bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022–10–23
twenty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Gene therapy for primary mitochondrial diseases: experimental advances and clinical challenges.
  2. Double administration of self-complementary AAV9NDUFS4 prevents Leigh disease in Ndufs4-/- mice.
  3. Whole-genome sequencing for mitochondrial disorders identifies unexpected mimics.
  4. Pearson syndrome: a multisystem mitochondrial disease with bone marrow failure.
  5. Novel therapeutic strategies targeting mitochondria as a gateway in neurodegeneration.
  6. TRPV4 acts as a mitochondrial Ca2+-importer and regulates mitochondrial temperature and metabolism.
  7. Role of mitophagy in the neurodegenerative diseases and its pharmacological advances: A review.
  8. Parkin coordinates mitochondrial lipid remodeling to execute mitophagy.
  9. Parkin drives pS65-Ub turnover independently of canonical autophagy in Drosophila.
  10. Clinical Experience of Neurological Mitochondrial Diseases in Children and Adults: A Single-Center Study.
  11. Mitochondrial biogenesis, telomere length and cellular senescence in Parkinson's disease and Lewy body dementia.
  12. Mitochondrial donation is now possible: science must now ensure that it is safe.
  13. Prohibitin 1 regulates mtDNA release and downstream inflammatory responses.
  14. The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import.
  15. Berberine mitigates hepatic insulin resistance by enhancing mitochondrial architecture via the SIRT1/Opa1 signalling pathway.
  16. Splicing variants in NARS2 are associated with milder phenotypes and intra-familial variability.
  17. Leigh-Like Syndrome With a Novel, Complex Phenotype Due to m.10191T>C in Mt-ND3.
  18. Tipping the balance toward stemness in trophoblast: Metabolic programming by Cox6B2.
  19. Inducible deletion of Raptor and mTOR from adult skeletal muscle impairs muscle contractility and relaxation.
  20. Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment.
  21. Nicotinamide Riboside supplementation ameliorated postovulatory oocyte quality decline.
  22. COX7A2L genetic variants determine cardiorespiratory fitness in mice and human.
  1. Nat Rev Neurol. 2022 Oct 18.
    Gene therapy for primary mitochondrial diseases: experimental advances and clinical challenges.
    Micol Falabella, Michal Minczuk, Michael G Hanna, Carlo Viscomi, Robert D S Pitceathly.
      The variable clinical and biochemical manifestations of primary mitochondrial diseases (PMDs), and the complexity of mitochondrial genetics, have proven to be a substantial barrier to the development of effective disease-modifying therapies. Encouraging data from gene therapy trials in patients with Leber hereditary optic neuropathy and advances in DNA editing techniques have raised expectations that successful clinical transition of genetic therapies for PMDs is feasible. However, obstacles to the clinical application of genetic therapies in PMDs remain; the development of innovative, safe and effective genome editing technologies and vectors will be crucial to their future success and clinical approval. In this Perspective, we review progress towards the genetic treatment of nuclear and mitochondrial DNA-related PMDs. We discuss advances in mitochondrial DNA editing technologies alongside the unique challenges to targeting mitochondrial genomes. Last, we consider ongoing trials and regulatory requirements.
    DOI:  https://doi.org/10.1038/s41582-022-00715-9
  2. Brain. 2022 Oct 21. 145(10): 3405-3414
    Double administration of self-complementary AAV9NDUFS4 prevents Leigh disease in Ndufs4-/- mice.
    Samantha Corrà, Raffaele Cerutti, Valeria Balmaceda, Carlo Viscomi, Massimo Zeviani.
      Leigh disease, or subacute necrotizing encephalomyelopathy, a genetically heterogeneous condition consistently characterized by defective mitochondrial bioenergetics, is the most common oxidative-phosphorylation related disease in infancy. Both neurological signs and pathological lesions of Leigh disease are mimicked by the ablation of the mouse mitochondrial respiratory chain subunit Ndufs4-/-, which is part of, and crucial for, normal Complex I activity and assembly, particularly in the brains of both children and mice. We previously conveyed the human NDUFS4 gene to the mouse brain using either single-stranded adeno-associated viral 9 recombinant vectors or the PHP.B adeno-associated viral vector. Both these approaches significantly prolonged the lifespan of the Ndufs4-/- mouse model but the extension of the survival was limited to a few weeks by the former approach, whereas the latter was applicable to a limited number of mouse strains, but not to primates. Here, we exploited the recent development of new, self-complementary adeno-associated viral 9 vectors, in which the transcription rate of the recombinant gene is markedly increased compared with the single-stranded adeno-associated viral 9 and can be applied to all mammals, including humans. Either single intra-vascular or double intra-vascular and intra-cerebro-ventricular injections were performed at post-natal Day 1. The first strategy ubiquitously conveyed the human NDUFS4 gene product in Ndufs4-/- mice, doubling the lifespan from 45 to ≈100 days after birth, when the mice developed rapidly progressive neurological failure. However, the double, contemporary intra-vascular and intra-cerebroventricular administration of self-complementary-adeno-associated viral NDUFS4 prolonged healthy lifespan up to 9 months of age. These mice were well and active at euthanization, at 6, 7, 8 and 9 months of age, to investigate the brain and other organs post-mortem. Robust expression of hNDUFS4 was detected in different cerebral areas preserving normal morphology and restoring Complex I activity and assembly. Our results warrant further investigation on the translatability of self-complementary-adeno-associated viral 9 NDUFS4-based therapy in the prodromal phase of the disease in mice and eventually humans.
