bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024–05–05
twenty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondrial transfer mediates endothelial cell engraftment through mitophagy.
  2. PARKIN is not required to sustain OXPHOS function in adult mammalian tissues.
  3. Interferon-gamma contributes to disease progression in the Ndufs4(-/-) model of Leigh syndrome.
  4. Mitochondrial dynamics: updates and perspectives.
  5. Mitochondrial complex I deficiency stratifies idiopathic Parkinson's disease.
  6. A dynamin superfamily-like pseudoenzyme coordinates with MICOS to promote cristae architecture.
  7. An aldehyde-crosslinking mitochondrial probe for STED imaging in fixed cells.
  8. Mechanisms of mitochondrial dysfunction in ovarian aging and potential interventions.
  9. Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity.
  10. MCU genetically altered mice suggest how mitochondrial Ca2+ regulates metabolism.
  11. 4-Hydroxybenzoic acid rescues multisystemic disease and perinatal lethality in a mouse model of mitochondrial disease.
  12. Mitochondrial SIRT3 as a protective factor against cyclosporine A-induced nephrotoxicity.
  13. Dyslipidemia and hypercalciuria in a patient with pantothenate kinase 2 deficiency: A novel variant and case report.
  14. The mitochondrial multi-omic response to exercise training across rat tissues.
  15. Calcitriol Treatment Is Safe and Increases Frataxin Levels in Friedreich Ataxia Patients.
  16. Cells destroy donated mitochondria to build blood vessels.
  17. Socialized mitochondria: mitonuclear crosstalk in stress.
  18. Endurance exercise causes a multi-organ full-body molecular reaction.
  19. A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis.
  20. Biallelic Variants of MRPS36 Cause a New Form of Leigh Syndrome.
  21. First fetus-to-fetus transplant demonstrated in rats.
  22. Synergistic hyperactivation of both mTORC1 and mTORC2 underlies the neural abnormalities of PTEN-deficient human neurons and cortical organoids.
  1. Nature. 2024 May 01.
    Mitochondrial transfer mediates endothelial cell engraftment through mitophagy.
    Ruei-Zeng Lin, Gwang-Bum Im, Allen Chilun Luo, Yonglin Zhu, Xuechong Hong, Joseph Neumeyer, Hong-Wen Tang, Norbert Perrimon, Juan M Melero-Martin.
      Ischaemic diseases such as critical limb ischaemia and myocardial infarction affect millions of people worldwide1. Transplanting endothelial cells (ECs) is a promising therapy in vascular medicine, but engrafting ECs typically necessitates co-transplanting perivascular supporting cells such as mesenchymal stromal cells (MSCs), which makes clinical implementation complicated2,3. The mechanisms that enable MSCs to facilitate EC engraftment remain elusive. Here we show that, under cellular stress, MSCs transfer mitochondria to ECs through tunnelling nanotubes, and that blocking this transfer impairs EC engraftment. We devised a strategy to artificially transplant mitochondria, transiently enhancing EC bioenergetics and enabling them to form functional vessels in ischaemic tissues without the support of MSCs. Notably, exogenous mitochondria did not integrate into the endogenous EC mitochondrial pool, but triggered mitophagy after internalization. Transplanted mitochondria co-localized with autophagosomes, and ablation of the PINK1-Parkin pathway negated the enhanced engraftment ability of ECs. Our findings reveal a mechanism that underlies the effects of mitochondrial transfer between mesenchymal and endothelial cells, and offer potential for a new approach for vascular cell therapy.
    DOI:  https://doi.org/10.1038/s41586-024-07340-0
  2. NPJ Parkinsons Dis. 2024 Apr 29. 10(1): 93
    PARKIN is not required to sustain OXPHOS function in adult mammalian tissues.
    Roberta Filograna, Jule Gerlach, Hae-Na Choi, Giovanni Rigoni, Michela Barbaro, Mikael Oscarson, Seungmin Lee, Katarina Tiklova, Markus Ringnér, Camilla Koolmeister, Rolf Wibom, Sara Riggare, Inger Nennesmo, Thomas Perlmann, Anna Wredenberg, Anna Wedell, Elisa Motori, Per Svenningsson, Nils-Göran Larsson.
      Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson's disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development of Parkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygous PRKN pathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.
    DOI:  https://doi.org/10.1038/s41531-024-00707-0
  3. Neuropathol Appl Neurobiol. 2024 Jun;50(3): e12977
    Interferon-gamma contributes to disease progression in the Ndufs4(-/-) model of Leigh syndrome.
    Allison R Hanaford, Asheema Khanna, Katerina James, Vivian Truong, Ryan Liao, Yihan Chen, Michael Mulholland, Ernst-Bernhard Kayser, Kino Watanabe, Erin Shien Hsieh, Margaret Sedensky, Philip G Morgan, Vandana Kalia, Surojit Sarkar, Simon C Johnson.
       AIM: Leigh syndrome (LS), the most common paediatric presentation of genetic mitochondrial dysfunction, is a multi-system disorder characterised by severe neurologic and metabolic abnormalities. Symmetric, bilateral, progressive necrotizing lesions in the brainstem are defining features of the disease. Patients are often symptom free in early life but typically develop symptoms by about 2 years of age. The mechanisms underlying disease onset and progression in LS remain obscure. Recent studies have shown that the immune system causally drives disease in the Ndufs4(-/-) mouse model of LS: treatment of Ndufs4(-/-) mice with the macrophage-depleting Csf1r inhibitor pexidartinib prevents disease. While the precise mechanisms leading to immune activation and immune factors involved in disease progression have not yet been determined, interferon-gamma (IFNγ) and interferon gamma-induced protein 10 (IP10) were found to be significantly elevated in Ndufs4(-/-) brainstem, implicating these factors in disease. Here, we aimed to explore the role of IFNγ and IP10 in LS.
    METHODS: To establish the role of IFNγ and IP10 in LS, we generated IFNγ and IP10 deficient Ndufs4(-/-)/Ifng(-/-) and Ndufs4(-/-)/IP10(-/-) double knockout animals, as well as IFNγ and IP10 heterozygous, Ndufs4(-/-)/Ifng(+/-) and Ndufs4(-/-)/IP10(+/-), animals. We monitored disease onset and progression to define the impact of heterozygous or homozygous loss of IFNγ and IP10 in LS.
    RESULTS: Loss of IP10 does not significantly impact the onset or progression of disease in the Ndufs4(-/-) model. IFNγ loss significantly extends survival and delays disease progression in a gene dosage-dependent manner, though the benefits are modest compared to Csf1r inhibition.
    CONCLUSIONS: IFNγ contributes to disease onset and progression in LS. Our findings suggest that IFNγ targeting therapies may provide some benefits in genetic mitochondrial disease, but targeting IFNγ alone would likely yield only modest benefits in LS.
    Keywords:  Leigh disease; chemokine CXCL10; interferon‐gamma; mitochondrial diseases
    DOI:  https://doi.org/10.1111/nan.12977
  4. Sci Rep. 2024 04 30. 14(1): 9936
    Mitochondrial dynamics: updates and perspectives.
    Kezhong Zhang, Ježek Petr.
      
    DOI:  https://doi.org/10.1038/s41598-024-59998-1
  5. Nat Commun. 2024 Apr 29. 15(1): 3631
    Mitochondrial complex I deficiency stratifies idiopathic Parkinson's disease.
    Irene H Flønes, Lilah Toker, Dagny Ann Sandnes, Martina Castelli, Sepideh Mostafavi, Njål Lura, Omnia Shadad, Erika Fernandez-Vizarra, Cèlia Painous, Alexandra Pérez-Soriano, Yaroslau Compta, Laura Molina-Porcel, Guido Alves, Ole-Bjørn Tysnes, Christian Dölle, Gonzalo S Nido, Charalampos Tzoulis.
      Idiopathic Parkinson's disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies.
    DOI:  https://doi.org/10.1038/s41467-024-47867-4
  6. Curr Biol. 2024 Apr 24. pii: S0960-9822(24)00468-8. [Epub ahead of print]
    A dynamin superfamily-like pseudoenzyme coordinates with MICOS to promote cristae architecture.
    Abhishek Kumar, Mehmet Oguz Gok, Kailey N Nguyen, Olivia M Connor, Michael L Reese, Jeremy G Wideman, Sergio A Muñoz-Gómez, Jonathan R Friedman.
