bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2022–11–27
53 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. A Multisystem Mitochondrial Disease Caused by a Novel MT-TL1 mtDNA Variant: A Case Report.
  2. MPC2 variants disrupt mitochondrial pyruvate metabolism and cause an early-onset mitochondriopathy.
  3. Activating mitofusins interrupts mitochondrial degeneration and delays disease progression in SOD1 mutant amyotrophic lateral sclerosis.
  4. Highly asymmetrical distribution of muscle wasting correlates to the heteroplasmy in a patient carrying a large-scale mitochondrial DNA deletion: a novel pathophysiological mechanism for explaining asymmetry in mitochondrial myopathies.
  5. Mito-SiPE is a sequence-independent and PCR-free mtDNA enrichment method for accurate ultra-deep mitochondrial sequencing.
  6. iPSC-derived neurons from patients with POLG mutations exhibit decreased mitochondrial content and dendrite simplification.
  7. Compact zinc finger base editors that edit mitochondrial or nuclear DNA in vitro and in vivo.
  8. Molecular basis of diseases induced by the mitochondrial DNA mutation m.9032 T > C.
  9. SELECTIVE AND REVERSIBLE DISRUPTION OF MITOCHONDRIAL INNER MEMBRANE PROTEIN COMPLEXES BY LIPOPHILIC CATIONS.
  10. Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency.
  11. Developments in the Treatment of Leber Hereditary Optic Neuropathy.
  12. Autophagy promotes cell survival by maintaining NAD levels.
  13. OXPHOS deficiency induces mitochondrial DNA synthesis through non-canonical AMPK-dependent mRNA compartmentalization.
  14. Mitochondrial genomic integrity and the nuclear epigenome in health and disease.
  15. Malate dehydrogenase 2 deficiency is an emerging cause of pediatric epileptic encephalopathy with a recognizable biochemical signature.
  16. Mechanistic study of optic atrophy 1 in ischemia-reperfusion disease.
  17. Mitochondrion-targeted RNA therapies as a potential treatment strategy for mitochondrial diseases.
  18. Prohibitins in neurodegeneration and mitochondrial homeostasis.
  19. Understanding the Role of Yeast Yme1 in Mitochondrial Function Using Biochemical and Proteomics Analyses.
  20. Mitochondrial Respiratory Chain Supercomplexes: From Structure to Function.
  21. Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene.
  22. The many genomes of Parkinson's disease.
  23. Skeletal muscle mitochondrial inertia associates with carnitine acetyltransferase activity and physical function in humans.
  24. New insights into vascular aging: Emerging role of mitochondria function.
  25. MELAS a clinically and genetically heterogeneous syndrome.
  26. Mitochondrial interactome quantitation reveals structural changes in metabolic machinery in the failing murine heart.
  27. Prenatal phenotype of FBXL4-associated encephalomyopathic mitochondrial DNA depletion syndrome-13.
  28. Changes in Mitochondrial Size and Morphology in the RPE and Photoreceptors of the Developing and Ageing Zebrafish.
  29. Pentatricopeptide Protein PTCD2 Regulates COIII Translation in Mitochondria of the HeLa Cell Line.
  30. Enhanced access to the human phosphoproteome with genetically encoded phosphothreonine.
  31. One potential hotspot SLC25A20 gene variants in Chinese patients with carnitine-acylcarnitine translocase deficiency.
  32. Neuronal mitochondrial morphology is significantly affected by both fixative and oxygen level during perfusion.
  33. Mitochondrial Quality Control Mechanisms during Diabetic Cardiomyopathy.
  34. Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria.
  35. Metabolic substrates, histone modifications, and heart failure.
  36. Microvesicle release from inner segments of healthy photoreceptors is a conserved phenomenon in mammalian species.
  37. Clinically relevant mouse models of Charcot-Marie-Tooth Type 2S.
  38. mTORC1 signaling facilitates differential stem cell differentiation to shape the developing murine lung and is associated with mitochondrial capacity.
  39. Coenzyme Q10: Role in Less Common Age-Related Disorders.
  40. Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction.
  41. Dissecting the multifaceted contribution of the mitochondrial genome to autism spectrum disorder.
  42. Genetic therapy in a mitochondrial disease model suggests a critical role for liver dysfunction in mortality.
  43. Inhibition of mitochondrial complex III or dihydroorotate dehydrogenase (DHODH) triggers formation of poly(A)+ RNA foci adjacent to nuclear speckles following activation of ATM (ataxia telangiectasia mutated).
  44. Mitochondria Transfer in Brain Injury and Disease.
  45. Characterization of Mitochondrial Alterations in Aicardi-Goutières Patients Mutated in RNASEH2A and RNASEH2B Genes.
  46. Parkinson disease-associated Leucine-rich repeat kinase regulates UNC-104-dependent axonal transport of Arl8-positive vesicles in Drosophila.
  47. Mitochondrial connections with immune system in Zebrafish.
  48. Genomic technologies to improve variation identification in undiagnosed diseases.
  49. Acquired and hereditary bone marrow failure: A mitochondrial perspective.
  50. Mitochondrial Fatty Acid β-Oxidation Disorders: From Disease to Lipidomic Studies-A Critical Review.
  51. Folate regulates RNA m5C modification and translation in neural stem cells.
  52. Mechanical characterization of isolated mitochondria under conditions of oxidative stress.
  53. Ancient endosymbiont-mediated transmission of a selfish gene provides a model for overcoming barriers to gene transfer into animal mitochondrial genomes.
  1. J Neuromuscul Dis. 2022 Nov 16.
    A Multisystem Mitochondrial Disease Caused by a Novel MT-TL1 mtDNA Variant: A Case Report.
    Giannese Domenico, Montano Vincenzo, Lopriore Piervito, Nesti Claudia, LoGerfo Annalisa, Caligo Maria Adelaide, Dal Canto Flavio, Pasquinelli Gianandrea, Bonadio Angelo Giovanni, Moriconi Diego, Siciliano Gabriele, Mancuso Michelangelo.
       BACKGROUND: Mitochondrial tRNA (MTT) genes are hotspot for mitochondrial DNA mutation and are responsible of half mitochondrial disease. MTT mutations are associated with a broad spectrum of phenotype often with complex multisystem involvement and complex genotype-phenotype correlations. MT-TL1 mutations, among which the m.3243A>G mutation is the most frequent, are associated with myopathy, maternal inherited diabetes and deafness, MELAS, cardiomyopathy, and focal segmental glomerulosclerosis.
    CASE STUDY: Here we report the case of an Italian 49-years old female presenting with encephalomyopathy, chronic proteinuric kidney disease and a new heteroplasmic m.3274_3275delAC MT-TL1 gene mutation.
    CONCLUSIONS: Our case demonstrates a systemic mitochondrial disease caused by the heteroplasmic m.3274_3275delAC MT-TL1 gene mutation, not yet described in the literature. A mitochondrial disease should be suspected in case of complex multisystem phenotypes, including steroid-resistant nephrotic syndrome with multisystemic involvement.
    Keywords:  glomerulosclerosis; kidney disease; mitochondrial diseases; mitochondrial myopathies; mtDNA
    DOI:  https://doi.org/10.3233/JND-221526
  2. Brain. 2022 Nov 23. pii: awac444. [Epub ahead of print]
    MPC2 variants disrupt mitochondrial pyruvate metabolism and cause an early-onset mitochondriopathy.
    Claire Pujol, Elise Lebigot, Pauline Gaignard, Said Galai, Ichraf Kraoua, Jean-Philippe Bault, Rodolphe Dard, Ilhem Ben Youssef-Turki, Souheil Omar, Audrey Boutron, Timothy Wai, Abdelhamid Slama.
      Pyruvate is an essential metabolite produced by glycolysis in the cytosol and must be transported across the inner mitochondrial membrane (IMM) into the mitochondrial matrix, where it is oxidized to fuel mitochondrial respiration. Pyruvate import is performed by Mitochondrial Pyruvate Carrier (MPC), a hetero-oligomeric complex composed by interdependent subunits MPC1 and MPC2. Pathogenic variants in MPC1 gene disrupt mitochondrial pyruvate uptake and oxidation and cause autosomal-recessive early-onset neurological dysfunction in humans. The present work describes the first pathogenic variants in MPC2 associated with human disease in four patients from two unrelated families. In the first family, patients presented with antenatal developmental abnormalities, harbored a homozygous c.148T > C (p.Trp50Arg) variant. In the second family, patients that presented with infantile encephalopathy carried missense c.2T > G (p.Met1? ) variant disrupting the initiation codon. Patient-derived skin fibroblasts exhibit decreased pyruvate-driven oxygen consumption rates with normal activities of the pyruvate dehydrogenase complex and mitochondrial respiratory chain and no defects in mitochondrial content nor morphology. Re-expression of wild type MPC2 restored pyruvate-dependent respiration rates in patient-derived fibroblasts. The discovery of pathogenic variants in MPC2 therefore broadens the clinical and genetic landscape associated with inborn errors in pyruvate metabolism.
    Keywords:  metabolism; mitochondria; pyruvate carrier
    DOI:  https://doi.org/10.1093/brain/awac444
  3. Hum Mol Genet. 2022 Nov 23. pii: ddac287. [Epub ahead of print]
    Activating mitofusins interrupts mitochondrial degeneration and delays disease progression in SOD1 mutant amyotrophic lateral sclerosis.
    Xiawei Dang, Lihong Zhang, Antonietta Franco, Gerald W Dorn.
      Mitochondrial involvement in neurodegenerative diseases is widespread and multifactorial. Targeting mitochondrial pathology is therefore of interest. The recent development of bioactive molecules that modulate mitochondrial dynamics (fusion, fission and motility) offers a new therapeutic approach for neurodegenerative diseases with either indirect or direct mitochondrial involvement. Here, we asked: 1. Can enhanced mitochondrial fusion and motility improve secondary mitochondrial pathology in SOD1 mutant amyotrophic lateral sclerosis (ALS)? And: 2. What is the impact of enhancing mitochondria fitness on in vivo manifestations of SOD1 mutant ALS? We observed that small molecule mitofusin activators corrected mitochondrial fragmentation, depolarization and dysmotility in genetically diverse ALS patient reprogrammed motor neurons and fibroblasts, and in motor neurons, sensory neurons and fibroblasts from SOD1 G93A mice. Continuous, but not intermittent, pharmacologic mitofusin activation delayed phenotype progression and lethality in SOD1 G93A mice, reducing neuron loss and improving neuromuscular connectivity. Mechanistically, mitofusin activation increased mitochondrial motility, fitness and residency within neuromuscular synapses, reduced mitochondrial ROS production, and diminished apoptosis in SOD1 mutant neurons. These benefits were accompanied by improved mitochondrial respiratory coupling, despite characteristic SOD1 mutant ALS-associated downregulation of mitochondrial respiratory complexes. Targeting mitochondrial dysdynamism is a promising approach to alleviate pathology caused by secondary mitochondrial dysfunction in some neurodegenerative diseases.
