Background: The genetic diagnosis of mitochondrial disorders is complicated by its genetic and phenotypic complexity. Next generation sequencing techniques have much improved the diagnostic yield for these conditions. A cohort of individuals with multiple respiratory chain deficiencies, reported in the literature 10 years ago, had a diagnostic rate of 60% by whole exome sequencing (WES) but 40% remained undiagnosed.
    Objective: We aimed to identify a genetic diagnosis by reanalysis of the WES data for the undiagnosed arm of this 10-year-old cohort of patients with suspected mitochondrial disorders.
    Methods: The WES data was transferred and processed by the RD-Connect Genome-Phenome Analysis Platform (GPAP) using their standardized pipeline. Variant prioritisation was carried out on the RD-Connect GPAP.
    Results: Singleton WES data from 14 individuals was reanalysed. We identified a possible or likely genetic diagnosis in 8 patients (8/14, 57%). The variants identified were in a combination of mitochondrial DNA (n = 1, MT-TN), nuclear encoded mitochondrial genes (n = 2, PDHA1, and SUCLA2) and nuclear genes associated with nonmitochondrial disorders (n = 5, PNPLA2, CDC40, NBAS and SLC7A7). Variants in both the NBAS and CDC40 genes were established as disease causing after the original cohort was published. We increased the diagnostic yield for the original cohort by 15% without generating any further genomic data.
    CONCLUSIONS: In the era of multiomics we highlight that reanalysis of existing WES data is a valid tool for generating additional diagnosis in patients with suspected mitochondrial disease, particularly when more time has passed to allow for new bioinformatic pipelines to emerge, for the development of new tools in variant interpretation aiding in reclassification of variants and the expansion of scientific knowledge on additional genes.
    Keywords:  Mitochondrial diseases; mitochondrial genes; next generation sequencing; respiratory chain deficiencies
    DOI:  https://doi.org/10.3233/JND-240020
  3. Orphanet J Rare Dis. 2024 May 16. 19(1): 200
    A novel MT-ATP6 variant associated with complicated ataxia in two unrelated Italian patients: case report and functional studies.
    Daniele Sala, Silvia Marchet, Lorenzo Nanetti, Andrea Legati, Caterina Mariotti, Eleonora Lamantea, Daniele Ghezzi, Alessia Catania, Costanza Lamperti.
       BACKGROUND: MT-ATP6 is a mitochondrial gene which encodes for the intramembrane subunit 6 (or A) of the mitochondrial ATP synthase, also known asl complex V, which is involved in the last step of oxidative phosphorylation to produce cellular ATP through aerobic metabolism. Although classically associated with the NARP syndrome, recent evidence highlights an important role of MT-ATP6 pathogenic variants in complicated adult-onset ataxias.
    METHODS: We describe two unrelated patients with adult-onset cerebellar ataxia associated with severe optic atrophy and mild cognitive impairment. Whole mitochondrial DNA sequencing was performed in both patients. We employed patients' primary fibroblasts and cytoplasmic hybrids (cybrids), generated from patients-derived cells, to assess the activity of respiratory chain complexes, oxygen consumption rate (OCR), ATP production and mitochondrial membrane potential.
    RESULTS: In both patients, we identified the same novel m.8777 T > C variant in MT-ATP6 with variable heteroplasmy level in different tissues. We identifed an additional heteroplasmic novel variant in MT-ATP6, m.8879G > T, in the patients with the most severe phenotype. A significant reduction in complex V activity, OCR and ATP production was observed in cybrid clones homoplasmic for the m.8777 T > C variant, while no functional defect was detected in m.8879G > T homoplasmic clones. In addition, fibroblasts with high heteroplasmic levelsof m.8777 T > C variant showed hyperpolarization of mitochondrial membranes.
    CONCLUSIONS: We describe a novel pathogenic mtDNA variant in MT-ATP6 associated with adult-onset ataxia, reinforcing the value of mtDNA screening within the diagnostic workflow of selected patients with late onset ataxias.
    Keywords:   MT-ATP6 ; ATP synthase; Ataxia; Complex V; Cybrids; Mitochondria; OXPHOS; Oxygen consumption
    DOI:  https://doi.org/10.1186/s13023-024-03212-y
  4. Front Cell Dev Biol. 2024 ;12 1417802
    Editorial: Molecular links between mitochondrial damage and human neurodegenerative disorders, volume II.
    Yuzuru Imai.
      
    Keywords:  CHCHD10; CHCHD2; FMR1; Parkin (PARK2); fragile X syndrome; mitochondria; mitophagy; mtDNA
    DOI:  https://doi.org/10.3389/fcell.2024.1417802
  5. Int J Mol Sci. 2024 Apr 29. pii: 4855. [Epub ahead of print]25(9):
    Mitochondrial Biomarkers in the Omics Era: A Clinical-Pathophysiological Perspective.
    Jacopo Gervasoni, Aniello Primiano, Michela Cicchinelli, Lavinia Santucci, Serenella Servidei, Andrea Urbani, Guido Primiano, Federica Iavarone.
      Mitochondrial diseases (MDs) affect 4300 individuals, with different ages of presentation and manifestation in any organ. How defects in mitochondria can cause such a diverse range of human diseases remains poorly understood. In recent years, several published research articles regarding the metabolic and protein profiles of these neurogenetic disorders have helped shed light on the pathogenetic mechanisms. By investigating different pathways in MDs, often with the aim of identifying disease biomarkers, it is possible to identify molecular processes underlying the disease. In this perspective, omics technologies such as proteomics and metabolomics considered in this review, can support unresolved mitochondrial questions, helping to improve outcomes for patients.
    Keywords:  FTIR; LC-MS; biomarkers; metabolomics; mitochondrial diseases; personalized medicine; proteomics
    DOI:  https://doi.org/10.3390/ijms25094855
  6. Int J Mol Sci. 2024 Apr 23. pii: 4602. [Epub ahead of print]25(9):
    Digenic Inheritance in Rare Disorders and Mitochondrial Disease-Crossing the Frontier to a More Comprehensive Understanding of Etiology.
    Christiane M Neuhofer, Holger Prokisch.
      Our understanding of rare disease genetics has been shaped by a monogenic disease model. While the traditional monogenic disease model has been successful in identifying numerous disease-associated genes and significantly enlarged our knowledge in the field of human genetics, it has limitations in explaining phenomena like phenotypic variability and reduced penetrance. Widening the perspective beyond Mendelian inheritance has the potential to enable a better understanding of disease complexity in rare disorders. Digenic inheritance is the simplest instance of a non-Mendelian disorder, characterized by the functional interplay of variants in two disease-contributing genes. Known digenic disease causes show a range of pathomechanisms underlying digenic interplay, including direct and indirect gene product interactions as well as epigenetic modifications. This review aims to systematically explore the background of digenic inheritance in rare disorders, the approaches and challenges when investigating digenic inheritance, and the current evidence for digenic inheritance in mitochondrial disorders.
    Keywords:  digenic inheritance; mitochondrial disorders; molecular genetics
    DOI:  https://doi.org/10.3390/ijms25094602
  7. Cardiol Young. 2024 May 16. 1-4
    Mitochondrial cardiomyopathy: a puzzle for the final diagnosis.
    Andreia Duarte Constante, Susana Martins Abreu, Conceição Trigo.
      Hypertrophic cardiomyopathy in children has diverse causes. Mitochondrial diseases, a rare aetiology leading to cardiomyopathy in 20-40% of affected children, predominantly present as hypertrophic cardiomyopathy. Diagnosis is challenging due to inconsistent genotype-phenotype correlation, resulting in various clinical presentations. We present a case of a one-month-old infant with severe hypertrophic cardiomyopathy and cardiac tamponade. Genetic diagnosis revealed a Valyl-tRNA synthetase 2 (VARS2) gene mutation, linking it to mitochondrial encephalopathy-cardiomyopathy. This case highlights novel variants and expands the understanding of hypertrophic cardiomyopathy aetiology in infants.
    Keywords:  VARS2; hypertrophic cardiomyopathy; mitochondrial diseases
    DOI:  https://doi.org/10.1017/S1047951124025095
  8. Am J Ophthalmol Case Rep. 2024 Jun;34 102070
    Leber's hereditary optic neuropathy like disease in MT-ATP6 variant m.8969G>A.