      Mitochondrial cristae architecture is crucial for optimal respiratory function of the organelle. Cristae shape is maintained in part by the mitochondrial contact site and cristae organizing system (MICOS) complex. While MICOS is required for normal cristae morphology, the precise mechanistic role of each of the seven human MICOS subunits, and how the complex coordinates with other cristae-shaping factors, has not been fully determined. Here, we examine the MICOS complex in Schizosaccharomyces pombe, a minimal model whose genome only encodes for four core subunits. Using an unbiased proteomics approach, we identify a poorly characterized inner mitochondrial membrane protein that interacts with MICOS and is required to maintain cristae morphology, which we name Mmc1. We demonstrate that Mmc1 works in concert with MICOS to promote normal mitochondrial morphology and respiratory function. Mmc1 is a distant relative of the dynamin superfamily of proteins (DSPs), GTPases, which are well established to shape and remodel membranes. Similar to DSPs, Mmc1 self-associates and forms high-molecular-weight assemblies. Interestingly, however, Mmc1 is a pseudoenzyme that lacks key residues required for GTP binding and hydrolysis, suggesting that it does not dynamically remodel membranes. These data are consistent with the model that Mmc1 stabilizes cristae architecture by acting as a scaffold to support cristae ultrastructure on the matrix side of the inner membrane. Our study reveals a new class of proteins that evolved early in fungal phylogeny and is required for the maintenance of cristae architecture. This highlights the possibility that functionally analogous proteins work with MICOS to establish cristae morphology in metazoans.
    Keywords:  MICOS; cristae; dynamin; fission yeast; membrane remodeling; mitochondria; pseudoenzyme
    DOI:  https://doi.org/10.1016/j.cub.2024.04.028
  7. Proc Natl Acad Sci U S A. 2024 May 07. 121(19): e2317703121
    An aldehyde-crosslinking mitochondrial probe for STED imaging in fixed cells.
    Jingting Chen, Till Stephan, Felix Gaedke, Tianyan Liu, Yiyan Li, Astrid Schauss, Peng Chen, Veronika Wulff, Stefan Jakobs, Christian Jüngst, Zhixing Chen.
      Fluorescence labeling of chemically fixed specimens, especially immunolabeling, plays a vital role in super-resolution imaging as it offers a convenient way to visualize cellular structures like mitochondria or the distribution of biomolecules with high detail. Despite the development of various distinct probes that enable super-resolved stimulated emission depletion (STED) imaging of mitochondria in live cells, most of these membrane-potential-dependent fluorophores cannot be retained well in mitochondria after chemical fixation. This lack of suitable mitochondrial probes has limited STED imaging of mitochondria to live cell samples. In this study, we introduce a mitochondria-specific probe, PK Mito Orange FX (PKMO FX), which features a fixation-driven cross-linking motif and accumulates in the mitochondrial inner membrane. It exhibits high fluorescence retention after chemical fixation and efficient depletion at 775 nm, enabling nanoscopic imaging both before and after aldehyde fixation. We demonstrate the compatibility of this probe with conventional immunolabeling and other strategies commonly used for fluorescence labeling of fixed samples. Moreover, we show that PKMO FX facilitates correlative super-resolution light and electron microscopy, enabling the correlation of multicolor fluorescence images and transmission EM images via the characteristic mitochondrial pattern. Our probe further expands the mitochondrial toolkit for multimodal microscopy at nanometer resolutions.
    Keywords:  CLEM; fixation; mitochondrial imaging; super-resolution imaging
    DOI:  https://doi.org/10.1073/pnas.2317703121
  8. Front Endocrinol (Lausanne). 2024 ;15 1361289
    Mechanisms of mitochondrial dysfunction in ovarian aging and potential interventions.
    Wenhan Ju, Yuewen Zhao, Yi Yu, Shuai Zhao, Shan Xiang, Fang Lian.