    Keywords:   Ndufs4 ; Complex I; Leigh disease; gene therapy; mitochondrial disease
    DOI:  https://doi.org/10.1093/brain/awac182
  3. Pract Neurol. 2022 Oct 17. pii: pn-2022-003570. [Epub ahead of print]
    Whole-genome sequencing for mitochondrial disorders identifies unexpected mimics.
    Katherine R Schon, Patrick F Chinnery.
      
    Keywords:  genetics; mitochondrial disorders; neurogenetics
    DOI:  https://doi.org/10.1136/pn-2022-003570
  4. Orphanet J Rare Dis. 2022 10 17. 17(1): 379
    Pearson syndrome: a multisystem mitochondrial disease with bone marrow failure.
    Ayami Yoshimi, Kaori Ishikawa, Charlotte Niemeyer, Sarah C Grünert.
      Pearson syndrome (PS) is a rare fatal mitochondrial disorder caused by single large-scale mitochondrial DNA deletions (SLSMDs). Most patients present with anemia in infancy. Bone marrow cytology with vacuolization in erythroid and myeloid precursors and ring-sideroblasts guides to the correct diagnosis, which is established by detection of SLSMDs. Non hematological symptoms suggesting a mitochondrial disease are often lacking at initial presentation, thus PS is an important differential diagnosis in isolated hypogenerative anemia in infancy. Spontaneous resolution of anemia occurs in two-third of patients at the age of 1-3 years, while multisystem non-hematological complications such as failure to thrive, muscle hypotonia, exocrine pancreas insufficiency, renal tubulopathy and cardiac dysfunction develop during the clinical course. Some patients with PS experience a phenotypical change to Kearns-Sayre syndrome. In the absence of curative therapy, the prognosis of patients with PS is dismal. Most patients die of acute lactic acidosis and multi-organ failure in early childhood. There is a great need for the development of novel therapies to alter the natural history of patients with PS.
    Keywords:  Mitochondrial DNA deletion; Natural history; Pearson syndrome
    DOI:  https://doi.org/10.1186/s13023-022-02538-9
  5. Neural Regen Res. 2023 May;18(5): 991-995
    Novel therapeutic strategies targeting mitochondria as a gateway in neurodegeneration.
    Diogo Trigo, José João Vitória, Odete A B da Cruz E Silva.
      In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that have a variety of functions in ensuring cellular health and homeostasis. The plethora of mitochondrial functionalities confers them an intrinsic susceptibility to internal and external stressors (such as mutation accumulation or environmental toxins), particularly so in long-lived postmitotic cells such as neurons. Thus, it is reasonable to postulate an involvement of mitochondria in aging-associated neurological disorders, notably neurodegenerative pathologies including Alzheimer's disease and Parkinson's disease. On the other hand, biological effects resulting from neurodegeneration can in turn affect mitochondrial health and function, promoting a feedback loop further contributing to the progression of neuronal dysfunction and cellular death. This review examines state-of-the-art knowledge, focus on current research exploring mitochondrial health as a contributing factor to neuroregeneration, and the development of therapeutic approaches aimed at restoring mitochondrial homeostasis in a pathological setting.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; axon; energy homeostasis; glymphatic system; mitochondria; mitostasis; neurodegeneration; neuroregeneration; therapeutical strategies
    DOI:  https://doi.org/10.4103/1673-5374.355750
  6. Mitochondrion. 2022 Oct 16. pii: S1567-7249(22)00085-X. [Epub ahead of print]
    TRPV4 acts as a mitochondrial Ca2+-importer and regulates mitochondrial temperature and metabolism.
    Tusar Kanta Acharya, Ashutosh Kumar, Rakesh Kumar Majhi, Shamit Kumar, Ranabir Chakraborty, Ankit Tiwari, Karl-Heinz Smalla, Xiao Liu, Young-Tae Chang, Eckart D Gundelfinger, Chandan Goswami.