    DOI:  https://doi.org/10.1093/hmg/ddac287
  4. Neuromuscul Disord. 2022 Oct 27. pii: S0960-8966(22)00700-3. [Epub ahead of print]
    Highly asymmetrical distribution of muscle wasting correlates to the heteroplasmy in a patient carrying a large-scale mitochondrial DNA deletion: a novel pathophysiological mechanism for explaining asymmetry in mitochondrial myopathies.
    M Masingue, B Rucheton, C Bris, N B Romero, V Procaccio, B Eymard.
      Mitochondrial diseases are a heterogeneous group of pathologies, caused by missense mutations, sporadic large-scale deletions of mitochondrial DNA (mtDNA) or mutations of nuclear maintenance genes. We report the case of a patient in whom extended muscle pathology, biochemical and genetic mtDNA analyses have proven to be essential to elucidate a unique asymmetrical myopathic presentation. From the age of 34 years on, the patient has presented with oculomotor disorders, right facial peripheral palsy and predominantly left upper limb muscle weakness and atrophy. By contrast, he displayed no motor weakness on the right hemi-body, and no sensory symptoms, cerebellar syndrome, hypoacusis, or parkinsonism. Cardiac function was normal. CK levels were elevated (671 UI/L). Electroneuromyography (ENMG) and muscle MRI showed diffuse myogenic alterations, more pronounced on the left side muscles. Biopsy of the left deltoid muscle showed multiple mitochondrial defects, whereas in the right deltoid, mitochondrial defects were much less marked. Extended mitochondrial biochemical and molecular workup revealed a unique mtDNA deletion, with a 63.4% heteroplasmy load in the left deltoid, versus 8.1% in the right one. This case demonstrates that, in mitochondrial myopathies, heteroplasmy levels may drastically vary for the same type of muscle, rising the hypothesis of a new pathophysiological mechanism explaining asymmetry in hereditary myopathies.
    Keywords:  Asymmetrical genetic myopathy; Mitochondrial DNA deletion; eKLIPse
    DOI:  https://doi.org/10.1016/j.nmd.2022.10.006
  5. Commun Biol. 2022 Nov 19. 5(1): 1269
    Mito-SiPE is a sequence-independent and PCR-free mtDNA enrichment method for accurate ultra-deep mitochondrial sequencing.
    Darren J Walsh, David J Bernard, Faith Pangilinan, Madison Esposito, Denise Harold, Anne Parle-McDermott, Lawrence C Brody.
      The analysis of somatic variation in the mitochondrial genome requires deep sequencing of mitochondrial DNA. This is ordinarily achieved by selective enrichment methods, such as PCR amplification or probe hybridization. These methods can introduce bias and are prone to contamination by nuclear-mitochondrial sequences (NUMTs), elements that can introduce artefacts into heteroplasmy analysis. We isolated intact mitochondria using differential centrifugation and alkaline lysis and subjected purified mitochondrial DNA to a sequence-independent and PCR-free method to obtain ultra-deep (>80,000X) sequencing coverage of the mitochondrial genome. This methodology avoids false-heteroplasmy calls that occur when long-range PCR amplification is used for mitochondrial DNA enrichment. Previously published methods employing mitochondrial DNA purification did not measure mitochondrial DNA enrichment or utilise high coverage short-read sequencing. Here, we describe a protocol that yields mitochondrial DNA and have quantified the increased level of mitochondrial DNA post-enrichment in 7 different mouse tissues. This method will enable researchers to identify changes in low frequency heteroplasmy without introducing PCR biases or NUMT contamination that are incorrectly identified as heteroplasmy when long-range PCR is used.
    DOI:  https://doi.org/10.1038/s42003-022-04182-2
  6. Am J Pathol. 2022 Nov 19. pii: S0002-9440(22)00360-1. [Epub ahead of print]
    iPSC-derived neurons from patients with POLG mutations exhibit decreased mitochondrial content and dendrite simplification.
    Manish Verma, Lily Francis, Britney N Lizama, Jason Callio, Gabriella Fricklas, Kent Z Q Wang, Brett A Kaufman, Leonardo D'Aiuto, Donna B Stolz, Simon C Watkins, Vishwajit L Nimgaonkar, Alejandro Soto-Gutierrez, Amy Goldstein, Charleen T Chu.
      Mutations in POLG, the gene encoding the catalytic subunit of DNA polymerase gamma (Polγ), result in clinical syndromes characterized by mitochondrial DNA (mtDNA) depletion in affected tissues with variable organ involvement. The brain is one of the most affected organs, and symptoms include intractable seizures, developmental delay, dementia, and ataxia. Patient-derived induced pluripotent stem cells (iPSCs) provide opportunities to explore mechanisms in affected cell types and potential therapeutic strategies. Fibroblasts from two patients were reprogrammed to create new iPSC models of POLG-related mitochondrial diseases. Compared to control iPSC-derived neurons, mtDNA depletion was observed upon differentiation of the POLG-mutated lines to cortical neurons. POLG-mutated neurons exhibited neurite simplification with decreased mitochondrial content, abnormal mitochondrial structure and function, and increased cell death. Expression of the mitochondrial kinase PTEN-induced kinase 1 (PINK1) mRNA was decreased in patient neurons. Overexpression of PINK1 increased mitochondrial content and ATP:ADP ratios in neurites, decreasing cell death and rescuing neuritic complexity. These data indicate an intersection of Polγ and PINK1 pathways that may offer a novel therapeutic option for patients affected by this spectrum of disorders.
    Keywords:  Alpers-Huttenlocher syndrome; POLG-related disorders; iPSC-derived neurons; mitochondrial disease model; myoclonic epilepsy myopathy sensory ataxia; neuropathology; patient-derived iPSCs
    DOI:  https://doi.org/10.1016/j.ajpath.2022.11.002
  7. Nat Commun. 2022 Nov 23. 13(1): 7204
    Compact zinc finger base editors that edit mitochondrial or nuclear DNA in vitro and in vivo.
    Julian C W Willis, Pedro Silva-Pinheiro, Lily Widdup, Michal Minczuk, David R Liu.
      DddA-derived cytosine base editors (DdCBEs) use programmable DNA-binding TALE repeat arrays, rather than CRISPR proteins, a split double-stranded DNA cytidine deaminase (DddA), and a uracil glycosylase inhibitor to mediate C•G-to-T•A editing in nuclear and organelle DNA. Here we report the development of zinc finger DdCBEs (ZF-DdCBEs) and the improvement of their editing performance through engineering their architectures, defining improved ZF scaffolds, and installing DddA activity-enhancing mutations. We engineer variants with improved DNA specificity by integrating four strategies to reduce off-target editing. We use optimized ZF-DdCBEs to install or correct disease-associated mutations in mitochondria and in the nucleus. Leveraging their small size, we use a single AAV9 to deliver into heart, liver, and skeletal muscle in post-natal mice ZF-DdCBEs that efficiently install disease-associated mutations. While off-target editing of ZF-DdCBEs is likely too high for therapeutic applications, these findings demonstrate a compact, all-protein base editing research tool for precise editing of organelle or nuclear DNA without double-strand DNA breaks.
    DOI:  https://doi.org/10.1038/s41467-022-34784-7
  8. Hum Mol Genet. 2022 Nov 26. pii: ddac292. [Epub ahead of print]
    Molecular basis of diseases induced by the mitochondrial DNA mutation m.9032 T > C.
    Emilia Baranowska, Katarzyna Niedzwiecka, Chiranjit Panja, Camille Charles, Alain Dautant, Jean-Paul Rago, Déborah Tribouillard-Tanvier, Roza Kucharczyk.
      The mitochondrial DNA mutation m.9032 T > C was previously identified in patients presenting with NARP (Neuropathy Ataxia Retinitis Pigmentosa). Their clinical features had a maternal transmission and patient's cells showed a reduced oxidative phosphorylation capacity, elevated reactive oxygen species (ROS) production and hyperpolarization of the mitochondrial inner membrane, providing evidence that m.9032 T > C is truly pathogenic. This mutation leads to replacement of a highly conserved leucine residue with proline at position 169 of ATP synthase subunit a (L169P). This protein and a ring of identical c-subunits (c-ring) move protons through the mitochondrial inner membrane coupled to ATP synthesis. We herein investigated the consequences of m.9032 T > C on ATP synthase in a strain of Saccharomyces cerevisiae with an equivalent mutation (L186P). The mutant enzyme assembled correctly but was mostly inactive as evidenced by a > 95% drop in the rate of mitochondrial ATP synthesis and absence of significant ATP-driven proton pumping across the mitochondrial membrane. Intragenic suppressors selected from L186P yeast restoring ATP synthase function to varying degrees (30-70%) were identified at the original mutation site (L186S) or in another position of the subunit a (H114Q, I118T). In light of atomic structures of yeast ATP synthase recently described, we conclude from these results that m.9032 T > C disrupts proton conduction between the external side of the membrane and the c-ring, and that H114Q and I118T enable protons to access the c-ring through a modified pathway.
    Keywords:  mitochondrial diseasesNARP syndromemitochondrial DNAATP synthase subunit ayeastsuppressor genetics
    DOI:  https://doi.org/10.1093/hmg/ddac292
  9. Mitochondrion. 2022 Nov 16. pii: S1567-7249(22)00103-9. [Epub ahead of print]
    SELECTIVE AND REVERSIBLE DISRUPTION OF MITOCHONDRIAL INNER MEMBRANE PROTEIN COMPLEXES BY LIPOPHILIC CATIONS.
    Anezka Kafkova, Lisa Tilokani, Filip Trčka, Veronika Šrámková, Marie Vancová, Tomáš Bílý, Jana Nebesařová, Julien Prudent, Jan Trnka.
      Triphenylphosphonium (TPP) derivatives are commonly used to target chemical into mitochondria. We show that alkyl-TPP cause reversible, dose- and hydrophobicity-dependent alterations of mitochondrial morphology and function and a selective decrease of mitochondrial inner membrane proteins including subunits of the respiratory chain complexes, as well as components of the mitochondrial calcium uniporter complex. The treatment with alkyl-TPP resulted in the cleavage of the pro-fusion and cristae organisation regulator Optic atrophy-1. The structural and functional effects of alkyl-TPP were found to be reversible and not merely due to loss of membrane potential. A similar effect was observed with the mitochondria-targeted antioxidant MitoQ.