      Mitochondria plays an essential role in regulating cellular metabolic homeostasis, proliferation/differentiation, and cell death. Mitochondrial dysfunction is implicated in many age-related pathologies. Evidence supports that the dysfunction of mitochondria and the decline of mitochondrial DNA copy number negatively affect ovarian aging. However, the mechanism of ovarian aging is still unclear. Treatment methods, including antioxidant applications, mitochondrial transplantation, emerging biomaterials, and advanced technologies, are being used to improve mitochondrial function and restore oocyte quality. This article reviews key evidence and research updates on mitochondrial damage in the pathogenesis of ovarian aging, emphasizing that mitochondrial damage may accelerate and lead to cellular senescence and ovarian aging, as well as exploring potential methods for using mitochondrial mechanisms to slow down aging and improve oocyte quality.
    Keywords:  aging; fertility preservation; mechanism; mitochondria; oocyte
    DOI:  https://doi.org/10.3389/fendo.2024.1361289
  9. Nat Metab. 2024 Apr 30.
    Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity.
    Shan Jiang, Taolin Yuan, Florian A Rosenberger, Arnaud Mourier, Nathalia R V Dragano, Laura S Kremer, Diana Rubalcava-Gracia, Fynn M Hansen, Melissa Borg, Mara Mennuni, Roberta Filograna, David Alsina, Jelena Misic, Camilla Koolmeister, Polyxeni Papadea, Martin Hrabe de Angelis, Lipeng Ren, Olov Andersson, Anke Unger, Tim Bergbrede, Raffaella Di Lucrezia, Rolf Wibom, Juleen R Zierath, Anna Krook, Patrick Giavalisco, Matthias Mann, Nils-Göran Larsson.
      The oxidative phosphorylation system1 in mammalian mitochondria plays a key role in transducing energy from ingested nutrients2. Mitochondrial metabolism is dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases and promotes tumour growth3-5. Here, we demonstrate that oral treatment with an inhibitor of mitochondrial transcription (IMT)6 shifts whole-animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of normal glucose tolerance in male mice on a high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of oxidative phosphorylation capacity concomitant with marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase feeding electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a principle for drug treatment of obesity and obesity-related pathology.
    DOI:  https://doi.org/10.1038/s42255-024-01038-3
  10. Trends Endocrinol Metab. 2024 Apr 29. pii: S1043-2760(24)00088-2. [Epub ahead of print]
    MCU genetically altered mice suggest how mitochondrial Ca2+ regulates metabolism.
    Jiuzhou Huo, Jeffery D Molkentin.
      Skeletal muscle has a major impact on total body metabolism and obesity, and is characterized by dynamic regulation of substrate utilization. While it is accepted that acute increases in mitochondrial matrix Ca2+ increase carbohydrate usage to augment ATP production, recent studies in mice with deleted genes for components of the mitochondrial Ca2+ uniporter (MCU) complex have suggested a more complicated regulatory scenario. Indeed, mice with a deleted Mcu gene in muscle, which lack acute mitochondrial Ca2+ uptake, have greater fatty acid oxidation (FAO) and less adiposity. By contrast, mice deleted for the inhibitory Mcub gene in skeletal muscle, which have greater acute mitochondrial Ca2+ uptake, antithetically display reduced FAO and progressive obesity. In this review we discuss the emerging concept that dynamic fluxing of mitochondrial matrix Ca2+ regulates metabolism.
    Keywords:  Ca(2+) signaling; metabolism; mitochondria; obesity; skeletal muscle
    DOI:  https://doi.org/10.1016/j.tem.2024.04.005
  11. Cell Rep. 2024 Apr 26. pii: S2211-1247(24)00476-5. [Epub ahead of print] 114148
    4-Hydroxybenzoic acid rescues multisystemic disease and perinatal lethality in a mouse model of mitochondrial disease.
    Julia Corral-Sarasa, Juan Manuel Martínez-Gálvez, Pilar González-García, Olivia Wendling, Laura Jiménez-Sánchez, Sergio López-Herrador, Catarina M Quinzii, María Elena Díaz-Casado, Luis C López.