      TRPV4 is associated with the development of neuropathic pain, sensory defects, muscular dystrophies, neurodegenerative disorders, Charcot Marie Tooth and skeletal dysplasia. In all these cases, mitochondrial abnormalities are prominent. Here, we demonstrate that TRPV4, localizes to a subpopulation of mitochondria in various cell lines. Improper expression and/or function of TRPV4 induces several mitochondrial abnormalities. TRPV4 is also involved in the regulation of mitochondrial numbers, Ca2+-levels and mitochondrial temperature. Accordingly, several naturally occurring TRPV4 mutations affect mitochondrial morphology and distribution. These findings may help in understanding the significance of mitochondria in TRPV4-mediated channelopathies possibly classifying them as mitochondrial diseases.
    Keywords:  Mitochondrial Ca(2+); Neuro-Muscular Dystrophies Mitochondrial diseases; TRP channels; mitochondrial dynamics; mitochondrial temperature
    DOI:  https://doi.org/10.1016/j.mito.2022.10.001
  7. Front Mol Neurosci. 2022 ;15 1014251
    Role of mitophagy in the neurodegenerative diseases and its pharmacological advances: A review.
    Qixia Wang, Haoyuan Xue, Yundi Yue, Shiqi Hao, Shu-Hong Huang, Zhaoqiang Zhang.
      Neurodegenerative diseases are a class of incurable and debilitating diseases characterized by progressive degeneration and death of cells in the central nervous system. They have multiple underlying mechanisms; however, they all share common degenerative features, such as mitochondrial dysfunction. According to recent studies, neurodegenerative diseases are associated with the accumulation of dysfunctional mitochondria. Selective autophagy of mitochondria, called mitophagy, can specifically degrade excess or dysfunctional mitochondria within cells. In this review, we highlight recent findings on the role of mitophagy in neurodegenerative disorders. Multiple studies were collected, including those related to the importance of mitochondria, the mechanism of mitophagy in protecting mitochondrial health, and canonical and non-canonical pathways in mitophagy. This review elucidated the important function of mitophagy in neurodegenerative diseases, discussed the research progress of mitophagy in neurodegenerative diseases, and summarized the role of mitophagy-related proteins in neurological diseases. In addition, we also highlight pharmacological advances in neurodegeneration.
    Keywords:  Alzheimer's disease; Huntington's disease; Parkinson's disease; amyotrophic lateral sclerosis; mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnmol.2022.1014251
  8. EMBO Rep. 2022 Oct 18. e55191
    Parkin coordinates mitochondrial lipid remodeling to execute mitophagy.
    Chao-Chieh Lin, Jin Yan, Meghan D Kapur, Kristi L Norris, Cheng-Wei Hsieh, De Huang, Nicolas Vitale, Kah-Leong Lim, Ziqiang Guan, Xiao-Fan Wang, Jen-Tsan Chi, Wei-Yuan Yang, Tso-Pang Yao.
      Autophagy has emerged as the prime machinery for implementing organelle quality control. In the context of mitophagy, the ubiquitin E3 ligase Parkin tags impaired mitochondria with ubiquitin to activate autophagic degradation. Although ubiquitination is essential for mitophagy, it is unclear how ubiquitinated mitochondria activate autophagosome assembly locally to ensure efficient destruction. Here, we report that Parkin activates lipid remodeling on mitochondria targeted for autophagic destruction. Mitochondrial Parkin induces the production of phosphatidic acid (PA) and its subsequent conversion to diacylglycerol (DAG) by recruiting phospholipase D2 and activating the PA phosphatase, Lipin-1. The production of DAG requires mitochondrial ubiquitination and ubiquitin-binding autophagy receptors, NDP52 and optineurin (OPTN). Autophagic receptors, via Golgi-derived vesicles, deliver an autophagic activator, EndoB1, to ubiquitinated mitochondria. Inhibition of Lipin-1, NDP52/OPTN, or EndoB1 results in a failure to produce mitochondrial DAG, autophagosomes, and mitochondrial clearance, while exogenous cell-permeable DAG can induce autophagosome production. Thus, mitochondrial DAG production acts downstream of Parkin to enable the local assembly of autophagosomes for the efficient disposal of ubiquitinated mitochondria.
    Keywords:  Lipin-1; PLD2; Parkin; diacylglycerol; mitophagy
    DOI:  https://doi.org/10.15252/embr.202255191
  9. EMBO Rep. 2022 Oct 17. e202153552
    Parkin drives pS65-Ub turnover independently of canonical autophagy in Drosophila.
    Joanne L Usher, Alvaro Sanchez-Martinez, Ana Terriente-Felix, Po-Lin Chen, Juliette J Lee, Chun-Hong Chen, Alexander J Whitworth.