    Cansu de Muijnck, Mary J van Schooneveld, Astrid S Plomp, Richard J Rodenburg, Maria M van Genderen, Camiel J F Boon.
       Purpose: To describe a case with Leber's hereditary optic neuropathy (LHON) like optic atrophy in the presence of MT-ATP6 gene variant m.8969G > A.
    Observations: A 20-year-old patient with a history of mild developmental delay, mild cognitive impairment, and positional tremor presented with subacute painless visual loss over a few weeks. Mitochondrial genome sequencing revealed a variant in MT-ATP6, m.8969G > A (p.Ser148Asn). This variant was previously reported in association with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) and with nephropathy, followed by brain atrophy, muscle weakness and arrhythmias, but not with optic atrophy.
    Conclusions and importance: Rare variants in MT-ATP6 can also cause LHON like optic atrophy. It is important to perform further genetic analysis of mitochondrial DNA in genetically unsolved cases suspected of Leber's hereditary optic neuropathy to confirm the clinical diagnosis.
    Keywords:  Leber's hereditary optic neuropathy; MT-ATP6; Optic atrophy
    DOI:  https://doi.org/10.1016/j.ajoc.2024.102070
  9. Int J Mol Sci. 2024 Apr 29. pii: 4828. [Epub ahead of print]25(9):
    The Blood-Brain Barrier Is Unaffected in the Ndufs4-/- Mouse Model of Leigh Syndrome.
    Robin Reynaud-Dulaurier, Romain Clément, Sara Yjjou, Cassandra Cresson, Yasmina Saoudi, Mathilde Faideau, Michael Decressac.
      Mitochondrial dysfunction plays a major role in physiological aging and in many pathological conditions. Yet, no study has explored the consequence of primary mitochondrial deficiency on the blood-brain barrier (BBB) structure and function. Addressing this question has major implications for pharmacological and genetic strategies aimed at ameliorating the neurological symptoms that are often predominant in patients suffering from these conditions. In this study, we examined the permeability of the BBB in the Ndufs4-/- mouse model of Leigh syndrome (LS). Our results indicated that the structural and functional integrity of the BBB was preserved in this severe model of mitochondrial disease. Our findings suggests that pharmacological or gene therapy strategies targeting the central nervous system in this mouse model and possibly other models of mitochondrial dysfunction require the use of specific tools to bypass the BBB. In addition, they raise the need for testing the integrity of the BBB in complementary in vivo models.
    Keywords:  AAV vector; Leigh syndrome; blood–brain barrier; mitochondrial diseases
    DOI:  https://doi.org/10.3390/ijms25094828
  10. iScience. 2024 May 17. 27(5): 109789
    SIN-3 transcriptional coregulator maintains mitochondrial homeostasis and polyamine flux.
    Giovannetti Marina, Rodríguez-Palero María-Jesús, Fabrizio Paola, Nicolle Ophélie, Bedet Cécile, Michaux Grégoire, Witting Michael, Artal-Sanz Marta, Palladino Francesca.
      Mitochondrial function relies on the coordinated transcription of mitochondrial and nuclear genomes to assemble respiratory chain complexes. Across species, the SIN3 coregulator influences mitochondrial functions, but how its loss impacts mitochondrial homeostasis and metabolism in the context of a whole organism is unknown. Exploring this link is important because SIN3 haploinsufficiency causes intellectual disability/autism syndromes and SIN3 plays a role in tumor biology. Here we show that loss of C. elegans SIN-3 results in transcriptional deregulation of mitochondrial- and nuclear-encoded mitochondrial genes, potentially leading to mito-nuclear imbalance. Consistent with impaired mitochondrial function, sin-3 mutants show extensive mitochondrial fragmentation by transmission electron microscopy (TEM) and in vivo imaging, and altered oxygen consumption. Metabolomic analysis of sin-3 mutant animals revealed a mitochondria stress signature and deregulation of methionine flux, resulting in decreased S-adenosyl methionine (SAM) and increased polyamine levels. Our results identify SIN3 as a key regulator of mitochondrial dynamics and metabolic flux, with important implications for human pathologies.
    Keywords:  Cell biology; Omics; Systems biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109789
  11. Nat Cell Biol. 2024 May;26(5): 674-686
    Mitochondrial heterogeneity and adaptations to cellular needs.
    Melia Granath-Panelo, Shingo Kajimura.
      Although it is well described that mitochondria are at the epicentre of the energy demands of a cell, it is becoming important to consider how each cell tailors its mitochondrial composition and functions to suit its particular needs beyond ATP production. Here we provide insight into mitochondrial heterogeneity throughout development as well as in tissues with specific energy demands and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.
    DOI:  https://doi.org/10.1038/s41556-024-01410-1
  12. Res Sq. 2024 May 03. pii: rs.3.rs-4314324. [Epub ahead of print]
    Heme allocation in eukaryotic cells relies on mitochondrial heme export through FLVCR1b to cytosolic GAPDH.
    Dennis Stuehr, Dhanya Jayaram, Pranav Sivaram, Pranjal Biswas, Yue Dai, Elizabeth Sweeny.
      Heme is an iron-containing cofactor essential for life. In eukaryotes heme is generated in the mitochondria and must leave this organelle to reach protein targets in other cell compartments. Mitochondrial heme binding by cytosolic GAPDH was recently found essential for heme distribution in eukaryotic cells. Here, we sought to uncover how mitochondrial heme reaches GAPDH. Experiments involving a human cell line and a novel GAPDH reporter construct whose heme binding in live cells can be followed by fluorescence revealed that the mitochondrial transmembrane protein FLVCR1b exclusively transfers mitochondrial heme to GAPDH through a direct protein-protein interaction that rises and falls as heme transfers. In the absence of FLVCR1b, neither GAPDH nor downstream hemeproteins received any mitochondrial heme. Cell expression of TANGO2 was also required, and we found it interacts with FLVCR1b to likely support its heme exporting function. Finally, we show that purified GAPDH interacts with FLVCR1b in isolated mitochondria and triggers heme transfer to GAPDH and its downstream delivery to two client proteins. Identifying FLVCR1b as the sole heme source for GAPDH completes the path by which heme is exported from mitochondria, transported, and delivered into protein targets within eukaryotic cells.
    DOI:  https://doi.org/10.21203/rs.3.rs-4314324/v1
  13. Aging Cell. 2024 May 16. e14165
    The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration.
    Mohamed Ariff Iqbal, Maria Bilen, Yubing Liu, Vanessa Jabre, Bensun C Fong, Imane Chakroun, Smitha Paul, Jingwei Chen, Steven Wade, Michel Kanaan, Mary-Ellen Harper, Mireille Khacho, Ruth S Slack.
      Impaired mitochondrial function is a hallmark of aging and a major contributor to neurodegenerative diseases. We have shown that disrupted mitochondrial dynamics typically found in aging alters the fate of neural stem cells (NSCs) leading to impairments in learning and memory. At present, little is known regarding the mechanisms by which neural stem and progenitor cells survive and adapt to mitochondrial dysfunction. Using Opa1-inducible knockout as a model of aging and neurodegeneration, we identify a decline in neurogenesis due to impaired stem cell activation and progenitor proliferation, which can be rescued by the mitigation of oxidative stress through hypoxia. Through sc-RNA-seq, we identify the ATF4 pathway as a critical mechanism underlying cellular adaptation to metabolic stress. ATF4 knockdown in Opa1-deficient NSCs accelerates cell death, while the increased expression of ATF4 enhances proliferation and survival. Using a Slc7a11 mutant, an ATF4 target, we show that ATF4-mediated glutathione production plays a critical role in maintaining NSC survival and function under stress conditions. Together, we show that the activation of the integrated stress response (ISR) pathway enables NSCs to adapt to metabolic stress due to mitochondrial dysfunction and metabolic stress and may serve as a therapeutic target to enhance NSC survival and function in aging and neurodegeneration.
    Keywords:  Hypoxia; Opa1; adult neurogenesis; intergrated stress response; metabolic adaptation; mitochondrial dynamics; neurodegeneration
    DOI:  https://doi.org/10.1111/acel.14165
  14. JPGN Rep. 2024 May;5(2): 213-217
    Shwachman-Diamond syndrome mimicking mitochondrial hepatopathy.