      Coenzyme Q (CoQ) deficiency syndrome is conventionally treated with limited efficacy using exogenous CoQ10. Poor outcomes result from low absorption and bioavailability of CoQ10 and the clinical heterogenicity of the disease. Here, we demonstrate that supplementation with 4-hydroxybenzoic acid (4HB), the precursor of the benzoquinone ring in the CoQ biosynthetic pathway, completely rescues multisystemic disease and perinatal lethality in a mouse model of CoQ deficiency. 4HB stimulates endogenous CoQ biosynthesis in tissues of Coq2 mutant mice, normalizing mitochondrial function and rescuing cardiac insufficiency, edema, and neurodevelopmental delay. In contrast, exogenous CoQ10 supplementation falls short in fully restoring the phenotype. The treatment is translatable to human use, as proven by in vitro studies in skin fibroblasts from patients with pathogenic variants in COQ2. The therapeutic approach extends to other disorders characterized by deficiencies in the production of 4HB and early steps of CoQ biosynthesis and instances of secondary CoQ deficiency.
    Keywords:  4-hydroxybenzoic acid; CP: Metabolism; CoQ biosynthesis; cardiac insufficiency; coenzyme Q deficiency; metabolic disorders; mitochondrial diseases; neurodevelopmental disorders; perinatal lethality; pharmacological therapy; translational medicine
    DOI:  https://doi.org/10.1016/j.celrep.2024.114148
  12. Sci Rep. 2024 May 02. 14(1): 10143
    Mitochondrial SIRT3 as a protective factor against cyclosporine A-induced nephrotoxicity.
    Ji Eun Kim, Min Jee Jo, So Yeon Bae, Shin Young Ahn, Gang Jee Ko, Young Joo Kwon.
      Sirtuin3 (SIRT3), a mitochondrial deacetylase, has been shown to be involved in various kidney diseases. In this study, we aimed to clarify the role of SIRT3 in cyclosporine-induced nephrotoxicity and the associated mitochondrial dysfunction. Madin-Darby canine kidney (MDCK) cells were transfected with Flag-tagged SIRT3 for SIRT3 overexpression or SIRT3 siRNA for the inhibition of SIRT3. Subsequently, the cells were treated with cyclosporine A (CsA) or vehicle. Wild-type and SIRT3 knockout (KO) mice were randomly assigned to receive cyclosporine A or olive oil. Furthermore, SIRT3 activator, honokiol, was treated alongside CsA to wild type mice. Our results revealed that CsA treatment inhibited mitochondrial SIRT3 expression in MDCK cells. Inhibition of SIRT3 through siRNA transfection exacerbated apoptosis, impaired the expression of the AMP-activated protein kinase-peroxisome proliferator-activated receptor gamma coactivator 1 alpha (AMPK-PGC1α) pathway, and worsened mitochondrial dysfunction induced by CsA treatment. Conversely, overexpression of SIRT3 through Flag-tagged SIRT3 transfection ameliorated apoptosis, increased the expression of mitochondrial superoxide dismutase 2, and restored the mitochondrial regulator pathway, AMPK-PGC1α. In SIRT3 KO mice, CsA treatment led to aggravated kidney dysfunction, increased kidney tubular injury, and accumulation of oxidative end products indicative of oxidative stress injury. Meanwhile, SIRT3 activation in vivo significantly mitigated these adverse effects, improving kidney function, reducing oxidative stress markers, and enhancing mitochondrial health following CsA treatment. Overall, our findings suggest that SIRT3 plays a protective role in alleviating mitochondrial dysfunction caused by CsA through the activation of the AMPK-PGC1α pathway, thereby preventing further kidney injury.
    DOI:  https://doi.org/10.1038/s41598-024-60453-4
  13. SAGE Open Med Case Rep. 2024 ;12 2050313X241249088
    Dyslipidemia and hypercalciuria in a patient with pantothenate kinase 2 deficiency: A novel variant and case report.
    Henry-Marcelo Rodriguez-Perez, Olga-Berenice Reyes-Flores, Yazmin Quiñonez-Pacheco, Yahir-Arturo Centeno-Navarrete, Cruz Gonzalez-Vazquez, Felix-Julian Campos-Garcia.