      Parkinson's disease-related proteins, PINK1 and Parkin, act in a common pathway to maintain mitochondrial quality control. While the PINK1-Parkin pathway can promote autophagic mitochondrial turnover (mitophagy) following mitochondrial toxification in cell culture, alternative quality control pathways are suggested. To analyse the mechanisms by which the PINK1-Parkin pathway operates in vivo, we developed methods to detect Ser65-phosphorylated ubiquitin (pS65-Ub) in Drosophila. Exposure to the oxidant paraquat led to robust, Pink1-dependent pS65-Ub production, while pS65-Ub accumulates in unstimulated parkin-null flies, consistent with blocked degradation. Additionally, we show that pS65-Ub specifically accumulates on disrupted mitochondria in vivo. Depletion of the core autophagy proteins Atg1, Atg5 and Atg8a did not cause pS65-Ub accumulation to the same extent as loss of parkin, and overexpression of parkin promoted turnover of both basal and paraquat-induced pS65-Ub in an Atg5-null background. Thus, we have established that pS65-Ub immunodetection can be used to analyse Pink1-Parkin function in vivo as an alternative to reporter constructs. Moreover, our findings suggest that the Pink1-Parkin pathway can promote mitochondrial turnover independently of canonical autophagy in vivo.
    Keywords:   in vivo ; Parkinson's disease; mitochondria; mitophagy; phospho-ubiquitin
    DOI:  https://doi.org/10.15252/embr.202153552
  10. Balkan J Med Genet. 2021 Nov;24(2): 5-14
    Clinical Experience of Neurological Mitochondrial Diseases in Children and Adults: A Single-Center Study.
    M Rogac, D Neubauer, L Leonardis, N Pecaric, M Meznaric, A Maver, W Sperl, B M Garavaglia, E Lamantea, B Peterlin.
      The goal of the study was to retrospectively evaluate a cohort of children and adults with mitochondrial diseases (MDs) in a single-center experience. Neurological clinical examination, brain magnetic resonance imaging (MRI) and spectroscopy, muscle biopsy, metabolic and molecular-genetic analysis were evaluated in 26 children and 36 adult patients with MD in Slovenia from 2004 to 2018. Nijmegen MD criteria (MDC) were applied to all patients and the need for a muscle biopsy was estimated. Exome-sequencing was used in half of the patients. Twenty children (77.0%) and 12 adults (35.0%) scored a total of ≥8 on MDC, a result that is compatible with the diagnosis of definite MD. Yield of exome-sequencing was 7/22 (31.0%), but the method was not applied systematically in all patients from the beginning of diagnostics. Brain MRI morphological changes, which can be an imaging clue for the diagnosis of MD, were found in 17/24 children (71.0%). In 7/26 (29.0%) children, and in 20/30 (67.0%) adults, abnormal mitochondria were found on electron microscopy (EM) and ragged-red fibers were found in 16/30 (53.0%) adults. Respiratory chain enzymes (RCEs) and/or pyruvate dehydrogenase complex (PDHc) activities were abnormal in all the children and six adult cases. First, our data revealed that MDC was useful in the clinical diagnosis of MD, and second, until the use of NGS methods, extensive, laborious and invasive diagnostic procedures were performed to reach a final diagnosis. In patients with suspected MD, there is a need to prioritize molecular diagnosis with the more modern next-generation sequencing (NGS) method.
    Keywords:  Exome-sequencing; Magnetic resonance imaging (MRI); Mitochondrial disease (MD); Muscle biopsy; Nijmegen mitochondrial disease criteria (MDC)
    DOI:  https://doi.org/10.2478/bjmg-2021-0019
  11. Sci Rep. 2022 Oct 20. 12(1): 17578
    Mitochondrial biogenesis, telomere length and cellular senescence in Parkinson's disease and Lewy body dementia.
    Muhammad Asghar, Amani Odeh, Ahmad Jouni Fattahi, Alexandra Edwards Henriksson, Aurelie Miglar, Shervin Khosousi, Per Svenningsson.
      Progressive age is the single major risk factor for neurodegenerative diseases. Cellular aging markers during Parkinson's disease (PD) have been implicated in previous studies, however the majority of studies have investigated the association of individual cellular aging hallmarks with PD but not jointly. Here, we have studied the association of PD with three aging hallmarks (telomere attrition, mitochondrial dysfunction, and cellular senescence) in blood and the brain tissue. Our results show that PD patients had 20% lower mitochondrial DNA copies but 26% longer telomeres in blood compared to controls. Moreover, telomere length in blood was positively correlated with medication (Levodopa Equivalent Daily Dose, LEDD) and disease duration. Similar results were found in brain tissue, where patients with Parkinson's disease (PD), Parkinson's disease dementia (PDD) and Dementia with Lewy Bodies (DLB) showed (46-95%) depleted mtDNA copies, but (7-9%) longer telomeres compared to controls. In addition, patients had lower mitochondrial biogenesis (PGC-1α and PGC-1β) and higher load of a cellular senescence marker in postmortem prefrontal cortex tissue, with DLB showing the highest effect among the patient groups. Our results suggest that mitochondrial dysfunction (copy number and biogenesis) in blood might be a valuable marker to assess the risk of PD. However, further studies with larger sample size are needed to evaluate these findings.