    Keywords:  MitoQ; inner mitochondrial membrane; lipophilic cations; mitochondria; mitochondrial dynamics; respiratory chain
    DOI:  https://doi.org/10.1016/j.mito.2022.11.006
  10. Genes (Basel). 2022 Nov 14. pii: 2113. [Epub ahead of print]13(11):
    Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency.
    Brianna L Kline, Sylvie Jaillard, Katrina M Bell, Shabnam Bakhshalizadeh, Gorjana Robevska, Jocelyn van den Bergen, Jérôme Dulon, Katie L Ayers, John Christodoulou, Michel C Tchan, Philippe Touraine, Andrew H Sinclair, Elena J Tucker.
      The mitochondrial ribosome is critical to mitochondrial protein synthesis. Defects in both the large and small subunits of the mitochondrial ribosome can cause human disease, including, but not limited to, cardiomyopathy, hypoglycaemia, neurological dysfunction, sensorineural hearing loss and premature ovarian insufficiency (POI). POI is a common cause of infertility, characterised by elevated follicle-stimulating hormone and amenorrhea in women under the age of 40. Here we describe a patient with POI, sensorineural hearing loss and Hashimoto's disease. The co-occurrence of POI with sensorineural hearing loss indicates Perrault syndrome. Whole exome sequencing identified two compound heterozygous variants in mitochondrial ribosomal protein 7 (MRPS7), c.373A>T/p.(Lys125*) and c.536G>A/p.(Arg179His). Both novel variants are predicted to be pathogenic via in-silico algorithms. Variants in MRPS7 have been described only once in the literature and were identified in sisters, one of whom presented with congenital sensorineural hearing loss and POI, consistent with our patient phenotype. The other affected sister had a more severe disease course and died in early adolescence due to liver and renal failure before the reproductive phenotype was known. This second independent report validates that variants in MRPS7 are a cause of syndromic POI/Perrault syndrome. We present this case and review the current evidence supporting the integral role of the mitochondrial ribosome in supporting ovarian function.
    Keywords:  MRPS7; Perrault syndrome; mitochondrial disease; mitochondrial ribosome; ovarian dysfunction; premature ovarian insufficiency
    DOI:  https://doi.org/10.3390/genes13112113
  11. Curr Neurol Neurosci Rep. 2022 Nov 21.
    Developments in the Treatment of Leber Hereditary Optic Neuropathy.
    Benson S Chen, Patrick Yu-Wai-Man, Nancy J Newman.
       PURPOSEOF REVIEW: To outline the current landscape of treatments for Leber hereditary optic neuropathy (LHON) along the therapeutic delivery pipeline, exploring the mechanisms of action and evidence for these therapeutic approaches.
    RECENT FINDINGS: Treatments for LHON can be broadly classified as either mutation-specific or mutation-independent. Mutation-specific therapies aim to correct the underlying mutation through the use of a gene-editing platform or replace the faulty mitochondrial DNA-encoded protein by delivering the wild-type gene using a suitable vector. Recent gene therapy clinical trials assessing the efficacy of allotopically expressed MT-ND4 for the treatment of LHON due to the m.11778G > A mutation in MT-ND4 have shown positive results when treated within 12 months of symptom onset. Mutation-independent therapies can have various downstream targets that aim to improve mitochondrial respiration, reduce mitochondrial stress, inhibit or delay retinal ganglion cell apoptosis, and/or promote retinal ganglion cell survival. Idebenone, a synthetic hydrosoluble analogue of co-enzyme Q10 (ubiquinone), is the only approved treatment for LHON. Mutation-independent approaches to gene therapy under pre-clinical investigation for other neurodegenerative disorders may have the potential to benefit patients with LHON. Although approved treatments are presently limited, innovations in gene therapy and editing are driving the expansion of the therapeutic delivery pipeline for LHON.
    Keywords:  Allotopic expression; Gene therapy; Idebenone; Leber hereditary optic neuropathy; Mitochondrial disease; Optic atrophy
    DOI:  https://doi.org/10.1007/s11910-022-01246-y
  12. Dev Cell. 2022 Nov 21. pii: S1534-5807(22)00760-2. [Epub ahead of print]57(22): 2584-2598.e11
    Autophagy promotes cell survival by maintaining NAD levels.
    Tetsushi Kataura, Lucia Sedlackova, Elsje G Otten, Ruchika Kumari, David Shapira, Filippo Scialo, Rhoda Stefanatos, Kei-Ichi Ishikawa, George Kelly, Elena Seranova, Congxin Sun, Dorothea Maetzel, Niall Kenneth, Sergey Trushin, Tong Zhang, Eugenia Trushina, Charles C Bascom, Ryan Tasseff, Robert J Isfort, John E Oblong, Satomi Miwa, Michael Lazarou, Rudolf Jaenisch, Masaya Imoto, Shinji Saiki, Manolis Papamichos-Chronakis, Ravi Manjithaya, Oliver D K Maddocks, Alberto Sanz, Sovan Sarkar, Viktor I Korolchuk.
      Autophagy is an essential catabolic process that promotes the clearance of surplus or damaged intracellular components. Loss of autophagy in age-related human pathologies contributes to tissue degeneration through a poorly understood mechanism. Here, we identify an evolutionarily conserved role of autophagy from yeast to humans in the preservation of nicotinamide adenine dinucleotide (NAD) levels, which are critical for cell survival. In respiring mouse fibroblasts with autophagy deficiency, loss of mitochondrial quality control was found to trigger hyperactivation of stress responses mediated by NADases of PARP and Sirtuin families. Uncontrolled depletion of the NAD(H) pool by these enzymes ultimately contributed to mitochondrial membrane depolarization and cell death. Pharmacological and genetic interventions targeting several key elements of this cascade improved the survival of autophagy-deficient yeast, mouse fibroblasts, and human neurons. Our study provides a mechanistic link between autophagy and NAD metabolism and identifies targets for interventions in human diseases associated with autophagic, lysosomal, and mitochondrial dysfunction.
    Keywords:  DNA damage; NAD; PARP; Sirtuins; ageing; autophagy; metabolism; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.devcel.2022.10.008
  13. J Biosci. 2022 ;pii: 67. [Epub ahead of print]47
    OXPHOS deficiency induces mitochondrial DNA synthesis through non-canonical AMPK-dependent mRNA compartmentalization.
    Milon Banik, Samit Adhya.
      Eukaryotic cells contain multiple copies of mitochondrial DNA (mtDNA) in discrete organelles or as tubular networks throughout the cytoplasm. The mtDNA copy number is dynamically regulated by mitochondrial biogenesis and mitophagy processes. However, the conditions regulating mtDNA replication, an essential component of biogenesis, are unknown. We observed that short-term (2 h) treatment of rat myoblasts with oligomycin, a specific inhibitor of the mitochondrial F1F0 ATP synthase, resulted in stimulation of mtDNA synthesis from the OH replication origin. This effect was abrogated by Compound C, an antagonist of the AMP-dependent protein kinase (AMPK), a universal intracellular energy sensor, and in AMPK-knockdown cells, indicating that mtDNA replication is regulated by AMPK under oxidative phosphorylation (OXPHOS)- deficient conditions. Using antibody decoration, enzymatically active AMPK, phosphorylated at T172 of the α1 subunit, was found to be located on the mitochondrial surface. Furthermore, oligomycin induced the compartmentalization of several mRNAs encoding OXPHOS components and mtDNA replication factors to mitochondria. Compartmentalization of mRNAs was inhibited by Compound C. We infer that AMPK is locally activated by inhibition of the F1F0 ATP synthase to stimulate association of mtDNA replication factor mRNAs, leading to stimulation of mtDNA synthesis. The findings have implications for the clonal expansion of OXPHOS-deficient mtDNA mutant mitochondria in human patients, with clinical consequences.
  14. Front Endocrinol (Lausanne). 2022 ;13 1059085
    Mitochondrial genomic integrity and the nuclear epigenome in health and disease.
    Amanda L Morin, Phyo W Win, Angela Z Lin, Christina A Castellani.
      Bidirectional crosstalk between the nuclear and mitochondrial genomes is essential for proper cell functioning. Mitochondrial DNA copy number (mtDNA-CN) and heteroplasmy influence mitochondrial function, which can influence the nuclear genome and contribute to health and disease. Evidence shows that mtDNA-CN and heteroplasmic variation are associated with aging, complex disease, and all-cause mortality. Further, the nuclear epigenome may mediate the effects of mtDNA variation on disease. In this way, mitochondria act as an environmental biosensor translating vital information about the state of the cell to the nuclear genome. Cellular communication between mtDNA variation and the nuclear epigenome can be achieved by modification of metabolites and intermediates of the citric acid cycle and oxidative phosphorylation. These essential molecules (e.g. ATP, acetyl-CoA, ɑ-ketoglutarate and S-adenosylmethionine) act as substrates and cofactors for enzymes involved in epigenetic modifications. The role of mitochondria as an environmental biosensor is emerging as a critical modifier of disease states. Uncovering the mechanisms of these dynamics in disease processes is expected to lead to earlier and improved treatment for a variety of diseases. However, the influence of mtDNA-CN and heteroplasmy variation on mitochondrially-derived epigenome-modifying metabolites and intermediates is poorly understood. This perspective will focus on the relationship between mtDNA-CN, heteroplasmy, and epigenome modifying cofactors and substrates, and the influence of their dynamics on the nuclear epigenome in health and disease.
    Keywords:  DNA methylation; aging; disease; epigenome; histone acetylation; metabolism; mitochondrial DNA
    DOI:  https://doi.org/10.3389/fendo.2022.1059085
  15. Mol Genet Metab Rep. 2022 Dec;33 100931
    Malate dehydrogenase 2 deficiency is an emerging cause of pediatric epileptic encephalopathy with a recognizable biochemical signature.
    Jessica R C Priestley, Lisa M Pace, Kuntal Sen, Anjali Aggarwal, Cesar Augusto P F Alves, Ian M Campbell, Sanmati R Cuddapah, Nicole M Engelhardt, Marina Eskandar, Paloma C Jolín García, Andrea Gropman, Ingo Helbig, Xinying Hong, Vykuntaraju K Gowda, Laina Lusk, Pamela Trapane, Varunvenkat M Srinivasan, Pim Suwannarat, Rebecca D Ganetzky.