    Odelya Kaufman, Colleen Donnelly, Emalyn Cork, Maria I Fiel, Jaime Chu, Jaya Ganesh.
      Shwachman-Diamond syndrome (SDS) is a genetic disorder caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. The syndrome is characterized by multiorgan dysfunction primarily involving the bone marrow and exocrine pancreas. Frequently overlooked is the hepatic dysfunction seen in early childhood which tends to improve by adulthood. Here, we report a child who initially presented with failure to thrive and elevated transaminases, and was ultimately diagnosed with SDS. A liver biopsy electron micrograph revealed hepatocytes crowded with numerous small mitochondria, resembling the hepatic architecture from patients with inborn errors of metabolism, including mitochondrial diseases. To our knowledge, this is the first report of the mitochondrial phenotype in an SDS patient. These findings are compelling given the recent cellular and molecular research studies which have identified SBDS as an essential regulator of mitochondrial function and have also implicated SBDS in the maintenance of mitochondrial DNA.
    Keywords:  SDS; elevated transaminases; failure to thrive
    DOI:  https://doi.org/10.1002/jpr3.12064
  15. Apoptosis. 2024 May 17.
    Mitophagy in health and disease. Molecular mechanisms, regulatory pathways, and therapeutic implications.
    Mark S D'Arcy.
      Mitophagy, a specialised form of autophagy, selectively targeting damaged or dysfunctional mitochondria, and is crucial for maintaining cellular homeostasis and mitochondrial quality control. Dysregulation of mitophagy contributes to various pathological conditions, including cancer, neurodegenerative and cardiovascular diseases. This review presents a comprehensive analysis of the molecular mechanisms, regulatory pathways, and interplay with other cellular processes governing mitophagy, emphasizing its importance in physiological and pathological contexts. We explore the PINK1/Parkin-mediated and receptor-mediated mitophagy pathways, encompassing BNIP3/NIX, FUNDC1, and Bcl2-L-13. Additionally, we discuss post-translational modifications and cellular signalling pathways modulating mitophagy, as well as the connection between mitophagy and ageing, highlighting the decline in mitophagy efficiency and its impact on age-related pathologies. The review also investigates mitophagy's role in human diseases such as cancer, myocardial ischemia-reperfusion injury, Parkinson's, and Alzheimer's disease. We assess the potential of mitophagy-targeting therapeutic strategies, focusing on the development of dietary therapies, small molecules, drugs, and gene therapy approaches that modulate mitophagy levels and efficiency for treating these diseases and dysfunctions commonly observed in ageing individuals. In summary, this review offers an extensive overview of the molecular mechanisms and regulatory networks involved in mitophagy, its association with autophagy, and implications in human health and disease. By examining the potential of mitophagy-modulating therapies in disease and non-disease settings, we aim to inspire further research to develop innovative treatment strategies for various pathological conditions linked to mitochondrial dysfunction and to ageing.
    Keywords:  Ageing; Autophagy; Mitophagy
    DOI:  https://doi.org/10.1007/s10495-024-01977-y
  16. Orphanet J Rare Dis. 2024 May 15. 19(1): 198
    Clinical and genetic analysis of methylmalonic aciduria in 60 patients from Southern China: a single center retrospective study.
    Ling Su, Huiying Sheng, Xiuzhen Li, Yanna Cai, Huifen Mei, Jing Cheng, Duan Li, Zhikun Lu, Yunting Lin, Xiaodan Chen, Minzhi Peng, Yonglan Huang, Wen Zhang, Li Liu.
       BACKGROUND: Methylmalonic aciduria (MMA) is a group of rare genetic metabolic disorders resulting from defects in methylmalonyl coenzyme A mutase (MCM) or intracellular cobalamin (cbl) metabolism. MMA patients show diverse clinical and genetic features across different subtypes and populations.
    METHODS: We retrospectively recruited 60 MMA patients from a single center and diagnosed them based on their clinical manifestations and biochemical assays. We then performed genetic analysis to confirm the diagnosis and identify the causal variants.
    RESULTS: We confirmed the common clinical manifestations of MMA reported previously. We also described four rare MMA cases with unusual symptoms or genetic variants, such as pulmonary hypertension or limb weakness in late-onset patients. We identified 15 MMACHC and 26 MMUT variants in 57 patients, including 6 novel MMUT variants. Two patients had only one MMAA variant each, and one patient had mild MMA due to mitochondrial DNA depletion syndrome caused by a SUCLA2 variant. Among 12 critically ill patients, isolated MMA was associated with higher C3, blood ammonia, and acidosis, while combined MMA was linked to hydrocephalus on skull MRI. MMACHC c.658-660delAAG and MMUT c.1280G > A variants were correlated with more severe phenotypes.
    CONCLUSIONS: Our study demonstrates the clinical and genotypic heterogeneity of MMA patients and indicates that metabolic screening and genetic analysis are useful tools to identify rare cases.
    Keywords:  MMACHC gene; MMUT gene; Methylmalonic aciduria; Pulmonary hypertension; SUCLA2 gene
    DOI:  https://doi.org/10.1186/s13023-024-03210-0
  17. Eur J Neurol. 2024 May 17. e16344
    Co-occurrence of glial fibrillary acidic protein astrocytopathy in a patient with Leber's hereditary optic neuropathy due to DNAJC30 mutations.
    Maria Pia Giannoccaro, Luana Morelli, Fortuna Ricciardiello, Vincenzo Donadio, Fiorina Bartiromo, Caterina Tonon, Michele Carbonelli, Giulia Amore, Valerio Carelli, Rocco Liguori, Chiara La Morgia.
      Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by visual loss, and rarely associated with extraocular manifestations including multiple sclerosis-like lesions. The association of LHON and neuromyelitis optica spectrum disorders has rarely been reported. Here is reported a case of glial fibrillary acidic protein astrocytopathy presenting with area postrema syndrome in a patient with previously diagnosed recessive LHON due to mutations in the nuclear gene DNAJC30. This case emphasizes the necessity of extensive investigations for other treatable conditions in patients with LHON and otherwise unexplained extraocular involvement and the possibility that also visual symptoms can respond to immune therapy.
    Keywords:  GFAP antibodies; GFAP astrocytopathy; Leber's hereditary optic neuropathy; NMOSD; area postrema syndrome; neuromyelitis optica
    DOI:  https://doi.org/10.1111/ene.16344
  18. Signal Transduct Target Ther. 2024 May 15. 9(1): 124
    Mitochondrial dysfunction: mechanisms and advances in therapy.
    Yao Zong, Hao Li, Peng Liao, Long Chen, Yao Pan, Yongqiang Zheng, Changqing Zhang, Delin Liu, Minghao Zheng, Junjie Gao.
      Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identified in many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, and cancer. However, the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among the most important therapeutic targets. In recent years, strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials. Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria, has shown promise in preclinical trials of various diseases. Mitochondrial components, including mtDNA, mitochondria-located microRNA, and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries. Here, we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases. We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies, as well as the clinical translational situation of related pharmacology agents. Finally, this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment.
    DOI:  https://doi.org/10.1038/s41392-024-01839-8
  19. MedComm (2020). 2024 Jun;5(6): e568
    Neurotransmitter accumulation and Parkinson's disease-like phenotype caused by anion channelrhodopsin opto-controlled astrocytic mitochondrial depolarization in substantia nigra pars compacta.
    Sen-Miao Li, Dian-Dian Wang, Dan-Hua Liu, Xiao-Yan Meng, Zhizhong Wang, Xitong Guo, Qian Liu, Pei-Pei Liu, Shu-Ang Li, Songwei Wang, Run-Zhou Yang, Yuming Xu, Longde Wang, Jian-Sheng Kang.