    DOI:  https://doi.org/10.1038/s41598-022-22400-z
  12. Intern Med J. 2022 Oct;52(10): 1663-1665
    Mitochondrial donation is now possible: science must now ensure that it is safe.
    Paul A Komesaroff, Ian Kerridge, Robert J Norman.
      
    DOI:  https://doi.org/10.1111/imj.15925
  13. EMBO J. 2022 Oct 17. e111173
    Prohibitin 1 regulates mtDNA release and downstream inflammatory responses.
    Hao Liu, Hualin Fan, Pengcheng He, Haixia Zhuang, Xiao Liu, Meiting Chen, Wenwei Zhong, Yi Zhang, Cien Zhen, Yanling Li, Huilin Jiang, Tian Meng, Yiming Xu, Guojun Zhao, Du Feng.
      Exposure of mitochondrial DNA (mtDNA) to the cytosol activates innate immune responses. But the mechanisms by which mtDNA crosses the inner mitochondrial membrane are unknown. Here, we found that the inner mitochondrial membrane protein prohibitin 1 (PHB1) plays a critical role in mtDNA release by regulating permeability across the mitochondrial inner membrane. Loss of PHB1 results in alterations in mitochondrial integrity and function. PHB1-deficient macrophages, serum from myeloid-specific PHB1 KO (Phb1MyeKO) mice, and peripheral blood mononuclear cells from neonatal sepsis patients show increased interleukin-1β (IL-1β) levels. PHB1 KO mice are also intolerant of lipopolysaccharide shock. Phb1-depleted macrophages show increased cytoplasmic release of mtDNA and inflammatory responses. This process is suppressed by cyclosporine A and VBIT-4, which inhibit the mitochondrial permeability transition pore (mPTP) and VDAC oligomerization. Inflammatory stresses downregulate PHB1 expression levels in macrophages. Under normal physiological conditions, the inner mitochondrial membrane proteins, AFG3L2 and SPG7, are tethered to PHB1 to inhibit mPTP opening. Downregulation of PHB1 results in enhanced interaction between AFG3L2 and SPG7, mPTP opening, mtDNA release, and downstream inflammatory responses.
    Keywords:  AFG3L2; MIMP; PHB; SPG7; mtDNA
    DOI:  https://doi.org/10.15252/embj.2022111173
  14. Life Sci Alliance. 2023 Jan;pii: e202201526. [Epub ahead of print]6(1):
    The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import.
    Saskia Rödl, Fabian den Brave, Markus Räschle, Büsra Kizmaz, Svenja Lenhard, Carina Groh, Hanna Becker, Jannik Zimmermann, Bruce Morgan, Elke Richling, Thomas Becker, Johannes M Herrmann.
      Mitochondria play a key role in cellular energy metabolism. Transitions between glycolytic and respiratory conditions induce considerable adaptations of the cellular proteome. These metabolism-dependent changes are particularly pronounced for the protein composition of mitochondria. Here, we show that the yeast cytosolic ubiquitin conjugase Ubc8 plays a crucial role in the remodeling process when cells transition from respiratory to fermentative conditions. Ubc8 is a conserved and well-studied component of the catabolite control system that is known to regulate the stability of gluconeogenic enzymes. Unexpectedly, we found that Ubc8 also promotes the assembly of the translocase of the outer membrane of mitochondria (TOM) and increases the levels of its cytosol-exposed receptor subunit Tom22. Ubc8 deficiency results in compromised protein import into mitochondria and reduced steady-state levels of mitochondrial proteins. Our observations show that Ubc8, which is controlled by the prevailing metabolic conditions, promotes the switch from glucose synthesis to glucose usage in the cytosol and induces the biogenesis of the mitochondrial TOM machinery to improve mitochondrial protein import during phases of metabolic transition.
    DOI:  https://doi.org/10.26508/lsa.202201526
  15. Acta Biochim Biophys Sin (Shanghai). 2022 Jan 25.
    Berberine mitigates hepatic insulin resistance by enhancing mitochondrial architecture via the SIRT1/Opa1 signalling pathway.
    Jia Xu, Yining Zhang, Zhiyi Yu, Yueqi Guan, Yuqian Lv, Meishuang Zhang, Ming Zhang, Li Chen, Xiaoyan Lv, Fengying Guan.