      Pantothenate kinase-associated neurodegeneration (PKAN, OMIM: 234200) results from biallelic pathogenic variants in PANK2 which encodes pantothenate kinase 2, a crucial mitochondrial enzyme involved in coenzyme A biosynthesis. Pantothenate kinase-associated neurodegeneration patients typically exhibit the distinctive "eye of the tiger" sign on brain magnetic resonance imaging in the globus pallidus, along with psychiatric symptoms, extrapyramidal movements such as parkinsonism and dystonia, eventual speech and gait impairments, and the presence of dysphagia. An 11-year-old girl, with fifth-degree consanguinity, demonstrated typical psychomotor development and growth until the age of 5, when she began experiencing psychiatric symptoms. At the age of 9, she developed hand tremors, progressing to generalized muscular dystonia. By age 10, she exhibited gait and speech impairment. Physical examination revealed extensive generalized dystonia, hand tremors, speech impairment, dysphagia, inability to walk, and heightened osteotendinous reflexes. Metabolic analysis identified dyslipidemia with partial response to statin treatment and normocalcemic hypercalciuria. Exome sequencing revealed a novel likely pathogenic variant in PANK2 (NM_001386393.1:c.526C > G) in a homozygotic state. Pantothenate kinase-associated neurodegeneration typically manifests with generalized dystonia and psychiatric symptoms. Here, we present a Pantothenate kinase-associated neurodegeneration patient with dyslipidemia and hypercalciuria as potentially previously undescribed metabolic phenotype.
    Keywords:  PANK2; PKAN; dystonia; pantothenate kinase 2
    DOI:  https://doi.org/10.1177/2050313X241249088
  14. Cell Metab. 2024 Apr 15. pii: S1550-4131(23)00472-2. [Epub ahead of print]
    The mitochondrial multi-omic response to exercise training across rat tissues.
    MoTrPAC Study Group
      Mitochondria have diverse functions critical to whole-body metabolic homeostasis. Endurance training alters mitochondrial activity, but systematic characterization of these adaptations is lacking. Here, the Molecular Transducers of Physical Activity Consortium mapped the temporal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats trained for 1, 2, 4, or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart, and skeletal muscle. The colon showed non-linear response dynamics, whereas mitochondrial pathways were downregulated in brown adipose and adrenal tissues. Protein acetylation increased in the liver, with a shift in lipid metabolism, whereas oxidative proteins increased in striated muscles. Exercise-upregulated networks were downregulated in human diabetes and cirrhosis. Knockdown of the central network protein 17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) elevated oxygen consumption, indicative of metabolic stress. We provide a multi-omic, multi-tissue, temporal atlas of the mitochondrial response to exercise training and identify candidates linked to mitochondrial dysfunction.
    Keywords:  HSD17B10; acetylome; aerobic; exercise; metabolism; metabolomics; mitochondria; multi-omics; proteomics; transcriptomics
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.021
  15. Mov Disord. 2024 May 02.
    Calcitriol Treatment Is Safe and Increases Frataxin Levels in Friedreich Ataxia Patients.
    Berta Alemany-Perna, Jordi Tamarit, Elisa Cabiscol, Fabien Delaspre, Albert Miguela, Joana Maria Huertas-Pons, Ana Quiroga-Varela, Miguel Merchan Ruiz, Daniel López Domínguez, Lluís Ramió I Torrentà, David Genís, Joaquim Ros.
       BACKGROUND: Calcitriol, the active form of vitamin D (also known as 1,25-dihydroxycholecalciferol), improves the phenotype and increases frataxin levels in cell models of Friedreich ataxia (FRDA).
    OBJECTIVES: Based on these results, we aimed measuring the effects of a calcitriol dose of 0.25 mcg/24h in the neurological function and frataxin levels when administered to FRDA patients for a year.
    METHODS: 20 FRDA patients where recluted and 15 patients completed the treatment for a year. Evaluations of neurological function changes (SARA scale, 9-HPT, 8-MWT, PATA test) and quality of life (Barthel Scale and Short Form (36) Health Survey [SF-36] quality of life questionnaire) were performed. Frataxin amounts were measured in isolated platelets obtained from these FRDA patients, from heterozygous FRDA carriers (relatives of the FA patients) and from non-heterozygous sex and age matched controls.