      Parkinson's disease (PD) is a mitochondria-related neurodegenerative disease characterized by locomotor deficits and loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Majority of PD research primarily focused on neuronal dysfunction, while the roles of astrocytes and their mitochondria remain largely unexplored. To bridge the gap and investigate the roles of astrocytic mitochondria in PD progression, we constructed a specialized optogenetic tool, mitochondrial-targeted anion channelrhodopsin, to manipulate mitochondrial membrane potential in astrocytes. Utilizing this tool, the depolarization of astrocytic mitochondria within the SNc in vivo led to the accumulation of γ-aminobutyric acid (GABA) and glutamate in SNc, subsequently resulting in excitatory/inhibitory imbalance and locomotor deficits. Consequently, in vivo calcium imaging and interventions of neurotransmitter antagonists demonstrated that GABA accumulation mediated movement deficits of mice. Furthermore, 1 h/day intermittent astrocytic mitochondrial depolarization for 2 weeks triggered spontaneous locomotor dysfunction, α-synuclein aggregation, and the loss of DA neurons, suggesting that astrocytic mitochondrial depolarization was sufficient to induce a PD-like phenotype. In summary, our findings suggest the maintenance of proper astrocytic mitochondrial function and the reinstatement of a balanced neurotransmitter profile may provide a new angle for mitigating neuronal dysfunction during the initial phases of PD.
    Keywords:  GABA; Parkinson's Disease; anion channelrhodopsin; astrocyte; glutamate; mitochondria; optogenetics
    DOI:  https://doi.org/10.1002/mco2.568
  20. Int J Biol Macromol. 2024 May 13. pii: S0141-8130(24)03169-6. [Epub ahead of print]270(Pt 1): 132364
    Mitochondrial citrate transporters Ctp1-Yhm2 and respiratory chain: A coordinated functional connection in Saccharomyces cerevisiae metabolism.
    Gabriella De Blasi, Paola Lunetti, Vincenzo Zara, Alessandra Ferramosca.
      The mitochondrial inner membrane contains some hydrophobic proteins that mediate the exchange of metabolites between the mitochondrial matrix and the cytosol. Ctp1 and Yhm2 are two carrier proteins in the yeast Saccharomyces cerevisiae responsible for the transport of citrate, a tricarboxylate involved in several metabolic pathways. Since these proteins also contribute to respiratory metabolism, in this study we investigated for the first time whether changes in citrate transport can affect the structural organization and functional properties of respiratory complexes. Through experiments in yeast mutant cells in which the gene encoding Ctp1 or Yhm2 was deleted, we found that in the absence of either mitochondrial citrate transporter, mitochondrial respiration was impaired. Structural analysis of the respiratory complexes III and IV revealed different expression levels of the catalytic and supernumerary subunits in the Δctp1 and Δyhm2 strains. In addition, Δyhm2 mitochondria appeared to be more sensitive than Δctp1 to the oxidative damage. Our results provide the first evidence for a coordinated modulation of mitochondrial citrate transport and respiratory chain activity in S. cerevisiae metabolism.
    Keywords:  Carrier; Citrate; Mitochondria; Respiratory chain; Respiratory complexes
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.132364
  21. Proc Natl Acad Sci U S A. 2024 May 21. 121(21): e2400740121
    Requirements for the biogenesis of [2Fe-2S] proteins in the human and yeast cytosol.
    Joseph J Braymer, Oliver Stehling, Martin Stümpfig, Ralf Rösser, Farah Spantgar, Catharina M Blinn, Ulrich Mühlenhoff, Antonio J Pierik, Roland Lill.
      The biogenesis of iron-sulfur (Fe/S) proteins entails the synthesis and trafficking of Fe/S clusters, followed by their insertion into target apoproteins. In eukaryotes, the multiple steps of biogenesis are accomplished by complex protein machineries in both mitochondria and cytosol. The underlying biochemical pathways have been elucidated over the past decades, yet the mechanisms of cytosolic [2Fe-2S] protein assembly have remained ill-defined. Similarly, the precise site of glutathione (GSH) requirement in cytosolic and nuclear Fe/S protein biogenesis is unclear, as is the molecular role of the GSH-dependent cytosolic monothiol glutaredoxins (cGrxs). Here, we investigated these questions in human and yeast cells by various in vivo approaches. [2Fe-2S] cluster assembly of cytosolic target apoproteins required the mitochondrial ISC machinery, the mitochondrial transporter Atm1/ABCB7 and GSH, yet occurred independently of both the CIA system and cGrxs. This mechanism was strikingly different from the ISC-, Atm1/ABCB7-, GSH-, and CIA-dependent assembly of cytosolic-nuclear [4Fe-4S] proteins. One notable exception to this cytosolic [2Fe-2S] protein maturation pathway defined here was yeast Apd1 which used the CIA system via binding to the CIA targeting complex through its C-terminal tryptophan. cGrxs, although attributed as [2Fe-2S] cluster chaperones or trafficking proteins, were not essential in vivo for delivering [2Fe-2S] clusters to either CIA components or target apoproteins. Finally, the most critical GSH requirement was assigned to Atm1-dependent export, i.e. a step before GSH-dependent cGrxs function. Our findings extend the general model of eukaryotic Fe/S protein biogenesis by adding the molecular requirements for cytosolic [2Fe-2S] protein maturation.
    Keywords:  cytosolic iron-sulfur protein assembly (CIA); glutaredoxin; glutathione (GSH); iron homeostasis; iron-sulfur cluster assembly (ISC)
    DOI:  https://doi.org/10.1073/pnas.2400740121
  22. Brain Commun. 2024 ;6(3): fcae160
    Deoxyguanosine kinase deficiency: natural history and liver transplant outcome.
    Eleonora Manzoni, Sara Carli, Pauline Gaignard, Lea Dewi Schlieben, Michio Hirano, Dario Ronchi, Emmanuel Gonzales, Masaru Shimura, Kei Murayama, Yasushi Okazaki, Ivo Barić, Danijela Petkovic Ramadza, Daniela Karall, Johannes Mayr, Diego Martinelli, Chiara La Morgia, Guido Primiano, René Santer, Serenella Servidei, Céline Bris, Aline Cano, Francesca Furlan, Serena Gasperini, Nolwenn Laborde, Costanza Lamperti, Dominic Lenz, Michelangelo Mancuso, Vincenzo Montano, Francesca Menni, Olimpia Musumeci, Victoria Nesbitt, Elena Procopio, Cécile Rouzier, Christian Staufner, Jan-Willem Taanman, Galit Tal, Chiara Ticci, Duccio Maria Cordelli, Valerio Carelli, Vincent Procaccio, Holger Prokisch, Caterina Garone.
      Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death. This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency. A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates (P < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype-phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant. In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation.
    Keywords:  DGUOK; deoxyguanosine kinase; liver transplant; mitochondrial DNA; nucleosides
    DOI:  https://doi.org/10.1093/braincomms/fcae160
  23. Cell Rep. 2024 May 16. pii: S2211-1247(24)00546-1. [Epub ahead of print]43(5): 114218
    Metabolic regulation of single synaptic vesicle exo- and endocytosis in hippocampal synapses.
    Jongyun Myeong, Marion I Stunault, Vitaly A Klyachko, Ghazaleh Ashrafi.
      Glucose has long been considered a primary energy source for synaptic function. However, it remains unclear to what extent alternative fuels, such as lactate/pyruvate, contribute to powering synaptic transmission. By detecting individual release events in hippocampal synapses, we find that mitochondrial ATP production regulates basal vesicle release probability and release location within the active zone (AZ), evoked by single action potentials. Mitochondrial inhibition shifts vesicle release closer to the AZ center and alters the efficiency of vesicle retrieval by increasing the occurrence of ultrafast endocytosis. Furthermore, we uncover that terminals can use oxidative fuels to maintain the vesicle cycle during trains of activity. Mitochondria are sparsely distributed along hippocampal axons, and we find that terminals containing mitochondria display enhanced vesicle release and reuptake during high-frequency trains. Our findings suggest that mitochondria not only regulate several fundamental features of synaptic transmission but may also contribute to modulation of short-term synaptic plasticity.
    Keywords:  ATP; CP: Metabolism; CP: Neuroscience; glycolysis; hippocampal neuron; mitochondria; nerve terminal; synapse; synaptic transmission
    DOI:  https://doi.org/10.1016/j.celrep.2024.114218
  24. Int J Mol Sci. 2024 May 06. pii: 5044. [Epub ahead of print]25(9):
    Emerging Roles of Vitamin B12 in Aging and Inflammation.