      The aberrant changes of fussion/fission-related proteins can trigger mitochondrial dynamics imbalance, which cause mitochondrial dysfunctions and result insulin resistance (IR). However, the relationship between the inner mitochondrial membrane fusion protein optic atrophy 1 (Opa1) and hepatic IR as well as the specific molecular mechanisms of signal transduction has not been fully elucidated. In this study, we explore whether abnormalities in the Opa1 cause hepatic IR and whether berberine (BBR) can prevent hepatic IR through the SIRT1/Opa1 signalling pathway. High-fat diet (HFD)-fed mice and db/db mice are used as animal models to study hepatic IR in vivo. IR, morphological changes, and mitochondrial injury of the liver are examined to explore the effects of BBR. SIRT1/Opa1 protein expression is determined to confirm whether the signalling pathway is damaged in the model animals and is involved in BBR treatment-mediated mitigation of hepatic IR. A palmitate (PA)-induced hepatocyte IR model is established in HepG2 cells in vitro. Opa1 silencing and SIRT1 overexpression are induced to verify whether Opa1 deficiency causes hepatocyte IR and whether SIRT1 improves this dysfunction. BBR treatment and SIRT1 silencing are employed to confirm that BBR can prevent hepatic IR by activating the SIRT1/Opa1 signalling pathway. Western blot analysis and JC-1 fluorescent staining results show that Opa1 deficiency causes an imbalance in mitochondrial fusion/fission and impairs insulin signalling in HepG2 cells. SIRT1 and BBR overexpression ameliorates PA-induced IR, increases Opa1, and improves mitochondrial function. SIRT1 silencing partly reverses the effects of BBR on HepG2 cells. SIRT1 and Opa1 expressions are downregulated in the animal models. BBR attenuates hepatic IR and enhances SIRT1/Opa1 signalling in db/db mice. In summary, Opa1 silencing-mediated mitochondrial fusion/fission imbalance could lead to hepatocyte IR. BBR may improve hepatic IR by regulating the SIRT1/Opa1 signalling pathway, and thus, it may be used to treat type-2 diabetes.
    Keywords:  Opa1; SIRT1; berberine; hepatic insulin resistance; mitochondrial architecture
    DOI:  https://doi.org/10.3724/abbs.2022146
  16. Eur J Med Genet. 2022 Oct 14. pii: S1769-7212(22)00224-5. [Epub ahead of print] 104643
    Splicing variants in NARS2 are associated with milder phenotypes and intra-familial variability.
    Samira Ait-El-Mkadem Saadi, Elsa Kaphan, Amaya Morales Jaurrieta, Konstantina Fragaki, Annabelle Chaussenot, Sylvie Bannwarth, André Maues De Paula, Véronique Paquis-Flucklinger, Cécile Rouzier.
      Biallelic rare variants in NARS2 that encode the mitochondrial asparaginyl-tRNA synthetase are associated with a wide spectrum of clinical phenotypes ranging from severe neurodegenerative disorders to isolated mitochondrial myopathy or deafness. To date, only a small number of patients with NARS2 variants have been reported, and possible genotype-phenotype correlations are still lacking. Here, we present three siblings who had an early-onset hearing loss, while one developed severe symptoms in adulthood associated with early intellectual impairment, refractory seizures, moderate axonal sensorimotor neuropathy, and atypical psychiatric symptoms. Biochemical analysis revealed impairment of the activity and assembly of the respiratory chain complexes in this patient's muscle and fibroblasts. Whole Exome Sequencing allowed identification of a heterozygous variant NM_024678.5(NARS2):c.822G > C (p.Gln274His) that is known to be pathogenic and to affect splicing of the NARS2 gene, but was unable to detect a second variant in this gene. Coverage analysis and Sanger sequencing led to identification of a novel intronic deletion NM_024678.5(NARS2):c.922-21_922-19del in the three siblings in trans with the c.822G > C. Functional analysis by RT-PCR showed that this deletion was causing aberrant splicing and led to exon 9 skipping in NARS2 mRNA in patient fibroblasts. Our work expands the phenotype and genotype spectrum of NARS2-related disorders. We provide evidence of the pathogenic effect of a novel intronic deletion in the NARS2 gene and report on additional adult patients with a large intrafamilial variability associated with splice variants in this gene. More specifically, we detail the phenotype of the oldest living patient to date with NARS2 variants and, for the first time, we report the psychiatric symptoms associated with this gene. Our work confirms the complexity of genotype-phenotype correlation in patients with pathogenic NARS2 variants.
    Keywords:  Aberrant splicing; Aminoacyl-tRNA synthetase; Genotype-phenotype; NARS2; Splice variant
    DOI:  https://doi.org/10.1016/j.ejmg.2022.104643
  17. Cureus. 2022 Sep;14(9): e28986
    Leigh-Like Syndrome With a Novel, Complex Phenotype Due to m.10191T>C in Mt-ND3.
    Shaundra M Newstead, Josef Finsterer.