      Malate dehydrogenases (MDH) serve a critical role in maintaining equilibrium of the NAD+/NADH ratio between the mitochondria and cytosol through the catalysis of the oxidation of L-malate to oxaloacetate in a reversible, NADH-dependent manner. MDH2 encodes the mitochondrial isoform, which is integral to the tricarboxylic acid cycle and thus energy homeostasis. Recently, five patients harboring compound heterozygous MDH2 variants have been described, three with early-onset epileptic encephalopathy, one with a stroke-like episode, and one with dilated cardiomyopathy. Here, we describe an additional seven patients with biallelic variants in MDH2, the largest and most neurodevelopmentally and ethnically diverse cohort to-date, including homozygous variants, a sibling pair, non-European patients, and an adult. From these patients, we learn that MDH2 deficiency results in a biochemical signature including elevations of plasma lactate and the lactate:pyruvate ratio with urinary excretion of malate. It also results in a recognizable constellation of neuroimaging findings of anterior-predominant cerebral atrophy, subependymal cysts with ventricular septations. We also recognize MDH2 deficiency as a cause of Leigh syndrome. Taken with existing patient reports, we conclude that MDH2 deficiency is an emerging and likely under-recognized cause of infantile epileptic encephalopathy and provide a framework for medical evaluation of patients identified with biallelic MDH2 variants.
    Keywords:  Epileptic encephalopathy; Leigh syndrome; MDH2; Malate dehydrogenase; Mitochondrial malate dehydrogenase; TCA cycle
    DOI:  https://doi.org/10.1016/j.ymgmr.2022.100931
  16. J Mol Med (Berl). 2022 Nov 23.
    Mechanistic study of optic atrophy 1 in ischemia-reperfusion disease.
    Ying Yuan, Xiao-Ming Zhang.
      Mitochondria consist of the inner mitochondrial membrane and the outer mitochondrial membrane, which maintain mitochondrial homeostasis through continuous fission and fusion to ensure a healthy mitochondrial network and thus regulate normal cellular function, namely mitochondrial dynamics. The imbalance between mitochondrial fusion and fission results in abnormal mitochondrial structure and eventually mitochondrial dysfunction, which is involved in the pathological process of ischemia-reperfusion injury (IRI). Optic atrophy 1 (OPA1) is a key protein that regulates mitochondrial inner membrane fusion and ensures normal mitochondrial function by balancing mitochondrial dynamics, participating in various processes such as mitochondrial fusion, oxidative stress, and apoptosis. Ischemia-induced changes in mitochondrial dynamics may be a key factor in limiting the recanalization time window and exacerbating reperfusion injury, and the mechanisms of these changes deserve further attention. Therefore, targeting OPA1-related mitochondrial fusions, thereby balancing mitochondrial dynamics and improving mitochondrial dysfunction, is a promising therapeutic strategy for ischemia-reperfusion diseases. This review will elaborate on the structure and function of OPA1 and the role of OPA1 in IRI to provide promising therapeutic targets for the treatment of ischemia-reperfusion diseases.
    Keywords:  Ischemia-reperfusion injury; Mitochondrial dynamics; Mitochondrial fusion; Optic atrophy 1
    DOI:  https://doi.org/10.1007/s00109-022-02271-7
  17. Mol Ther Nucleic Acids. 2022 Dec 13. 30 359-377
    Mitochondrion-targeted RNA therapies as a potential treatment strategy for mitochondrial diseases.
    Timofei Chernega, Jaehyoung Choi, Leonardo Salmena, Ana Cristina Andreazza.
      Mitochondrial diseases are one of the largest groups of neurological genetic disorders. Despite continuous efforts of the scientific community, no cure has been developed, and most treatment strategies rely on managing the symptoms. After the success of coronavirus disease 2019 (COVID-19) mRNA vaccines and accelerated US Food and Drug Administration (FDA) approval of four new RNAi drugs, we sought to investigate the potential of mitochondrion-targeting RNA-based therapeutic agents for treatment of mitochondrial diseases. Here we describe the causes and existing therapies for mitochondrial diseases. We then detail potential RNA-based therapeutic strategies for treatment of mitochondrial diseases, including use of antisense oligonucleotides (ASOs) and RNAi drugs, allotopic therapies, and RNA-based antigenomic therapies that aim to decrease the level of deleterious heteroplasmy in affected tissues. Finally, we review different mechanisms by which RNA-based therapeutic agents can be delivered to the mitochondrial matrix, including mitochondrion-targeted nanocarriers and endogenous mitochondrial RNA import pathways.
    Keywords:  MT: Oligonucleotides, Therapies and Applications; RNA therapeutics; RNA therapy; mitochondrial DNA; mitochondrial RNA import; mitochondrial disease; mitochondrial therapy; mitochondrion-targeted nanocarrier
    DOI:  https://doi.org/10.1016/j.omtn.2022.10.012
  18. Front Aging. 2022 ;3 1043300
    Prohibitins in neurodegeneration and mitochondrial homeostasis.
    Jesus Fernandez-Abascal, Marta Artal-Sanz.
      The incidence of age-related neurodegenerative disorders has risen with the increase of life expectancy. Unfortunately, the diagnosis of such disorders is in most cases only possible when the neurodegeneration status is already advanced, and symptoms are evident. Although age-related neurodegeneration is a common phenomenon in living animals, the cellular and molecular mechanisms behind remain poorly understood. Pathways leading to neurodegeneration usually diverge from a common starting point, mitochondrial stress, which can serve as a potential target for early diagnosis and treatments. Interestingly, the evolutionarily conserved mitochondrial prohibitin (PHB) complex is a key regulator of ageing and metabolism that has been associated with neurodegenerative diseases. However, its role in neurodegeneration is still not well characterized. The PHB complex shows protective or toxic effects in different genetic and physiological contexts, while mitochondrial and cellular stress promote both up and downregulation of PHB expression. With this review we aim to shed light into the complex world of PHB's function in neurodegeneration by putting together the latest advances in neurodegeneration and mitochondrial homeostasis associated with PHB. A better understanding of the role of PHB in neurodegeneration will add knowledge to neuron deterioration during ageing and help to identify early molecular markers of mitochondrial stress. This review will deepen our understanding of age-related neurodegeneration and provide questions to be addressed, relevant to human health and to improve the life quality of the elderly.
    Keywords:  aging; mitochondria; nervous system; neurodegeneration; prohibitin (PHB)
    DOI:  https://doi.org/10.3389/fragi.2022.1043300
  19. Int J Mol Sci. 2022 Nov 08. pii: 13694. [Epub ahead of print]23(22):
    Understanding the Role of Yeast Yme1 in Mitochondrial Function Using Biochemical and Proteomics Analyses.
    Kwan Ting Kan, Michael G Nelson, Chris M Grant, Simon J Hubbard, Hui Lu.
      Mitochondrial i-AAA proteinase Yme1 is a multifunctional protein that plays important roles in maintaining mitochondrial protein homeostasis and regulating biogenesis and function of mitochondrial proteins. However, due to the complex interplay of mitochondria and the multifunctional nature of Yme1, how Yme1 affects mitochondrial function and protein homeostasis is still poorly understood. In this study, we investigated how YME1 deletion affects yeast Saccharomyces cerevisiae growth, chronological life span, mitochondrial protein homeostasis and function, with a focus on the mitochondrial oxidative phosphorylation (OXPHOS) complexes. Our results show that whilst the YME1 deleted cells grow poorly under respiratory conditions, they grow similar to wild-type yeast under fermentative conditions. However, the chronological life span is impaired, indicating that Yme1 plays a key role in longevity. Using highly enriched mitochondrial extract and proteomic analysis, we show that the abundances of many mitochondrial proteins are altered by YME1 deletion. Several components of the respiratory chain complexes II, III, IV and V were significantly decreased, suggesting that Yme1 plays an important role in maintaining the level and function of complexes II-V. This result was confirmed using blue native-PAGE and in-solution-based enzyme activity assays. Taken together, this study shows that Yme1 plays an important role in the chronological life span and mitochondrial protein homeostasis and has deciphered its function in maintaining the activity of mitochondrial OXPHOS complexes.
    Keywords:  AAA proteinase; OXPHOS complex; mitochondrial function; mitochondrial proteomics
    DOI:  https://doi.org/10.3390/ijms232213694
  20. Int J Mol Sci. 2022 Nov 10. pii: 13880. [Epub ahead of print]23(22):
    Mitochondrial Respiratory Chain Supercomplexes: From Structure to Function.
    Shuting Guan, Li Zhao, Ruiyun Peng.
      Mitochondrial oxidative phospho rylation, the center of cellular metabolism, is pivotal for the energy production in eukaryotes. Mitochondrial oxidative phosphorylation relies on the mitochondrial respiratory chain, which consists of four main enzyme complexes and two mobile electron carriers. Mitochondrial enzyme complexes also assemble into respiratory chain supercomplexes (SCs) through specific interactions. The SCs not only have respiratory functions but also improve the efficiency of electron transfer and reduce the production of reactive oxygen species (ROS). Impaired assembly of SCs is closely related to various diseases, especially neurodegenerative diseases. Therefore, SCs play important roles in improving the efficiency of the mitochondrial respiratory chain, as well as maintaining the homeostasis of cellular metabolism. Here, we review the structure, assembly, and functions of SCs, as well as the relationship between mitochondrial SCs and diseases.
    Keywords:  assembly; cytochrome c; mitochondria; respiratory chain; supercomplexes
    DOI:  https://doi.org/10.3390/ijms232213880
  21. Front Neurol. 2022 ;13 1008937
    Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene.
    Margarita Sharova, Mikhail Skoblov, Elena Dadali, Nina Demina, Olga Shchagina, Fedor Konovalov, Maria Ampleeva, Inna Sharkova, Sergey Kutsev.
      We present a patient with unusual episodes of muscular weakness due to homozygous deletion of exon 2 in the MICU1 gene. Forty-three patients from 33 families were previously described with homozygous and compound heterozygous, predominantly loss of function (LoF) variants in the MICU1 gene that lead to autosomal recessive myopathy with extrapyramidal signs. Most described patients developed muscle weakness and elevated CK levels, and half of the patients had progressive extrapyramidal signs and learning disabilities. Our patient had a few severe acute episodes of muscle weakness with minimal myopathy features between episodes and a strongly elevated Creatinine Kinase (CK). Whole exome sequencing (WES) was performed and the homozygous deletion of exon 2 was suspected. To validate the diagnosis, we performed an RNA analysis of all family members. To investigate the possible impact of this deletion on the phenotype, we predicted a new Kozak sequence in exon 4 that could lead to the formation of a truncated MICU1 protein that could partly interact with MCU protein in a mitochondrial Ca2+ complex. We suspect that this unusual phenotype of the proband with MICU1-related myopathy could be explained by the presence of the truncated but partly functional protein. This work helps to define the clinical polymorphism of MICU1 deficiency better.
    Keywords:  MICU1; RNA analysis; mitochondrial Ca2+ complex; molecular mechanism of inherited disease; myopathy with extrapyramidal signs
    DOI:  https://doi.org/10.3389/fneur.2022.1008937
  22. Int Rev Neurobiol. 2022 ;pii: S0074-7742(22)00078-2. [Epub ahead of print]167 59-80
    The many genomes of Parkinson's disease.