    Sergey Yu Simonenko, Daria A Bogdanova, Nikita A Kuldyushev.
      Vitamin B12 (cobalamin) is an essential nutrient for humans and animals. Metabolically active forms of B12-methylcobalamin and 5-deoxyadenosylcobalamin are cofactors for the enzymes methionine synthase and mitochondrial methylmalonyl-CoA mutase. Malfunction of these enzymes due to a scarcity of vitamin B12 leads to disturbance of one-carbon metabolism and impaired mitochondrial function. A significant fraction of the population (up to 20%) is deficient in vitamin B12, with a higher rate of deficiency among elderly people. B12 deficiency is associated with numerous hallmarks of aging at the cellular and organismal levels. Cellular senescence is characterized by high levels of DNA damage by metabolic abnormalities, increased mitochondrial dysfunction, and disturbance of epigenetic regulation. B12 deficiency could be responsible for or play a crucial part in these disorders. In this review, we focus on a comprehensive analysis of molecular mechanisms through which vitamin B12 influences aging. We review new data about how deficiency in vitamin B12 may accelerate cellular aging. Despite indications that vitamin B12 has an important role in health and healthy aging, knowledge of the influence of vitamin B12 on aging is still limited and requires further research.
    Keywords:  aging; cobalamin; inflammation; protein modifications; senescence; vitamin B12
    DOI:  https://doi.org/10.3390/ijms25095044
  25. bioRxiv. 2024 May 01. pii: 2024.04.29.591753. [Epub ahead of print]
    Alterations of PINK1-PRKN signaling in mice during normal aging.
    Zahra Baninameh, Jens O Watzlawik, Xu Hou, Tyrique Richardson, Nicholas W Kurchaba, Tingxiang Yan, Damian N Di Florio, DeLisa Fairweather, Lu Kang, Justin H Nguyen, Takahisa Kanekiyo, Dennis W Dickson, Sachiko Noda, Shigeto Sato, Nobutaka Hattori, Matthew S Goldberg, Ian G Ganley, Kelly L Stauch, Fabienne C Fiesel, Wolfdieter Springer.
      The ubiquitin kinase-ligase pair PINK1-PRKN identifies and selectively marks damaged mitochondria for elimination via the autophagy-lysosome system (mitophagy). While this cytoprotective pathway has been extensively studied in vitro upon acute and complete depolarization of mitochondria, the significance of PINK1-PRKN mitophagy in vivo is less well established. Here we used a novel approach to study PINK1-PRKN signaling in different energetically demanding tissues of mice during normal aging. We demonstrate a generally increased expression of both genes and enhanced enzymatic activity with aging across tissue types. Collectively our data suggest a distinct regulation of PINK1-PRKN signaling under basal conditions with the most pronounced activation and flux of the pathway in mouse heart compared to brain or skeletal muscle. Our biochemical analyses complement existing mitophagy reporter readouts and provide an important baseline assessment in vivo, setting the stage for further investigations of the PINK1-PRKN pathway during stress and in relevant disease conditions.
    DOI:  https://doi.org/10.1101/2024.04.29.591753
  26. Mol Biol Cell. 2024 May 17. mbcE23040139
    Matrix stiffening promotes perinuclear clustering of mitochondria.
    Piyush Daga, Basil Thurakkal, Simran Rawal, Tamal Das.
      Mechanical cues from the tissue microenvironment, such as the stiffness of the extracellular matrix, modulate cellular forms and functions. As numerous studies have shown, this modulation depends on the stiffness-dependent remodeling of cytoskeletal elements. In contrast, very little is known about how the intracellular organelles such as mitochondria respond to matrix stiffness and whether their form, function, and localization change accordingly. Here, we performed an extensive quantitative characterization of mitochondrial morphology, subcellular localization, dynamics, and membrane tension on soft and stiff matrices. This characterization revealed that while matrix stiffness affected all these aspects, matrix stiffening most distinctively led to an increased perinuclear clustering of mitochondria. Subsequently, we could identify the matrix stiffness-sensitive perinuclear localization of filamin as the key factor dictating this perinuclear clustering. The perinuclear and peripheral mitochondrial populations differed in their motility on soft matrix but surprisingly they did not show any difference on stiff matrix. Finally, perinuclear mitochondrial clustering appeared to be crucial for the nuclear localization of RUNX2 and hence for priming human mesenchymal stem cells towards osteogenesis on a stiff matrix. Taken together, we elucidate a dependence of mitochondrial localization on matrix stiffness, which possibly enables a cell to adapt to its microenvironment. [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E23-04-0139
  27. Circ Res. 2024 May 15.
    MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy.
    Barbara Roman, Yusuf Mastoor, Junhui Sun, Hector Chapoy Villanueva, Gabriela Hinojosa, Danielle Springer, Julia C Liu, Elizabeth Murphy.
       BACKGROUND: Calcium (Ca2+) uptake by mitochondria occurs via the mitochondrial Ca2+ uniporter. Mitochondrial Ca2+ uniporter exists as a complex, regulated by 3 MICU (mitochondrial Ca2+ uptake) proteins localized in the intermembrane space: MICU1, MICU2, and MICU3. Although MICU3 is present in the heart, its role is largely unknown.
    METHODS: We used CRISPR-Cas9 to generate a mouse with global deletion of MICU3 and an adeno-associated virus (AAV9) to overexpress MICU3 in wild-type mice. We examined the role of MICU3 in regulating mitochondrial calcium ([Ca2+]m) in ex vivo hearts using an optical method following adrenergic stimulation in perfused hearts loaded with a Ca2+-sensitive fluorophore. Additionally, we studied how deletion and overexpression of MICU3, respectively, impact cardiac function in vivo by echocardiography and the molecular composition of the mitochondrial Ca2+ uniporter complex via Western blot, immunoprecipitation, and Blue native-PAGE analysis. Finally, we measured MICU3 expression in failing human hearts.
    RESULTS: Knock out MICU3 hearts and cardiomyocytes exhibited a significantly smaller increase in [Ca2+]m than wild-type hearts following acute isoproterenol infusion. In contrast, overexpression of MICU3 hearts exhibited an enhanced increase in [Ca2+]m compared with control hearts. Echocardiography analysis showed no significant difference in cardiac function in knock out MICU3 mice relative to wild-type mice at baseline. However, overexpression of MICU3 animals exhibited significantly reduced ejection fraction and fractional shortening compared with control mice. We observed a significant increase in the ratio of heart weight to tibia length in overexpression of MICU3 hearts compared with controls, consistent with hypertrophy. We also found a significant decrease in MICU3 protein and expression in failing human hearts.
    CONCLUSIONS: Our results indicate that increased and decreased expression of MICU3 enhances and reduces, respectively, the uptake of [Ca2+]m in the heart. We conclude that MICU3 plays an important role in regulating [Ca2+]m physiologically, and overexpression of MICU3 is sufficient to induce cardiac hypertrophy, making MICU3 a possible therapeutic target.
    Keywords:  calcium; cardiomegaly; echocardiography; mitochondria; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.123.324026
  28. Cerebellum. 2024 May 13.
    Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay.
    Chunling Chen, Ronald A Merrill, Chian Ju Jong, Stefan Strack.
      Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived fibroblasts suggested that SACSIN mutations inhibit the function of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction. We experimentally tested this hypothesis by genetically manipulating the mitochondrial fission/fusion equilibrium, creating double KO (DKO) mice that also lack positive (PP2A/Bβ2) and negative (PKA/AKAP1) regulators of Drp1. Neither promoting mitochondrial fusion (Bβ2 KO) nor fission (Akap1 KO) influenced progression of motor symptoms in Sacs KO mice. However, our studies identified profound learning and memory deficits in aged Sacs KO mice. Moreover, this cognitive impairment was rescued in a gene dose-dependent manner by deletion of the Drp1 inhibitor PKA/Akap1. Our results are inconsistent with mitochondrial dysfunction as a primary pathogenic mechanism in ARSACS. Instead, they imply that promoting mitochondrial fission may be beneficial at later stages of the disease when pathology extends to brain regions subserving learning and memory.