      Leigh-like syndrome (LLS) due to the variant m.10191T>C in ND3 with a number of new phenotypic traits has not been published. In this case report, a 32-year-old woman diagnosed with Leigh-like syndrome presented with a complex novel, progressive, multisystem phenotype, manifesting in the brain (mild cognitive impairment, seizures, choreoathetosis, pseudotumor cerebri, hypersomnia, symmetric pallidal hypointensities, panda sign, calcifications, dysphagia), endocrine organs (empty sella syndrome, hypocorticism, hypoaldosteronism, hypogonadism), hematopoietic system (anemia, lymphocytosis), immune system (lymphocytosis, hypogammaglobulinemia), gut (reflux, diarrhea), kidneys (renal insufficiency, renal tubular acidosis, nephrolithiasis), muscles (myopathy, exercise intolerance, easy fatigability), peripheral nerves (small fiber neuropathy, dysautonomia), connective tissue (hyperlaxity of joints, bruising), and bones (scoliosis, Chiari malformation). A genetic workup revealed the known pathogenic variant m.10191T>C in ND3, which was also carried by the patient's mother. This case demonstrates that the m.10191T>C variant in ND3 can phenotypically manifest with multisystem disease and that this disease is responsive to symptomatic treatment and application of additional compounds.
    Keywords:  genetics; m.10191t>c; mitochondrial disorder; mtdna; respiratory chain
    DOI:  https://doi.org/10.7759/cureus.28986
  18. FASEB J. 2022 Nov;36(11): e22600
    Tipping the balance toward stemness in trophoblast: Metabolic programming by Cox6B2.
    Sarbani Saha, Rumela Bose, Shreeta Chakraborty, Rupasri Ain.
      Metabolic effector(s) driving cell fate is an emerging concept in stem cell biology. Here we showed that Cytochrome C Oxidase Subunit 6B2 (Cox6B2) is essential to maintain the stemness of trophoblast stem (TS) cells. RNA interference of Cox6b2 resulted in decreased mitochondrial Complex IV activity, ATP production, and oxygen consumption rate in TS cells. Furthermore, depletion of Cox6b2 in TS cells led to decreased self-renewal capacity indicated by compromised BrdU incorporation, Ki67 staining, and decreased expression of TS cell genetic markers. As expected, the consequence of Cox6b2 knockdown was the induction of differentiation. TS cell stemness factor CDX2 transactivates Cox6b2 promoter in TS cells. In differentiated cells, Cox6b2 is post-transcriptionally regulated by two microRNAs, miR-322-5p and miR-503-5p, leading to its downregulation as demonstrated by the gain-in or loss of function of these miRNAs. Cox6b2 transcripts gradually rise in placental trophoblast gestation progresses in both mice and rats with predominant expression in labyrinthine trophoblast. Cox6b2 expression is compromised in the growth-restricted placenta of rats with reciprocal up-regulation of miR-322-5p and miR-503-5p. These data highlight the importance of Cox6B2 in the regulation of TS cell state and uncompromised placental growth.
    Keywords:  CDX2; differentiation; miRNA; mitochondria; self-renewal; stem cell
    DOI:  https://doi.org/10.1096/fj.202200703RR
  19. J Physiol. 2022 Oct 18.
    Inducible deletion of Raptor and mTOR from adult skeletal muscle impairs muscle contractility and relaxation.
    Martina Baraldo, Sabrina Zorzato, Achille Homère Tchampda Dondjang, Alessia Geremia, Leonardo Nogara, Ana Georgia Dumitras, Marta Canato, Lorenzo Marcucci, Hendrik Nolte, Bert Blaauw.
       KEY POINTS: Skeletal muscle wasting and weakness have been associated with different pathological conditions, including sarcopenia and muscular dystrophy, and is accompanied by altered mTOR signaling Mammalian Target of Rapamycin (mTOR) plays a crucial role in the maintenance of muscle mass and functionality We found that the loss of both mTOR and Raptor results in contractile abnormalities, with severe muscle weakness and delayed relaxation following tetanic stimulation These results are associated with alterations in the expression of genes involved in sarcomere organization and calcium handling, and with an impairment in calcium reuptake after contraction Taken together, these results reveal a mechanistic insight into the role of mTOR in muscle contractility ABSTRACT: Skeletal muscle weakness has been associated with different pathological conditions, including sarcopenia and muscular dystrophy, and is accompanied by altered mTOR signaling. Here we wanted to better elucidate the functional role of mTOR on muscle contractility. Most loss of function studies for mTOR signaling have used the drug rapamycin to inhibit some of the signaling downstream of mTOR. However, as rapamycin does not completely inhibit all mTOR signaling, we generated a double k.o. for mTOR and for the scaffold protein of mTORC1, Raptor, in skeletal muscle. We found that dk.o. mice results in a more severe phenotype compared to Raptor or mTOR deletion alone. Indeed, they display muscle weakness, increased fiber denervation, and a slower muscle relaxation following tetanic stimulation. This is accompanied by a shift towards slow-twitch fibers and changes in the expression levels of calcium-related genes, like Serca1 and Casq1. Indeed, dk.o. mice show a decrease in calcium decay kinetics after tetanus in vivo, suggestive of a reduced calcium reuptake. In addition, RNA sequencing analysis revealed that many downregulated genes are linked to sarcomere organization, like Tcap and Fhod3. These results suggest a key role for mTOR signaling in maintaining a proper fiber relaxation in skeletal muscle. Abstract figure legend This article is protected by copyright. All rights reserved.