    RESULTS: Although the patients did not experience any observable neurological improvement, there was a statistically significant increase in frataxin levels from initial values, 5.5 to 7.0 pg/μg after 12 months. Differences in frataxin levels referred to total protein levels were observed among sex- and age-matched controls (18.1 pg/μg), relative controls (10.1 pg/μg), and FRDA patients (5.7 pg/μg). The treatment was well tolerated by most patients, and only some of them experienced minor adverse effects at the beginning of the trial.
    CONCLUSIONS: Calcitriol dosage used (0.25 mcg/24 h) is safe for FRDA patients, and it increases frataxin levels. We cannot rule out that higher doses administered longer could yield neurological benefits. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  Friedreich ataxia; ataxia; calcitriol; frataxin; vitamin D
    DOI:  https://doi.org/10.1002/mds.29808
  16. Nature. 2024 May 01.
    Cells destroy donated mitochondria to build blood vessels.
    Chantell S Evans.
      
    Keywords:  Cardiovascular biology; Cell biology; Diabetes; Regeneration
    DOI:  https://doi.org/10.1038/d41586-024-01233-y
  17. Exp Mol Med. 2024 May 01.
    Socialized mitochondria: mitonuclear crosstalk in stress.
    Kyung Hwa Kim, Cho Bi Lee.
      Traditionally, mitochondria are considered sites of energy production. However, recent studies have suggested that mitochondria are signaling organelles that are involved in intracellular interactions with other organelles. Remarkably, stressed mitochondria appear to induce a beneficial response that restores mitochondrial function and cellular homeostasis. These mitochondrial stress-centered signaling pathways have been rapidly elucidated in multiple organisms. In this review, we examine current perspectives on how mitochondria communicate with the rest of the cell, highlighting mitochondria-to-nucleus (mitonuclear) communication under various stresses. Our understanding of mitochondria as signaling organelles may provide new insights into disease susceptibility and lifespan extension.
    DOI:  https://doi.org/10.1038/s12276-024-01211-4
  18. Nature. 2024 May 01.
    Endurance exercise causes a multi-organ full-body molecular reaction.
      
    Keywords:  Health care; Metabolism; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-024-00585-9
  19. Nat Commun. 2024 May 01. 15(1): 2869
    A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis.
    Bani Mukhopadhyay, Cheryl Marietta, Pei-Hong Shen, Abdul Oiseni, Faridoddin Mirshahi, Maria Mazzu, Colin Hodgkinson, Eli Winkler, Qiaoping Yuan, Daniel Miranda, George Kunos, Arun J Sanyal, David Goldman.
      Only ~20% of heavy drinkers develop alcohol cirrhosis (AC). While differences in metabolism, inflammation, signaling, microbiome signatures and genetic variations have been tied to the pathogenesis of AC, the key underlying mechanisms for this interindividual variability, remain to be fully elucidated. Induced pluripotent stem cell-derived hepatocytes (iHLCs) from patients with AC and healthy controls differ transcriptomically, bioenergetically and histologically. They include a greater number of lipid droplets (LDs) and LD-associated mitochondria compared to control cells. These pre-pathologic indicators are effectively reversed by Aramchol, an inhibitor of stearoyl-CoA desaturase. Bioenergetically, AC iHLCs have lower spare capacity, slower ATP production and their mitochondrial fuel flexibility towards fatty acids and glutamate is weakened. MARC1 and PNPLA3, genes implicated by GWAS in alcohol cirrhosis, show to correlate with lipid droplet-associated and mitochondria-mediated oxidative damage in AC iHLCs. Knockdown of PNPLA3 expression exacerbates mitochondrial deficits and leads to lipid droplets alterations. These findings suggest that differences in mitochondrial bioenergetics and lipid droplet formation are intrinsic to AC hepatocytes and can play a role in its pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-47085-y
  20. Mov Disord. 2024 Apr 30.
    Biallelic Variants of MRPS36 Cause a New Form of Leigh Syndrome.
    Serena Galosi, Cecilia Mancini, Anna Commone, Paolo Calligari, Viviana Caputo, Francesca Nardecchia, Claudia Carducci, Lambertus P van den Heuvel, Simone Pizzi, Alessandro Bruselles, Marcello Niceta, Simone Martinelli, Richard J Rodenburg, Marco Tartaglia, Vincenzo Leuzzi.