    Keywords:  A kinase anchoring protein; ARSACS; Ataxia; Dynamin-related protein 1; Mitochondrial dynamics; Protein phosphatase 2A
    DOI:  https://doi.org/10.1007/s12311-024-01701-1
  29. Nucleic Acids Res. 2024 May 16. pii: gkae403. [Epub ahead of print]
    Two residues in the DNA binding site of Pif1 helicase are essential for nuclear functions but dispensable for mitochondrial respiratory growth.
    Jun Gao, David R Proffitt, John C Marecki, Reine U Protacio, Wayne P Wahls, Alicia K Byrd, Kevin D Raney.
      Pif1 helicase functions in both the nucleus and mitochondria. Pif1 tightly couples ATP hydrolysis, single-stranded DNA translocation, and duplex DNA unwinding. We investigated two Pif1 variants (F723A and T464A) that have each lost one site of interaction of the protein with the DNA substrate. Both variants exhibit minor reductions in affinity for DNA and ATP hydrolysis but have impaired DNA unwinding activity. However, these variants translocate on single-stranded DNA faster than the wildtype enzyme and can slide on the DNA substrate in an ATP-independent manner. This suggests they have lost their grip on the DNA, interfering with coupling ATP hydrolysis to translocation and unwinding. Yeast expressing these variants have increased gross chromosomal rearrangements, increased telomere length, and can overcome the lethality of dna2Δ, similar to phenotypes of yeast lacking Pif1. However, unlike pif1Δ mutants, they are viable on glycerol containing media and maintain similar mitochondrial DNA copy numbers as Pif1 wildtype. Overall, our data indicate that a tight grip of the trailing edge of the Pif1 enzyme on the DNA couples ATP hydrolysis to DNA translocation and DNA unwinding. This tight grip appears to be essential for the Pif1 nuclear functions tested but is dispensable for mitochondrial respiratory growth.
    DOI:  https://doi.org/10.1093/nar/gkae403
  30. J Neurol Neurosurg Psychiatry. 2024 May 14. pii: jnnp-2024-333436. [Epub ahead of print]
    Genetics of inherited peripheral neuropathies and the next frontier: looking backwards to progress forwards.
    Jevin M Parmar, Nigel G Laing, Marina L Kennerson, Gianina Ravenscroft.
      Inherited peripheral neuropathies (IPNs) encompass a clinically and genetically heterogeneous group of disorders causing length-dependent degeneration of peripheral autonomic, motor and/or sensory nerves. Despite gold-standard diagnostic testing for pathogenic variants in over 100 known associated genes, many patients with IPN remain genetically unsolved. Providing patients with a diagnosis is critical for reducing their 'diagnostic odyssey', improving clinical care, and for informed genetic counselling. The last decade of massively parallel sequencing technologies has seen a rapid increase in the number of newly described IPN-associated gene variants contributing to IPN pathogenesis. However, the scarcity of additional families and functional data supporting variants in potential novel genes is prolonging patient diagnostic uncertainty and contributing to the missing heritability of IPNs. We review the last decade of IPN disease gene discovery to highlight novel genes, structural variation and short tandem repeat expansions contributing to IPN pathogenesis. From the lessons learnt, we provide our vision for IPN research as we anticipate the future, providing examples of emerging technologies, resources and tools that we propose that will expedite the genetic diagnosis of unsolved IPN families.
    Keywords:  GENETICS; HMSN (CHARCOT-MARIE-TOOTH); NEUROGENETICS; NEUROMUSCULAR; NEUROPATHY
    DOI:  https://doi.org/10.1136/jnnp-2024-333436
  31. Int J Mol Sci. 2024 Apr 30. pii: 4924. [Epub ahead of print]25(9):
    D-Bifunctional Protein Deficiency Diagnosis-A Challenge in Low Resource Settings: Case Report and Review of the Literature.
    Maria Livia Ognean, Ioana Bianca Mutică, Gabriela Adriana Vișa, Ciprian Radu Șofariu, Claudiu Matei, Bogdan Neamțu, Manuela Cucerea, Radu Galiș, Gabriela Ariadna Cocișiu, Ioana Octavia Mătăcuță-Bogdan.
      D-bifunctional protein deficiency (D-BPD) is a rare, autosomal recessive peroxisomal disorder that affects the breakdown of long-chain fatty acids. Patients with D-BPD typically present during the neonatal period with hypotonia, seizures, and facial dysmorphism, followed by severe developmental delay and early mortality. While some patients have survived past two years of age, the detectable enzyme activity in these rare cases was likely a contributing factor. We report a D-BPD case and comment on challenges faced in diagnosis based on a narrative literature review. An overview of Romania's first patient diagnosed with D-BPD is provided, including clinical presentation, imaging, biochemical, molecular data, and clinical course. Establishing a diagnosis can be challenging, as the clinical picture is often incomplete or similar to many other conditions. Our patient was diagnosed with type I D-BPD based on whole-exome sequencing (WES) results revealing a pathogenic frameshift variant of the HSD17B4 gene, c788del, p(Pro263GInfs*2), previously identified in another D-BPD patient. WES also identified a variant of the SUOX gene with unclear significance. We advocate for using molecular diagnosis in critically ill newborns and infants to improve care, reduce healthcare costs, and allow for familial counseling.
    Keywords:  D-bifunctional protein deficiency; neonatal hypotonia; neonatal seizures; peroxisomal disorders; whole-exome sequencing
    DOI:  https://doi.org/10.3390/ijms25094924
  32. J Neuroophthalmol. 2024 Jun 01. 44(2): e227-e229
    Novel Mutations in the ND5 Gene Associated With Leber Hereditary Optic Neuropathy.
    Bhadra U Pandya, Nathania A Takyi, Amir R Vosoughi, Edward A Margolin, Jonathan A Micieli.
      
    DOI:  https://doi.org/10.1097/WNO.0000000000001796
  33. iScience. 2024 May 17. 27(5): 109808
    Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission.
    Charlène Lhuissier, Valérie Desquiret-Dumas, Anaïs Girona, Jennifer Alban, Justine Faure, Julien Cassereau, Philippe Codron, Guy Lenaers, Olivier R Baris, Naïg Gueguen, Arnaud Chevrollier.
      Mitochondrial dynamics is a process that balances fusion and fission events, the latter providing a mechanism for segregating dysfunctional mitochondria. Fission is controlled by the mitochondrial membrane potential (ΔΨm), optic atrophy 1 (OPA1) cleavage, and DRP1 recruitment. It is thought that this process is closely linked to the activity of the mitochondrial respiratory chain (MRC). However, we report here that MRC inhibition does not decrease ΔΨm nor increase fission, as evidenced by hyperconnected mitochondria. Conversely, blocking F0F1-ATP synthase activity induces fragmentation. We show that the F0F1-ATP synthase is sensing the inhibition of MRC activity by immediately promoting its reverse mode of action to hydrolyze matrix ATP and restoring ΔΨm, thus preventing fission. While this reverse mode is expected to be inhibited by the ATPase inhibitor ATPIF1, we show that this sensing is independent of this factor. We have unraveled an unexpected role of F0F1-ATP synthase in controlling the induction of fission by sensing and maintaining ΔΨm.
    Keywords:  Biochemistry; Cell biology; Functional aspects of cell biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109808
  34. J Transl Med. 2024 May 13. 22(1): 449
    Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE.
    Jixiang Du, Fuchen Liu, Xihan Liu, Dandan Zhao, Dongdong Wang, Hongsheng Sun, Chuanzhu Yan, Yuying Zhao.
      Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE.
    Keywords:  Lysosomal dysfunction; MNGIE; Nucleotide metabolism; TYMP; Thymidine phosphorylase
    DOI:  https://doi.org/10.1186/s12967-024-05275-8
  35. bioRxiv. 2024 May 03. pii: 2024.05.01.592120. [Epub ahead of print]
    Subcellular imaging of lipids and sugars using genetically encoded proximity sensors.
    William M Moore, Roberto J Brea, Caroline Knittel, Ellen Wrightsman, Brandon Hui, Jinchao Lou, Christelle F Ancajas, Michael D Best, Neal K Devaraj, Itay Budin.