    Haydeh Payami.
      Genetic component of Parkinson's disease, once firmly believed non-existent, involves the human genome, mitochondrial genome, and the microbiome. Understanding the genomics of PD requires identification of PD-relevant genes and learning how they interact within the hologenome and with their environment. This chapter is an evidence-based perspective of a geneticist on how far we have come in this endeavor. The contemporary scientific society started with a naive and simplistic view of PD, evolved to accept that Parkinson's disease is probably the most complex disease there is, the progress we have made in discovering the genes and elucidating their functions, and now assembling the parts to create the whole.
    Keywords:  Holobiont; Hologenome; Human genome; Metagenomics; Microbiome; Mitochondrial genome; Parkinson's disease
    DOI:  https://doi.org/10.1016/bs.irn.2022.07.007
  23. JCI Insight. 2022 Nov 22. pii: e163855. [Epub ahead of print]
    Skeletal muscle mitochondrial inertia associates with carnitine acetyltransferase activity and physical function in humans.
    Rodrigo F Mancilla, Lucas Lindeboom, Lotte Grevendonk, Joris Hoeks, Timothy R Koves, Deborah M Muoio, Patrick Schrauwen, Vera Schrauwen-Hinderling, Matthijs Kc Hesselink.
       BACKGROUND: At the onset of exercise, the speed at which PCr decreases towards a new steady state (PCr on-kinetics), reflects the readiness to activate mitochondrial ATP synthesis, which is secondary to Acetyl-CoA availability in skeletal muscle. We hypothesized that PCr on-kinetics are slower in metabolically compromised and older individuals, and associated with low carnitine acetyl-transferase (CrAT) protein activity and compromised physical function.
    METHODS: We applied 31P-Magnetic Resonance Spectroscopy (MRS) to assess PCr on-kinetics in two cohorts of human volunteers. Cohort 1: patients with type 2 diabetes, obese, lean trained and untrained individuals. Cohort 2: young and older individuals with normal physical activity and older trained. Previous results of CrAT protein activity and acetylcarnitine content in muscle tissue were used to explore the underlying mechanisms of PCr on-kinetics, along with various markers of physical function.
    RESULTS: PCr on-kinetics were significantly slower in metabolically compromised and older individuals (indicating mitochondrial inertia) as compared to young and older trained volunteers, regardless of in vivo skeletal muscle oxidative capacity (P<0.001). Mitochondrial inertia correlated with reduced CrAT protein activity, low acetylcarnitine content and also with functional outcomes (P<0.001).
    CONCLUSION: PCr on-kinetics are significantly slower in metabolically compromised and older individuals with normal physical activity compared to young and older trained, regardless of in vivo skeletal muscle oxidative capacity, indicating greater mitochondrial inertia. Thus, PCr on-kinetics are a currently unexplored signature of skeletal muscle mitochondrial metabolism, tightly linked to functional outcomes. Skeletal muscle mitochondrial inertia might emerge as a target of intervention to improve physical function.
    TRIAL REGISTRATION:
    CLINICALTRIALS: gov: NCT01298375 and clinicaltrials.gov: NCT03666013.
    FUNDING: R.M and M.H were granted with an EFSD/Lilly grant from the European Foundation for the Study of Diabetes (EFSD). V.S was supported by an ERC staring grant (Grant no. 759161) "MRS in Diabetes".
    Keywords:  Aging; Diabetes; Metabolism; Mitochondria; Skeletal muscle
    DOI:  https://doi.org/10.1172/jci.insight.163855
  24. Biomed Pharmacother. 2022 Dec;pii: S0753-3322(22)01343-9. [Epub ahead of print]156 113954
    New insights into vascular aging: Emerging role of mitochondria function.
    Yu-Juan Li, Xiao Jin, Dan Li, Jing Lu, Xiao-Nan Zhang, Sheng-Jie Yang, Yi-Xi Zhao, Min Wu.
      Vascular aging, a major risk factor for cardiovascular disease, contributes to morbidity and mortality in older people. Mitochondria play an important role in vascular aging. In endothelial and smooth muscle cells, multiple changes in the mitochondrial structure and function contribute to aging, including the effects of mitochondrial oxidative stress, mitochondrial DNA mutations, mitochondrial dynamics, and mitophagy. Mitochondrial dysfunction also contributes to other age-related molecular and cellular mechanisms, such as crosstalk with telomeres, senescence-associated secretory phenotypes, and low-grade inflammation. Thus, enhancing mitochondrial biogenesis, reducing oxidative stress, recovering dynamics, and mitophagy have been suggested as effective interventions to delay vascular aging and age-related cardiovascular diseases. Furthermore, accumulating evidence has shown that commonly used herbs and their natural compounds have great potential to improve mitochondrial function during vascular aging. Herein, we review the cellular and molecular mechanisms of mitochondrial effects on vascular aging, emphasizing the efficacy of natural compounds in the treatment of vascular aging by improving mitochondrial structure and function. We aim to provide new insights into delaying vascular aging and preventing cardiovascular diseases.
    Keywords:  Endothelial cell; Mitochondria; Natural compounds; Vascular aging; Vascular smooth muscle cell
    DOI:  https://doi.org/10.1016/j.biopha.2022.113954
  25. Clin Biochem. 2022 Nov 17. pii: S0009-9120(22)00244-2. [Epub ahead of print]
    MELAS a clinically and genetically heterogeneous syndrome.
    Liliana Casique, Marisel De Lucca, Antonieta Mahfoud, José Luis Ramírez.
      
    Keywords:  Heteroplasmy; MELAS; Mitochondrial DNA; Phenotype; m.3243A>G
    DOI:  https://doi.org/10.1016/j.clinbiochem.2022.11.007
  26. Nat Cardiovasc Res. 2022 Sep;1(9): 855-866
    Mitochondrial interactome quantitation reveals structural changes in metabolic machinery in the failing murine heart.
    Arianne Caudal, Xiaoting Tang, Juan D Chavez, Andrew Keller, Jared P Mohr, Anna A Bakhtina, Outi Villet, Hongye Chen, Bo Zhou, Matthew A Walker, Rong Tian, James E Bruce.
      Advancements in cross-linking mass spectrometry (XL-MS) bridge the gap between purified systems and native tissue environments, allowing the detection of protein structural interactions in their native state. Here we use isobaric quantitative protein interaction reporter technology (iqPIR) to compare the mitochondria protein interactomes in healthy and hypertrophic murine hearts, 4 weeks post-transaortic constriction. The failing heart interactome includes 588 statistically significant cross-linked peptide pairs altered in the disease condition. We observed an increase in the assembly of ketone oxidation oligomers corresponding to an increase in ketone metabolic utilization; remodeling of NDUA4 interaction in Complex IV, likely contributing to impaired mitochondria respiration; and conformational enrichment of ADP/ATP carrier ADT1, which is non-functional for ADP/ATP translocation but likely possesses non-selective conductivity. Our application of quantitative cross-linking technology in cardiac tissue provides molecular-level insights into the complex mitochondria remodeling in heart failure while bringing forth new hypotheses for pathological mechanisms.
    Keywords:  cardiac hypertrophy; heart failure; interactome; mass spectrometry; mitochondria; protein interactions; quantitative cross-linking; systems structural biology
    DOI:  https://doi.org/10.1038/s44161-022-00127-4
  27. Prenat Diagn. 2022 Nov 21.
    Prenatal phenotype of FBXL4-associated encephalomyopathic mitochondrial DNA depletion syndrome-13.
    Neelam Saini, Venkatapuram Vijayasree, Eshwar Chandra Nandury, Ashwin Dalal, Shagun Aggarwal.
      FBXL4 -associated encephalomyopathic mitochondrial DNA depletion syndrome-13 (MTDPS13) is a rare genetic disorder characterized by early neonatal onset of encephalopathy, seizures, lactic acidosis, hypotonia, dysmorphism, and severe global developmental delay. Prenatal phenotype of molecularly confirmed MTDPS13 has not been well studied. This is the case report of a non-consanguineously conceived fetus ascertained first at 20 weeks of gestation with multiple soft markers. Follow-up fetal ultrasonogram at 26 weeks revealed periventricular cysts, periventricular echogenicity, ventriculomegaly, thin corpus callosum, mega cisterna magna, and large cavum. Fetal MRI confirmed these findings. Postnatally, the baby had clinical and biochemical findings indicative of a mitochondriopathy and died on neonatal day 3. Whole exome sequencing on stored amniotic fluid DNA confirmed the diagnosis of encephalomyopathic mitochondrial DNA depletion syndrome-13 (MTDPS13). This report presents the prenatal phenotype of this rare mitochondriopathy, which has been recognized primarily in postnatal patients. The brain imaging findings in the reported fetus indicate that MTDPS13 is associated with progressive neurological involvement and brain tissue destructive changes starting as early as the second trimester of pregnancy. The case also raises concerns regarding the association of so-called soft markers, which were the only initial finding in this case, with severe monogenic diseases.
    DOI:  https://doi.org/10.1002/pd.6272
  28. Cells. 2022 Nov 09. pii: 3542. [Epub ahead of print]11(22):
    Changes in Mitochondrial Size and Morphology in the RPE and Photoreceptors of the Developing and Ageing Zebrafish.
    Thomas Burgoyne, Maria Toms, Chris Way, Dhani Tracey-White, Clare E Futter, Mariya Moosajee.
      Mitochondria are essential adenosine triphosphate (ATP)-generating cellular organelles. In the retina, they are highly numerous in the photoreceptors and retinal pigment epithelium (RPE) due to their high energetic requirements. Fission and fusion of the mitochondria within these cells allow them to adapt to changing demands over the lifespan of the organism. Using transmission electron microscopy, we examined the mitochondrial ultrastructure of zebrafish photoreceptors and RPE from 5 days post fertilisation (dpf) through to late adulthood (3 years). Notably, mitochondria in the youngest animals were large and irregular shaped with a loose cristae architecture, but by 8 dpf they had reduced in size and expanded in number with more defined cristae. Investigation of temporal gene expression of several mitochondrial-related markers indicated fission as the dominant mechanism contributing to the changes observed over time. This is likely to be due to continued mitochondrial stress resulting from the oxidative environment of the retina and prolonged light exposure. We have characterised retinal mitochondrial ageing in a key vertebrate model organism, that provides a basis for future studies of retinal diseases that are linked to mitochondrial dysfunction.
    Keywords:  ageing; mitochondria; retina; zebrafish
    DOI:  https://doi.org/10.3390/cells11223542
  29. Int J Mol Sci. 2022 Nov 17. pii: 14241. [Epub ahead of print]23(22):
    Pentatricopeptide Protein PTCD2 Regulates COIII Translation in Mitochondria of the HeLa Cell Line.