       BACKGROUND: The MRPS36 gene encodes a recently identified component of the 2-oxoglutarate dehydrogenase complex (OGDHC), a key enzyme of the Krebs cycle catalyzing the oxidative decarboxylation of 2-oxoglutarate to succinyl-CoA. Defective OGDHC activity causes a clinically variable metabolic disorder characterized by global developmental delay, severe neurological impairment, liver failure, and early-onset lactic acidosis.
    METHODS: We investigated the molecular cause underlying Leigh syndrome with bilateral striatal necrosis in two siblings through exome sequencing. Functional studies included measurement of the OGDHC enzymatic activity and MRPS36 mRNA levels in fibroblasts, assessment of protein stability in transfected cells, and structural analysis. A literature review was performed to define the etiological and phenotypic spectrum of OGDHC deficiency.
    RESULTS: In the two affected brothers, exome sequencing identified a homozygous nonsense variant (c.283G>T, p.Glu95*) of MRPS36. The variant did not affect transcript processing and stability, nor protein levels, but resulted in a shorter protein lacking nine residues that contribute to the structural and functional organization of the OGDHC complex. OGDHC enzymatic activity was significantly reduced. The review of previously reported cases of OGDHC deficiency supports the association of this enzymatic defect with Leigh phenotypic spectrum and early-onset movement disorder. Slightly elevated plasma levels of glutamate and glutamine were observed in our and literature patients with OGDHC defect.
    CONCLUSIONS: Our findings point to MRPS36 as a new disease gene implicated in Leigh syndrome. The slight elevation of plasma levels of glutamate and glutamine observed in patients with OGDHC deficiency represents a candidate metabolic signature of this neurometabolic disorder. © 2024 International Parkinson and Movement Disorder Society.
    Keywords:  2‐oxoglutaratedehydrogenase complex; Leigh syndrome; chorea; dystonia; mitochondrial disorders
    DOI:  https://doi.org/10.1002/mds.29795
  21. Nature. 2024 Apr 30.
    First fetus-to-fetus transplant demonstrated in rats.
    Smriti Mallapaty.
      
    Keywords:  Developmental biology; Medical research; Physiology
    DOI:  https://doi.org/10.1038/d41586-024-01152-y
  22. Cell Rep. 2024 May 02. pii: S2211-1247(24)00501-1. [Epub ahead of print]43(5): 114173
    Synergistic hyperactivation of both mTORC1 and mTORC2 underlies the neural abnormalities of PTEN-deficient human neurons and cortical organoids.
    Navroop K Dhaliwal, Octavia Yifang Weng, Xiaoxue Dong, Afrin Bhattacharya, Mai Ahmed, Haruka Nishimura, Wendy W Y Choi, Aditi Aggarwal, Bryan W Luikart, Qiang Shu, Xuekun Li, Michael D Wilson, Jason Moffat, Lu-Yang Wang, Julien Muffat, Yun Li.
      Mutations in the phosphatase and tensin homolog (PTEN) gene are associated with severe neurodevelopmental disorders. Loss of PTEN leads to hyperactivation of the mechanistic target of rapamycin (mTOR), which functions in two distinct protein complexes, mTORC1 and mTORC2. The downstream signaling mechanisms that contribute to PTEN mutant phenotypes are not well delineated. Here, we show that pluripotent stem cell-derived PTEN mutant human neurons, neural precursors, and cortical organoids recapitulate disease-relevant phenotypes, including hypertrophy, electrical hyperactivity, enhanced proliferation, and structural overgrowth. PTEN loss leads to simultaneous hyperactivation of mTORC1 and mTORC2. We dissect the contribution of mTORC1 and mTORC2 by generating double mutants of PTEN and RPTOR or RICTOR, respectively. Our results reveal that the synergistic hyperactivation of both mTORC1 and mTORC2 is essential for the PTEN mutant human neural phenotypes. Together, our findings provide insights into the molecular mechanisms that underlie PTEN-related neural disorders and highlight novel therapeutic targets.
    Keywords:  CP: Cell biology; CP: Neuroscience; PTEN; autism; brain organoids; epilepsy; mTOR; neurodevelopmental disorders; neurons
    DOI:  https://doi.org/10.1016/j.celrep.2024.114173
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