      Live cell imaging of lipids and other metabolites is a long-standing challenge in cell biology. Bioorthogonal labeling tools allow for the conjugation of fluorophores to several phospholipid classes, but cannot discern their trafficking between adjacent organelles or asymmetry across individual membrane leaflets. Here we present fluorogen-activating coincidence sensing (FACES), a chemogenetic tool capable of quantitatively imaging subcellular lipid pools and reporting their transbilayer orientation in living cells. FACES combines bioorthogonal chemistry with genetically encoded fluorogen-activating proteins (FAPs) for reversible proximity sensing of conjugated molecules. We first validate this approach for quantifying discrete phosphatidylcholine pools in the ER and mitochondria that are trafficked by lipid transfer proteins. We then show that transmembrane domain-containing FAPs can be used to reveal the membrane asymmetry of multiple lipid classes that are generated in the trans-Golgi network. Lastly, we demonstrate that FACES is a generalizable tool for subcellular bioorthogonal imaging by measuring changes in mitochondrial N -acetylhexosamine levels. These results demonstrate the use of fluorogenic tags for spatially-defined molecular imaging.
    DOI:  https://doi.org/10.1101/2024.05.01.592120
  36. Nucleic Acids Res. 2024 May 14. pii: gkae354. [Epub ahead of print]
    The mutation R107Q alters mtSSB ssDNA compaction ability and binding dynamics.
    Martial Martucci, Amandine Moretton, Aleix Tarrés-Solé, Virginie Ropars, Louise Lambert, Patrick Vernet, Maria Solà, Maria Falkenberg, Geraldine Farge, Siet van den Wildenberg.
      Mitochondrial single-stranded DNA-binding protein (mtSSB) is essential for mitochondrial DNA (mtDNA) replication. Recently, several mtSSB variants have been associated with autosomal dominant mitochondrial optic atrophy and retinal dystrophy. Here, we have studied at the molecular level the functional consequences of one of the most severe mtSSB variants, R107Q. We first studied the oligomeric state of this variant and observed that the mtSSBR107Q mutant forms stable tetramers in vitro. On the other hand, we showed, using complementary single-molecule approaches, that mtSSBR107Q displays a lower intramolecular ssDNA compaction ability and a higher ssDNA dissociation rate than the WT protein. Real-time competition experiments for ssDNA-binding showed a marked advantage of mtSSBWT over mtSSBR107Q. Combined, these results show that the R107Q mutation significantly impaired the ssDNA-binding and compacting ability of mtSSB, likely by weakening mtSSB ssDNA wrapping efficiency. These features are in line with our molecular modeling of ssDNA on mtSSB showing that the R107Q mutation may destabilize local interactions and results in an electronegative spot that interrupts an ssDNA-interacting-electropositive patch, thus reducing the potential mtSSB-ssDNA interaction sites.
    DOI:  https://doi.org/10.1093/nar/gkae354
  37. Int J Mol Sci. 2024 Apr 27. pii: 4801. [Epub ahead of print]25(9):
    The Role of Structural Variants in the Genetic Architecture of Parkinson's Disease.
    Abigail Miano-Burkhardt, Pilar Alvarez Jerez, Kensuke Daida, Sara Bandres Ciga, Kimberley J Billingsley.
      Parkinson's disease (PD) significantly impacts millions of individuals worldwide. Although our understanding of the genetic foundations of PD has advanced, a substantial portion of the genetic variation contributing to disease risk remains unknown. Current PD genetic studies have primarily focused on one form of genetic variation, single nucleotide variants (SNVs), while other important forms of genetic variation, such as structural variants (SVs), are mostly ignored due to the complexity of detecting these variants with traditional sequencing methods. Yet, these forms of genetic variation play crucial roles in gene expression and regulation in the human brain and are causative of numerous neurological disorders, including forms of PD. This review aims to provide a comprehensive overview of our current understanding of the involvement of coding and noncoding SVs in the genetic architecture of PD.
    Keywords:  Parkinson’s disease; genetics; long-read sequencing; structural variants
    DOI:  https://doi.org/10.3390/ijms25094801
  38. Nat Genet. 2024 May;56(5): 758-766
    Integrating population genetics, stem cell biology and cellular genomics to study complex human diseases.
    Nona Farbehi, Drew R Neavin, Anna S E Cuomo, Lorenz Studer, Daniel G MacArthur, Joseph E Powell.
      Human pluripotent stem (hPS) cells can, in theory, be differentiated into any cell type, making them a powerful in vitro model for human biology. Recent technological advances have facilitated large-scale hPS cell studies that allow investigation of the genetic regulation of molecular phenotypes and their contribution to high-order phenotypes such as human disease. Integrating hPS cells with single-cell sequencing makes identifying context-dependent genetic effects during cell development or upon experimental manipulation possible. Here we discuss how the intersection of stem cell biology, population genetics and cellular genomics can help resolve the functional consequences of human genetic variation. We examine the critical challenges of integrating these fields and approaches to scaling them cost-effectively and practically. We highlight two areas of human biology that can particularly benefit from population-scale hPS cell studies, elucidating mechanisms underlying complex disease risk loci and evaluating relationships between common genetic variation and pharmacotherapeutic phenotypes.
    DOI:  https://doi.org/10.1038/s41588-024-01731-9
  39. Redox Biol. 2024 May 08. pii: S2213-2317(24)00157-5. [Epub ahead of print]73 103179
    Mitochondrial GPX4 acetylation is involved in cadmium-induced renal cell ferroptosis.
    Yue-Yue Guo, Nan-Nan Liang, Xiao-Yi Zhang, Ya-Hui Ren, Wen-Zheng Wu, Zhi-Bing Liu, Yi-Zhang He, Yi-Hao Zhang, Yi-Chao Huang, Tao Zhang, De-Xiang Xu, Shen Xu.
      Increasing evidences demonstrate that environmental stressors are important inducers of acute kidney injury (AKI). This study aimed to investigate the impact of exposure to Cd, an environmental stressor, on renal cell ferroptosis. Transcriptomics analyses showed that arachidonic acid (ARA) metabolic pathway was disrupted in Cd-exposed mouse kidneys. Targeted metabolomics showed that renal oxidized ARA metabolites were increased in Cd-exposed mice. Renal 4-HNE, MDA, and ACSL4, were upregulated in Cd-exposed mouse kidneys. Consistent with animal experiments, the in vitro experiments showed that mitochondrial oxidized lipids were elevated in Cd-exposed HK-2 cells. Ultrastructure showed mitochondrial membrane rupture in Cd-exposed mouse kidneys. Mitochondrial cristae were accordingly reduced in Cd-exposed mouse kidneys. Mitochondrial SIRT3, an NAD+-dependent deacetylase that regulates mitochondrial protein stability, was reduced in Cd-exposed mouse kidneys. Subsequently, mitochondrial GPX4 acetylation was elevated and mitochondrial GPX4 protein was reduced in Cd-exposed mouse kidneys. Interestingly, Cd-induced mitochondrial GPX4 acetylation and renal cell ferroptosis were exacerbated in Sirt3-/- mice. Conversely, Cd-induced mitochondrial oxidized lipids were attenuated in nicotinamide mononucleotide (NMN)-pretreated HK-2 cells. Moreover, Cd-evoked mitochondrial GPX4 acetylation and renal cell ferroptosis were alleviated in NMN-pretreated mouse kidneys. These results suggest that mitochondrial GPX4 acetylation, probably caused by SIRT3 downregulation, is involved in Cd-evoked renal cell ferroptosis.
    Keywords:  Acute kidney injury; Ferroptosis; Mitochondrial GPX4 acetylation; Mitochondrial lipid peroxidation; Nicotinamide mononucleotide; SIRT3
    DOI:  https://doi.org/10.1016/j.redox.2024.103179
  40. Nat Commun. 2024 May 17. 15(1): 4214
    Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling.
    Dongliang Lu, Anyuan He, Min Tan, Marguerite Mrad, Amal El Daibani, Donghua Hu, Xuejing Liu, Brian Kleiboeker, Tao Che, Fong-Fu Hsu, Monika Bambouskova, Clay F Semenkovich, Irfan J Lodhi.