    Maria V Baleva, Ivan Chicherin, Uliana Piunova, Viktor Zgoda, Maxim V Patrushev, Sergey Levitskii, Piotr Kamenski.
      Protein biosynthesis in mitochondria is tightly coupled with assembly of inner membrane complexes and therefore must be coordinated with cytosolic translation of the mRNAs corresponding to the subunits which are encoded in the nucleus. Molecular mechanisms underlying the regulation of mitochondrial translation remain unclear despite recent advances in structural biology. Until now, only one translational regulator of protein biosynthesis in mammalian mitochondria is known-protein TACO1, which regulates translation of COI mRNA. Here we describe the function of pentatricopeptide-containing protein PTCD2 as a translational regulator of another mitochondrially encoded subunit of cytochrome c oxidase-COIII in the HeLa cell line. Deletion of the PTCD2 gene leads to significant decrease in COIII translation efficiency and impairment in CIV activity. Additionally, we show that PTCD2 protein is partially co-sedimentates with associated mitochondrial ribosome and associates with mitochondrial ribosome proteins in pull-down assays. These data allow concluding that PTCD2 is a specific translational regulator of COIII which attracts the mRNA to the mitochondrial ribosome.
    Keywords:  mitochondria; translation; translation regulation
    DOI:  https://doi.org/10.3390/ijms232214241
  30. Nat Commun. 2022 Nov 24. 13(1): 7226
    Enhanced access to the human phosphoproteome with genetically encoded phosphothreonine.
    Jack M Moen, Kyle Mohler, Svetlana Rogulina, Xiaojian Shi, Hongying Shen, Jesse Rinehart.
      Protein phosphorylation is a ubiquitous post-translational modification used to regulate cellular processes and proteome architecture by modulating protein-protein interactions. The identification of phosphorylation events through proteomic surveillance has dramatically outpaced our capacity for functional assignment using traditional strategies, which often require knowledge of the upstream kinase a priori. The development of phospho-amino-acid-specific orthogonal translation systems, evolutionarily divergent aminoacyl-tRNA synthetase and tRNA pairs that enable co-translational insertion of a phospho-amino acids, has rapidly improved our ability to assess the physiological function of phosphorylation by providing kinase-independent methods of phosphoprotein production. Despite this utility, broad deployment has been hindered by technical limitations and an inability to reconstruct complex phopho-regulatory networks. Here, we address these challenges by optimizing genetically encoded phosphothreonine translation to characterize phospho-dependent kinase activation mechanisms and, subsequently, develop a multi-level protein interaction platform to directly assess the overlap of kinase and phospho-binding protein substrate networks with phosphosite-level resolution.
    DOI:  https://doi.org/10.1038/s41467-022-34980-5
  31. Front Pediatr. 2022 ;10 1029004
    One potential hotspot SLC25A20 gene variants in Chinese patients with carnitine-acylcarnitine translocase deficiency.
    Xiaoli Li, Jian Shen.
       Background: Carnitine-acylcarnitine translocase deficiency (CACT deficiency) is a rare and life-threatening autosomal recessive disorder of mitochondrial fatty acid oxidation caused by variant of SLC25A20 gene. The most prevalent missense variant in the SLC25A20 gene in Asia was c.199-10T > G. Due to the c.199-10T > G variant, CACT deficiency is a severe phenotype.
    Materials and Methods: Herein, we present a neonatal case with c.199-10T > G variant in China and analyze the clinical, biochemical, and genetic aspects of 78 patients previously identified with CACT deficiency.
    Results: The patient presented with a series of severe metabolic crises that rapidly deteriorated and eventually died 3 days after delivery. The sequencing of the patient's genome indicated that he was homozygous for the c.199-10T > G variant. 30 patients were found to have the c.199-10T > G mutation, of which 23 were Chinese and 22 were afflicted by the c.199-10T > G splicing variation. In China, c.199-10T > G allele frequency was 82.6%.
    Conclusion: In CACT deficiency, prompt recognition and treatment are critical. Our data suggested that c.199-10T > G may be a potential hotspot SLC25A20 gene mutation in the Chinese population. Detection of single nucleotide polymorphism is possible for high-risk patients and parents in China.
    Keywords:  CACT deficiency; SLC25A20 gene; c.199–10T > G; hotspot mutation; single nucleotide polymorphism detection
    DOI:  https://doi.org/10.3389/fped.2022.1029004
  32. Front Mol Neurosci. 2022 ;15 1042616
    Neuronal mitochondrial morphology is significantly affected by both fixative and oxygen level during perfusion.
    Su Yeon Kim, Klaudia Strucinska, Bertha Osei, Kihoon Han, Seok-Kyu Kwon, Tommy L Lewis.
      Neurons in the brain have a uniquely polarized structure consisting of multiple dendrites and a single axon generated from a cell body. Interestingly, intracellular mitochondria also show strikingly polarized morphologies along the dendrites and axons: in cortical pyramidal neurons (PNs), dendritic mitochondria have a long and tubular shape, while axonal mitochondria are small and circular. Mitochondria play important roles in each compartment of the neuron by generating adenosine triphosphate (ATP) and buffering calcium, thereby affecting synaptic transmission and neuronal development. In addition, mitochondrial shape, and thereby function, is dynamically altered by environmental stressors such as oxidative stress or in various neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Although the importance of altered mitochondrial shape has been claimed by multiple studies, methods for studying this stress-sensitive organelle have not been standardized. Here we address pertinent steps that influence mitochondrial morphology during experimental processes. We demonstrate that fixative solutions containing only paraformaldehyde (PFA), or that introduce hypoxic conditions during the procedure, induce dramatic fragmentation of mitochondria both in vitro and in vivo. This disruption was not observed following the use of glutaraldehyde (GA) addition or oxygen supplementation, respectively. Finally, using pre-formed fibril α-synuclein treated neurons, we show fixative choice can alter experimental outcomes. Specifically, α-synuclein-induced mitochondrial remodeling could not be observed with PFA only fixation as fixation itself caused mitochondrial fragmentation. Our study provides optimized methods for examining mitochondrial morphology in neurons and demonstrates that fixation conditions are critical when investigating the underlying cellular mechanisms involving mitochondria in physiological and neurodegenerative disease models.
    Keywords:  fixation; hypoxia; mitochondria; neuron; perfusion
    DOI:  https://doi.org/10.3389/fnmol.2022.1042616
  33. JMA J. 2022 Oct 17. 5(4): 407-415
    Mitochondrial Quality Control Mechanisms during Diabetic Cardiomyopathy.
    Melis Ketenci, Daniela Zablocki, Junichi Sadoshima.
      One of the major complications of diabetes mellitus is diabetic cardiomyopathy. One of the mechanisms that initiates the irreversible deterioration of cardiac function in diabetic cardiomyopathy is mitochondrial dysfunction. Functionally impaired mitochondria result in greater levels of oxidative stress and lipotoxicity, both of which exacerbate mitochondrial damage. Mitochondrial health is constantly monitored by mitochondrial quality control mechanisms. Mitophagy selectively degrades damaged mitochondria, thereby maintaining the healthy pool of mitochondria and preserving myocardial function. Mitophagy in diabetic cardiomyopathy is mediated by multiple mechanisms in a time-dependent manner. Potential targets for the treatment of diabetic cardiomyopathy include increased oxidative stress, mitochondrial dynamics, and mitochondrial clearance. Thus, stimulation of mitophagy represents a promising strategy for the alleviation of diabetic cardiomyopathy.
    Keywords:  Autophagy; Diabetes Mellitus; Diabetic Cardiomyopathy; Heart Failure; Mitochondria; Mitophagy
    DOI:  https://doi.org/10.31662/jmaj.2022-0155
  34. Am J Hum Genet. 2022 Nov 18. pii: S0002-9297(22)00461-X. [Epub ahead of print]
    Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria.
    ClinGen Sequence Variant Interpretation Working Group
      Recommendations from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) for interpreting sequence variants specify the use of computational predictors as "supporting" level of evidence for pathogenicity or benignity using criteria PP3 and BP4, respectively. However, score intervals defined by tool developers, and ACMG/AMP recommendations that require the consensus of multiple predictors, lack quantitative support. Previously, we described a probabilistic framework that quantified the strengths of evidence (supporting, moderate, strong, very strong) within ACMG/AMP recommendations. We have extended this framework to computational predictors and introduce a new standard that converts a tool's scores to PP3 and BP4 evidence strengths. Our approach is based on estimating the local positive predictive value and can calibrate any computational tool or other continuous-scale evidence on any variant type. We estimate thresholds (score intervals) corresponding to each strength of evidence for pathogenicity and benignity for thirteen missense variant interpretation tools, using carefully assembled independent data sets. Most tools achieved supporting evidence level for both pathogenic and benign classification using newly established thresholds. Multiple tools reached score thresholds justifying moderate and several reached strong evidence levels. One tool reached very strong evidence level for benign classification on some variants. Based on these findings, we provide recommendations for evidence-based revisions of the PP3 and BP4 ACMG/AMP criteria using individual tools and future assessment of computational methods for clinical interpretation.
    Keywords:  ACMG/AMP recommendations; PP3/BP4 criteria; clinical classification; computational predictors; in silico tools; likelihood ratio; posterior probability; variant interpretation
    DOI:  https://doi.org/10.1016/j.ajhg.2022.10.013
  35. Biochim Biophys Acta Gene Regul Mech. 2022 Nov 17. pii: S1874-9399(22)00113-4. [Epub ahead of print]1866(1): 194898
    Metabolic substrates, histone modifications, and heart failure.
    Zihang Huang, Shuai Song, Xiaokai Zhang, Linqi Zeng, Aijun Sun, Junbo Ge.
      Histone epigenetic modifications are chemical modification changes to histone amino acid residues that modulate gene expression without altering the DNA sequence. As both the phenotypic and causal factors, cardiac metabolism disorder exacerbates mitochondrial ATP generation deficiency, thus promoting pathological cardiac hypertrophy. Moreover, several concomitant metabolic substrates also promote the expression of hypertrophy-responsive genes via regulating histone modifications as substrates or enzyme-modifiers, indicating their dual roles as metabolic and epigenetic regulators. This review focuses on the cardiac acetyl-CoA-dependent histone acetylation, NAD+-dependent SIRT-mediated deacetylation, FAD+-dependent LSD-mediated, and α-KG-dependent JMJD-mediated demethylation after briefly addressing the pathological and physiological cardiac energy metabolism. Besides using an "iceberg model" to explain the dual role of metabolic substrates as both metabolic and epigenetic regulators, we also put forward that the therapeutic supplementation of metabolic substrates is promising to blunt HF via re-establishing histone modifications.