    Keywords:  Raptor; calcium; mTOR; muscle force; relaxation; skeletal muscle
    DOI:  https://doi.org/10.1113/JP283686
  20. Science. 2022 Oct 21. 378(6617): eabq4835
    Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment.
    Shiya Cheng, Gerrit Altmeppen, Chun So, Luisa M Welp, Sarah Penir, Torben Ruhwedel, Katerina Menelaou, Katarina Harasimov, Alexandra Stützer, Martyn Blayney, Kay Elder, Wiebke Möbius, Henning Urlaub, Melina Schuh.
      Full-grown oocytes are transcriptionally silent and must stably maintain the messenger RNAs (mRNAs) needed for oocyte meiotic maturation and early embryonic development. However, where and how mammalian oocytes store maternal mRNAs is unclear. Here, we report that mammalian oocytes accumulate mRNAs in a mitochondria-associated ribonucleoprotein domain (MARDO). MARDO assembly around mitochondria was promoted by the RNA-binding protein ZAR1 and directed by an increase in mitochondrial membrane potential during oocyte growth. MARDO foci coalesced into hydrogel-like matrices that clustered mitochondria. Maternal mRNAs stored in the MARDO were translationally repressed. Loss of ZAR1 disrupted the MARDO, dispersed mitochondria, and caused a premature loss of MARDO-localized mRNAs. Thus, a mitochondria-associated membraneless compartment controls mitochondrial distribution and regulates maternal mRNA storage, translation, and decay to ensure fertility in mammals.
    DOI:  https://doi.org/10.1126/science.abq4835
  21. Reproduction. 2022 Oct 01. pii: REP-22-0095. [Epub ahead of print]
    Nicotinamide Riboside supplementation ameliorated postovulatory oocyte quality decline.
    Hui Li, Huan Wang, Jianmin Xu, Xinxin Zeng, Ying-Pu Sun, Qingling Yang.
      The quality of postovulatory oocytes deteriorates over time which impacts the outcome of early embryonic development during human assisted reproductive technology (ART). We and other groups have found that nicotinamide adenine dinucleotide (NAD+), a prominent redox cofactor and enzyme substrate, decreases in both aging ovaries and oocytes. In this study, we found that the NAD+ levels decreased in the postovulatory mouse oocytes during in vitro culture and this decrease was partly prevented by nicotinamide riboside (NR) supplementation. NR treatment not only restored MII oocyte quality but also enhanced early embryonic development potential of postovulatory oocytes via alleviating mitochondrial dysfunction and maintaining normal spindle/chromosome structure. Also, treatment with NR decreased the ROS levels and reduced DNA damage and apoptosis in postovulatory oocytes. Taken together, our findings indicated that NR supplementation increases the oocyte quality and early embryonic development potential in post-ovulatory oocytes which could potentially increase the successful rate in ART.
    DOI:  https://doi.org/10.1530/REP-22-0095
  22. Nat Metab. 2022 Oct;4(10): 1336-1351
    COX7A2L genetic variants determine cardiorespiratory fitness in mice and human.
    Giorgia Benegiamo, Maroun Bou Sleiman, Martin Wohlwend, Sandra Rodríguez-López, Ludger J E Goeminne, Pirkka-Pekka Laurila, Marie Klevjer, Minna K Salonen, Jari Lahti, Pooja Jha, Sara Cogliati, José Antonio Enriquez, Ben M Brumpton, Anja Bye, Johan G Eriksson, Johan Auwerx.
      Mitochondrial respiratory complexes form superassembled structures called supercomplexes. COX7A2L is a supercomplex-specific assembly factor in mammals, although its implication for supercomplex formation and cellular metabolism remains controversial. Here we identify a role for COX7A2L for mitochondrial supercomplex formation in humans. By using human cis-expression quantitative trait loci data, we highlight genetic variants in the COX7A2L gene that affect its skeletal muscle expression specifically. The most significant cis-expression quantitative trait locus is a 10-bp insertion in the COX7A2L 3' untranslated region that increases messenger RNA stability and expression. Human myotubes harboring this insertion have more supercomplexes and increased respiration. Notably, increased COX7A2L expression in the muscle is associated with lower body fat and improved cardiorespiratory fitness in humans. Accordingly, specific reconstitution of Cox7a2l expression in C57BL/6J mice leads to higher maximal oxygen consumption, increased lean mass and increased energy expenditure. Furthermore, Cox7a2l expression in mice is induced specifically in the muscle upon exercise. These findings elucidate the genetic basis of mitochondrial supercomplex formation and function in humans and show that COX7A2L plays an important role in cardiorespiratory fitness, which could have broad therapeutic implications in reducing cardiovascular mortality.
    DOI:  https://doi.org/10.1038/s42255-022-00655-0
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