      The liver gene expression of the peroxisomal β-oxidation enzyme acyl-coenzyme A oxidase 1 (ACOX1), which catabolizes very long chain fatty acids (VLCFA), increases in the context of obesity, but how this pathway impacts systemic energy metabolism remains unknown. Here, we show that hepatic ACOX1-mediated β-oxidation regulates inter-organ communication involved in metabolic homeostasis. Liver-specific knockout of Acox1 (Acox1-LKO) protects mice from diet-induced obesity, adipose tissue inflammation, and systemic insulin resistance. Serum from Acox1-LKO mice promotes browning in cultured white adipocytes. Global serum lipidomics show increased circulating levels of several species of ω-3 VLCFAs (C24-C28) with previously uncharacterized physiological role that promote browning, mitochondrial biogenesis and Glut4 translocation through activation of the lipid sensor GPR120 in adipocytes. This work identifies hepatic peroxisomal β-oxidation as an important regulator of metabolic homeostasis and suggests that manipulation of ACOX1 or its substrates may treat obesity-associated metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-024-48471-2
  41. Acta Neuropathol. 2024 May 15. 147(1): 84
    Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.
    Nicolas Leventoux, Satoru Morimoto, Mitsuru Ishikawa, Shiho Nakamura, Fumiko Ozawa, Reona Kobayashi, Hirotaka Watanabe, Sopak Supakul, Satoshi Okamoto, Zhi Zhou, Hiroya Kobayashi, Chris Kato, Yoshifumi Hirokawa, Ikuko Aiba, Shinichi Takahashi, Shinsuke Shibata, Masaki Takao, Mari Yoshida, Fumito Endo, Koji Yamanaka, Yasumasa Kokubo, Hideyuki Okano.
      Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Astrocyte; CHCHD2; Kii ALS/PDC; Mitochondria; Parkinsonism-dementia complex (PDC)
    DOI:  https://doi.org/10.1007/s00401-024-02734-w
  42. Cell Biosci. 2024 May 17. 14(1): 63
    Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions.
    Michele Costanzo, Armando Cevenini, Laxmikanth Kollipara, Marianna Caterino, Sabrina Bianco, Francesca Pirozzi, Gianluca Scerra, Massimo D'Agostino, Luigi Michele Pavone, Albert Sickmann, Margherita Ruoppolo.
       BACKGROUND: Methylmalonic acidemia (MMA) is a rare inborn error of propionate metabolism caused by deficiency of the mitochondrial methylmalonyl-CoA mutase (MUT) enzyme. As matter of fact, MMA patients manifest impairment of the primary metabolic network with profound damages that involve several cell components, many of which have not been discovered yet. We employed cellular models and patients-derived fibroblasts to refine and uncover new pathologic mechanisms connected with MUT deficiency through the combination of multi-proteomics and bioinformatics approaches.
    RESULTS: Our data show that MUT deficiency is connected with profound proteome dysregulations, revealing molecular actors involved in lysosome and autophagy functioning. To elucidate the effects of defective MUT on lysosomal and autophagy regulation, we analyzed the morphology and functionality of MMA-lysosomes that showed deep alterations, thus corroborating omics data. Lysosomes of MMA cells present as enlarged vacuoles with low degradative capabilities. Notwithstanding, treatment with an anti-propionigenic drug is capable of totally rescuing lysosomal morphology and functional activity in MUT-deficient cells. These results indicate a strict connection between MUT deficiency and lysosomal-autophagy dysfunction, providing promising therapeutic perspectives for MMA.
    CONCLUSIONS: Defective homeostatic mechanisms in the regulation of autophagy and lysosome functions have been demonstrated in MUT-deficient cells. Our data prove that MMA triggers such dysfunctions impacting on autophagosome-lysosome fusion and lysosomal activity.
    Keywords:  Autophagy; Lysosomes; MMA therapy; Metabolic disease; Methylmalonic acidemia; Multi-omics; Multi-proteomics
    DOI:  https://doi.org/10.1186/s13578-024-01245-1
  43. Nature. 2024 May 17.
    mRNA therapy is safe for treating the inherited metabolic condition propionic acidaemia.
      
    Keywords:  Diseases; Medical research; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-024-01364-2
  44. Sci Rep. 2024 05 14. 14(1): 10983
    Multi-omics integration of scRNA-seq time series data predicts new intervention points for Parkinson's disease.
    Katarina Mihajlović, Gaia Ceddia, Noël Malod-Dognin, Gabriela Novak, Dimitrios Kyriakis, Alexander Skupin, Nataša Pržulj.
      Parkinson's disease (PD) is a complex neurodegenerative disorder without a cure. The onset of PD symptoms corresponds to 50% loss of midbrain dopaminergic (mDA) neurons, limiting early-stage understanding of PD. To shed light on early PD development, we study time series scRNA-seq datasets of mDA neurons obtained from patient-derived induced pluripotent stem cell differentiation. We develop a new data integration method based on Non-negative Matrix Tri-Factorization that integrates these datasets with molecular interaction networks, producing condition-specific "gene embeddings". By mining these embeddings, we predict 193 PD-related genes that are largely supported (49.7%) in the literature and are specific to the investigated PINK1 mutation. Enrichment analysis in Kyoto Encyclopedia of Genes and Genomes pathways highlights 10 PD-related molecular mechanisms perturbed during early PD development. Finally, investigating the top 20 prioritized genes reveals 12 previously unrecognized genes associated with PD that represent interesting drug targets.
    DOI:  https://doi.org/10.1038/s41598-024-61844-3
  45. bioRxiv. 2024 May 05. pii: 2024.05.04.592445. [Epub ahead of print]
    A metabolic atlas of mouse aging.
    Steven E Pilley, Dominik Awad, Djakim Latumalea, Edgar Esparza, Li Zhang, Xuanyi Shi, Maximilian Unfried, Shuo Wang, Racheal Mulondo, Sriraksha Bharadwaj Kashyap, Darius Moaddeli, Peter Sajjakulnukit, Damien Sutton, Harrison Wong, Aeowynn J Coakley, Gilberto Garcia, Ryo Higuchi-Sanabria, Sophia Liu, Bingfei Yu, William B Tu, Brian K Kennedy, Costas A Lyssiotis, Peter J Mullen.
      Humans are living longer, but this is accompanied by an increased incidence of age-related chronic diseases. Many of these diseases are influenced by age-associated metabolic dysregulation, but how metabolism changes in multiple organs during aging in males and females is not known. Answering this could reveal new mechanisms of aging and age-targeted therapeutics. In this study, we describe how metabolism changes in 12 organs in male and female mice at 5 different ages. Organs show distinct patterns of metabolic aging that are affected by sex differently. Hydroxyproline shows the most consistent change across the dataset, decreasing with age in 11 out of 12 organs investigated. We also developed a metabolic aging clock that predicts biological age and identified alpha-ketoglutarate, previously shown to extend lifespan in mice, as a key predictor of age. Our results reveal fundamental insights into the aging process and identify new therapeutic targets to maintain organ health.
    DOI:  https://doi.org/10.1101/2024.05.04.592445
  46. Sci Adv. 2024 May 17. 10(20): eadn2867
    Serine synthesis controls mitochondrial biogenesis in macrophages.
    Chuanlong Wang, Muyang Zhao, Peng Bin, Yuyi Ye, Qingyi Chen, Zhiru Tang, Wenkai Ren.
      Mitochondrial dysfunction is the pivotal driving factor of multiple inflammatory diseases, and targeting mitochondrial biogenesis represents an efficacious approach to ameliorate such dysfunction in inflammatory diseases. Here, we demonstrated that phosphoglycerate dehydrogenase (PHGDH) deficiency promotes mitochondrial biogenesis in inflammatory macrophages. Mechanistically, PHGDH deficiency boosts mitochondrial reactive oxygen species (mtROS) by suppressing cytoplasmic glutathione synthesis. mtROS provokes hypoxia-inducible factor-1α signaling to direct nuclear specificity protein 1 and nuclear respiratory factor 1 transcription. Moreover, myeloid Phgdh deficiency reverses diet-induced obesity. Collectively, this study reveals that a mechanism involving de novo serine synthesis orchestrates mitochondrial biogenesis via mitochondrial-to-nuclear communication, and provides a potential therapeutic target for tackling inflammatory diseases and mitochondria-mediated diseases.
    DOI:  https://doi.org/10.1126/sciadv.adn2867
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