    Keywords:  Epigenetics; Heart failure; Histone acetylation; Histone methylation; Metabolic substrates
    DOI:  https://doi.org/10.1016/j.bbagrm.2022.194898
  36. Dis Model Mech. 2022 Nov 01. pii: dmm049871. [Epub ahead of print]15(11):
    Microvesicle release from inner segments of healthy photoreceptors is a conserved phenomenon in mammalian species.
    Tylor R Lewis, Sebastien Phan, Keun-Young Kim, Isha Jha, Carson M Castillo, Jin-Dong Ding, Benjamin S Sajdak, Dana K Merriman, Mark H Ellisman, Vadim Y Arshavsky.
      Many inherited visual diseases arise from mutations that affect the structure and function of photoreceptor cells. In some cases, the pathology is accompanied by a massive release of extracellular vesicles from affected photoreceptors. In this study, we addressed whether vesicular release is an exclusive response to ongoing pathology or a normal homeostatic phenomenon amplified in disease. We analyzed the ultrastructure of normal photoreceptors from both rod- and cone-dominant mammalian species and found that these cells release microvesicles budding from their inner segment compartment. Inner segment-derived microvesicles vary in their content, with some of them containing the visual pigment rhodopsin and others appearing to be interconnected with mitochondria. These data suggest the existence of a fundamental process whereby healthy mammalian photoreceptors release mistrafficked or damaged inner segment material as microvesicles into the interphotoreceptor space. This release may be greatly enhanced under pathological conditions associated with defects in protein targeting and trafficking. This article has an associated First Person interview with the first author of the paper.
    Keywords:  Microvesicle; Mitochondria; Photoreceptor; Retina; Rhodopsin; Vision
    DOI:  https://doi.org/10.1242/dmm.049871
  37. Hum Mol Genet. 2022 Nov 22. pii: ddac283. [Epub ahead of print]
    Clinically relevant mouse models of Charcot-Marie-Tooth Type 2S.
    Paige B Martin, Sarah E Holbrook, Amy N Hicks, Timothy J Hines, Laurent P Bogdanik, Robert W Burgess, Gregory A Cox.
      Charcot-Marie-Tooth disease is an inherited peripheral neuropathy that is clinically and genetically heterogenous. Mutations in IGHMBP2, a ubiquitously expressed DNA/RNA helicase, have been shown to cause the infantile motor neuron disease spinal muscular atrophy with respiratory distress type 1 (SMARD1), and, more recently, juvenile-onset Charcot-Marie-Tooth disease Type 2S (CMT2S). Using CRISPR-cas9 mutagenesis we developed the first mouse models of CMT2S (p.Glu365del (E365del) and p.Tyr918Cys (Y918C)). E365del is the first CMT2S mouse model to be discovered and Y918C is the first human CMT2S allele knock-in model. Phenotypic characterization of the homozygous models found progressive peripheral motor and sensory axonal degeneration. Neuromuscular and locomotor assays indicate that both E365del and Y918C mice have motor deficits, while neurobehavioral characterization of sensory function found that E365del mutants have mechanical allodynia. Analysis of femoral motor and sensory nerves identified axonal degeneration, which does not impact nerve conduction velocities in E365del mice, but does in the Y918C model. Based on these results, the E365del mutant mouse, as well as the human allele knock-in, Y918C, represent mouse models with the hallmark phenotypes of CMT2S, which will be critical for understanding the pathogenic mechanisms of IGHMBP2. These mice will complement existing Ighmbp2 alleles modeling SMARD1 to help understand the complex phenotypic and genotypic heterogeneity that is observed in patients with IGHMBP2 variants.
    DOI:  https://doi.org/10.1093/hmg/ddac283
  38. Nat Commun. 2022 Nov 25. 13(1): 7252
    mTORC1 signaling facilitates differential stem cell differentiation to shape the developing murine lung and is associated with mitochondrial capacity.
    Kuan Zhang, Erica Yao, Ethan Chuang, Biao Chen, Evelyn Y Chuang, Pao-Tien Chuang.
      Formation of branched organs requires sequential differentiation of stem cells. In this work, we find that the conducting airways derived from SOX2+ progenitors in the murine lungs fail to form without mTOR complex 1 (mTORC1) signaling and are replaced by lung cysts. Proximal-distal patterning through transitioning of distal SOX9+ progenitors to proximal SOX2+ cells is disrupted. Mitochondria number and ATP production are reduced. Compromised mitochondrial capacity results in a similar defect as that in mTORC1-deficient lungs. This suggests that mTORC1 promotes differentiation of SOX9+ progenitors to form the conducting airways by modulating mitochondrial capacity. Surprisingly, in all mutants, saccules are produced from lung cysts at the proper developmental time despite defective branching. SOX9+ progenitors also differentiate into alveolar epithelial type I and type II cells within saccules. These findings highlight selective utilization of energy and regulatory programs during stem cell differentiation to produce distinct structures of the mammalian lungs.
    DOI:  https://doi.org/10.1038/s41467-022-34763-y
  39. Antioxidants (Basel). 2022 Nov 19. pii: 2293. [Epub ahead of print]11(11):
    Coenzyme Q10: Role in Less Common Age-Related Disorders.
    David Mantle, Iain P Hargreaves.
      In this article we have reviewed the potential role of coenzyme Q10 (CoQ10) in the pathogenesis and treatment of a number of less common age-related disorders, for many of which effective therapies are not currently available. For most of these disorders, mitochondrial dysfunction, oxidative stress and inflammation have been implicated in the disease process, providing a rationale for the potential therapeutic use of CoQ10, because of its key roles in mitochondrial function, as an antioxidant, and as an anti-inflammatory agent. Disorders reviewed in the article include multi system atrophy, progressive supranuclear palsy, sporadic adult onset ataxia, and pulmonary fibrosis, together with late onset versions of Huntington's disease, Alexander disease, lupus, anti-phospholipid syndrome, lysosomal storage disorders, fibromyalgia, Machado-Joseph disease, acyl-CoA dehydrogenase deficiency, and Leber's optic neuropathy.
    Keywords:  age related disorders; coenzyme Q10; late onset disorders; multiple system atrophy; progressive supranuclear palsy; sporadic adult onset ataxia
    DOI:  https://doi.org/10.3390/antiox11112293
  40. Elife. 2022 Nov 21. pii: e82860. [Epub ahead of print]11
    Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction.
    Jacob M Winter, Heidi L Fresenius, Corey N Cunningham, Peng Wei, Heather R Keys, Jordan A Berg, Alex J Bott, Tarun Yadav, Jeremy A Ryan, Deepika Sirohi, Sheryl R Tripp, Paige Barta, Neeraj Agarwal, Anthony Letai, David M Sabatini, Matthew L Wohlever, Jared Rutter.
      The tumor suppressor gene PTEN is the second most commonly deleted gene in cancer. Such deletions often include portions of the chromosome 10q23 locus beyond the bounds of PTEN itself, which frequently disrupts adjacent genes. Coincidental loss of PTEN-adjacent genes might impose vulnerabilities that could either affect patient outcome basally or be exploited therapeutically. Here we describe how the loss of ATAD1, which is adjacent to and frequently co-deleted with PTEN, predisposes cancer cells to apoptosis triggered by proteasome dysfunction and correlates with improved survival in cancer patients. ATAD1 directly and specifically extracts the pro-apoptotic protein BIM from mitochondria to inactivate it. Cultured cells and mouse xenografts lacking ATAD1 are hypersensitive to clinically used proteasome inhibitors, which activate BIM and trigger apoptosis. This work furthers our understanding of mitochondrial protein homeostasis and could lead to new therapeutic options for the hundreds of thousands of cancer patients who have tumors with chromosome 10q23 deletion.
    Keywords:  biochemistry; cancer biology; chemical biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.82860
  41. Front Genet. 2022 ;13 953762
    Dissecting the multifaceted contribution of the mitochondrial genome to autism spectrum disorder.
    Leonardo Caporali, Claudio Fiorini, Flavia Palombo, Martina Romagnoli, Flavia Baccari, Corrado Zenesini, Paola Visconti, Annio Posar, Maria Cristina Scaduto, Danara Ormanbekova, Agatino Battaglia, Raffaella Tancredi, Cinzia Cameli, Marta Viggiano, Anna Olivieri, Antonio Torroni, Elena Maestrini, Magali Jane Rochat, Elena Bacchelli, Valerio Carelli, Alessandra Maresca.
      Autism spectrum disorder (ASD) is a clinically heterogeneous class of neurodevelopmental conditions with a strong, albeit complex, genetic basis. The genetic architecture of ASD includes different genetic models, from monogenic transmission at one end, to polygenic risk given by thousands of common variants with small effects at the other end. The mitochondrial DNA (mtDNA) was also proposed as a genetic modifier for ASD, mostly focusing on maternal mtDNA, since the paternal mitogenome is not transmitted to offspring. We extensively studied the potential contribution of mtDNA in ASD pathogenesis and risk through deep next generation sequencing and quantitative PCR in a cohort of 98 families. While the maternally-inherited mtDNA did not seem to predispose to ASD, neither for haplogroups nor for the presence of pathogenic mutations, an unexpected influence of paternal mtDNA, apparently centered on haplogroup U, came from the Italian families extrapolated from the test cohort (n = 74) when compared to the control population. However, this result was not replicated in an independent Italian cohort of 127 families and it is likely due to the elevated paternal age at time of conception. In addition, ASD probands showed a reduced mtDNA content when compared to their unaffected siblings. Multivariable regression analyses indicated that variants with 15%-5% heteroplasmy in probands are associated to a greater severity of ASD based on ADOS-2 criteria, whereas paternal super-haplogroups H and JT were associated with milder phenotypes. In conclusion, our results suggest that the mtDNA impacts on ASD, significantly modifying the phenotypic expression in the Italian population. The unexpected finding of protection induced by paternal mitogenome in term of severity may derive from a role of mtDNA in influencing the accumulation of nuclear de novo mutations or epigenetic alterations in fathers' germinal cells, affecting the neurodevelopment in the offspring. This result remains preliminary and needs further confirmation in independent cohorts of larger size. If confirmed, it potentially opens a different perspective on how paternal non-inherited mtDNA may predispose or modulate other complex diseases.
    Keywords:  autism risk; autism spectrum disorder; mitochondrial DNA; mitochondrial haplogroups; universal heteroplasmy
    DOI:  https://doi.org/10.3389/fgene.2022.953762
  42. Elife. 2022 Nov 21. pii: e65488. [Epub ahead of print]11
    Genetic therapy in a mitochondrial disease model suggests a critical role for liver dysfunction in mortality.
    Ankit Sabharwal, Mark D Wishman, Roberto Lopez Cervera, MaKayla R Serres, Jennifer L Anderson, Shannon R Holmberg, Bibekananda Kar, Anthony J Treichel, Noriko Ichino, Weibin Liu, Jingchun Yang, Yonghe Ding, Yun Deng, Jean M Lacey, William J Laxen, Perry R Loken, Devin Oglesbee, Steven Arthur Farber, Karl J Clark, Xiaolei Xu, Stephen C Ekker.
      The clinical and largely unpredictable heterogeneity of phenotypes in patients with mitochondrial disorders demonstrates the ongoing challenges in the understanding of this semi-autonomous organelle in biology and disease. Previously, we used the gene-breaking transposon to create 1200 transgenic zebrafish strains tagging protein-coding genes (1), including the lrpprc locus. Here we present and characterize a new genetic revertible animal model that recapitulates components of Leigh Syndrome French Canadian Type (LSFC), a mitochondrial disorder that includes diagnostic liver dysfunction. LSFC is caused by allelic variations in the LRPPRC gene, involved in mitochondrial mRNA polyadenylation and translation. lrpprc zebrafish homozygous mutants displayed biochemical and mitochondrial phenotypes similar to clinical manifestations observed in patients, including dysfunction in lipid homeostasis. We were able to rescue these phenotypes in the disease model using a liver-specific genetic model therapy, functionally demonstrating a previously under-recognized critical role for the liver in the pathophysiology of this disease.
    Keywords:  developmental biology; genetics; genomics; zebrafish
    DOI:  https://doi.org/10.7554/eLife.65488
  43. RNA Biol. 2022 Jan;19(1): 1244-1255
    Inhibition of mitochondrial complex III or dihydroorotate dehydrogenase (DHODH) triggers formation of poly(A)+ RNA foci adjacent to nuclear speckles following activation of ATM (ataxia telangiectasia mutated).
    Shuntaro Miyake, Seiji Masuda.
      Intracellular and intercellular signalling networks play an essential role in optimizing cellular homoeostasis and are thought to be partly reflected in nuclear mRNA dynamics. However, the regulation of nuclear mRNA dynamics by intracellular and intercellular signals remains largely unexplored, and research tools are lacking. Through an original screening based on the mRNA metabolic mechanism, we discovered that eight well-known inhibitors cause significant nuclear poly(A)+ RNA accumulation. Among these inhibitors, we discovered a new mRNA metabolic response in which the addition of antimycin A, an inhibitor of mitochondrial respiratory-chain complex III (complex III), resulted in a marked accumulation of poly(A)+ RNA near the nuclear speckles. Furthermore, dihydroorotate dehydrogenase (DHODH) inhibitors, a rate-limiting enzyme in the intracellular de novo pyrimidine synthesis reaction that specifically exchanges electrons with complex III, also caused a remarkable accumulation of nuclear poly(A)+ RNA adjacent to the nuclear speckles, which was abolished by extracellular uridine supply, indicating that the depletion of intracellular pyrimidine affects poly(A)+ RNA metabolism. Further analysis revealed that ataxia telangiectasia mutated (ATM), a serine and threonine kinase and a master regulator of DNA double-strand break (DSB) and nucleolar stress, is required for this poly(A)+ RNA nuclear accumulation phenomenon. This study reports new insights into novel aspects of nuclear poly(A)+ RNA metabolism, especially the relationship between mitochondrial respiratory-chain functions, pyrimidine metabolism, and nuclear RNA metabolism.
    Keywords:  Poly(A)+ RNA; ataxia telangiectasia mutated (ATM); dihydroorotate dehydrogenase (DHODH); pyrimidine; respiratory chain complex III
    DOI:  https://doi.org/10.1080/15476286.2022.2146919
  44. Cells. 2022 Nov 14. pii: 3603. [Epub ahead of print]11(22):
    Mitochondria Transfer in Brain Injury and Disease.
    Lauren H Fairley, Amandine Grimm, Anne Eckert.
      Intercellular mitochondria transfer is a novel form of cell signalling in which whole mitochondria are transferred between cells in order to enhance cellular functions or aid in the degradation of dysfunctional mitochondria. Recent studies have observed intercellular mitochondria transfer between glia and neurons in the brain, and mitochondrial transfer has emerged as a key neuroprotective mechanism in a range of neurological conditions. In particular, artificial mitochondria transfer has sparked widespread interest as a potential therapeutic strategy for brain disorders. In this review, we discuss the mechanisms and effects of intercellular mitochondria transfer in the brain. The role of mitochondrial transfer in neurological conditions, including neurodegenerative disease, brain injury, and neurodevelopmental disorders, is discussed as well as therapeutic strategies targeting mitochondria transfer in the brain.
    Keywords:  brain; glia; mitochondria; neuron
    DOI:  https://doi.org/10.3390/cells11223603
  45. Int J Mol Sci. 2022 Nov 21. pii: 14482. [Epub ahead of print]23(22):
    Characterization of Mitochondrial Alterations in Aicardi-Goutières Patients Mutated in RNASEH2A and RNASEH2B Genes.
    Francesca Dragoni, Jessica Garau, Daisy Sproviero, Simona Orcesi, Costanza Varesio, Silvia De Siervi, Stella Gagliardi, Cristina Cereda, Orietta Pansarasa.
      Aicardi-Goutières syndrome (AGS) is a rare encephalopathy characterized by neurological and immunological features. Mitochondrial dysfunctions may lead to mitochondrial DNA (mtDNA) release and consequent immune system activation. We investigated the role of mitochondria and mtDNA in AGS pathogenesis by studying patients mutated in RNASEH2B and RNASEH2A genes. Lymphoblastoid cell lines (LCLs) from RNASEH2A- and RNASEH2B-mutated patients and healthy control were used. Transmission Electron Microscopy (TEM) and flow cytometry were used to assess morphological alterations, reactive oxygen species (ROS) production and mitochondrial membrane potential variations. Seahorse Analyzer was used to investigate metabolic alterations, and mtDNA oxidation and VDAC1 oligomerization were assessed by immunofluorescence. Western blot and RT-qPCR were used to quantify mtTFA protein and mtDNA release. Morphological alterations of mitochondria were observed in both mutated LCLs, and loss of physiological membrane potential was mainly identified in RNASEH2A LCLs. ROS production and 8-oxoGuanine levels were increased in RNASEH2B LCLs. Additionally, the VDAC1 signal was increased, suggesting a mitochondrial pore formation possibly determining mtDNA release. Indeed, higher cytoplasmic mtDNA levels were found in RNASEH2B LCLs. Metabolic alterations confirmed mitochondrial damage in both LCLs. Data highlighted mitochondrial alterations in AGS patients' LCLs suggesting a pivotal role in AGS pathogenesis.
    Keywords:  Aicardi–Goutières syndrome; IFN-α; ROS; autoimmune diseases; inflammation; mitochondrial disorder; mitochondrial stress; mtDNA
    DOI:  https://doi.org/10.3390/ijms232214482
  46. iScience. 2022 Dec 22. 25(12): 105476
    Parkinson disease-associated Leucine-rich repeat kinase regulates UNC-104-dependent axonal transport of Arl8-positive vesicles in Drosophila.
    Tsuyoshi Inoshita, Jun-Yi Liu, Daisuke Taniguchi, Ryota Ishii, Kahori Shiba-Fukushima, Nobutaka Hattori, Yuzuru Imai.
      Some Parkinson's disease (PD)-causative/risk genes, including the PD-associated kinase leucine-rich repeat kinase 2 (LRRK2), are involved in membrane dynamics. Although LRRK2 and other PD-associated genes are believed to regulate synaptic functions, axonal transport, and endolysosomal activity, it remains unclear whether a common pathological pathway exists. Here, we report that the loss of Lrrk, an ortholog of human LRRK2, leads to the accumulation of the lysosome-related organelle regulator, Arl8 along with dense core vesicles at the most distal boutons of the neuron terminals in Drosophila. Moreover, the inactivation of a small GTPase Rab3 and altered Auxilin activity phenocopied Arl8 accumulation. The accumulation of Arl8-positive vesicles is UNC-104-dependent and modulated by PD-associated genes, Auxilin, VPS35, RME-8, and INPP5F, indicating that VPS35, RME-8, and INPP5F are upstream regulators of Lrrk. These results indicate that certain PD-related genes, along with LRRK2, drive precise neuroaxonal transport of dense core vesicles.
    Keywords:  Biological sciences; Cell biology; Genetics; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2022.105476
  47. Fish Shellfish Immunol Rep. 2021 Dec;2 100019
    Mitochondrial connections with immune system in Zebrafish.
    Mariana Abrantes do Amaral, Lais Cavalieri Paredes, Barbara Nunes Padovani, Juliana Moreira Mendonça-Gomes, Luan Fávero Montes, Niels Olsen Saraiva Câmara, Camila Morales Fénero.
      Mitochondria are organelles commonly associated with adenosine triphosphate (ATP) formation through the oxidative phosphorylation (OXPHOS) process. However, mitochondria are also responsible for functions such as calcium homeostasis, apoptosis, autophagy, and production of reactive oxygen species (ROS) that, in conjunction, can lead to different cell fate decisions. Mitochondrial morphology changes rely on nutrients' availability and the bioenergetics demands of the cells, in a process known as mitochondrial dynamics, which includes both fusion and fission. This organelle senses the microenvironment and can modify the cells to either a pro or anti-inflammatory profile. The zebrafish has been increasingly used to research mitochondrial dynamics and its connection with the immune system since the pathways and molecules involved in these processes are conserved on this fish. Several genetic tools and technologies are currently available to analyze the behavior of mitochondria in zebrafish. However, even though zebrafish presents several similar processes known in mammals, the effect of the mitochondria in the immune system has not been so broadly studied in this model. In this review, we summarize the current knowledge in zebrafish studies regarding mitochondrial function and immuno metabolism.
    Keywords:  Fish; Immuno metabolism; Immunology; Metabolism; Mitochondria; Mitochondrial functions
    DOI:  https://doi.org/10.1016/j.fsirep.2021.100019
  48. Pediatr Neonatol. 2022 Nov 09. pii: S1875-9572(22)00226-1. [Epub ahead of print]
    Genomic technologies to improve variation identification in undiagnosed diseases.
    Joseph T C Shieh.
      Human genome variation has increasingly posed challenges and opportunities for patients, medical providers, and an increasing group of stakeholders including advocacy groups, disadvantaged communities, public health experts, and scientists. Here, advances in genomic sequencing and mapping technologies are discussed with particular attention to the increasing ability to detect personal and population genome variation and the potential for accurate integration of variation into health and disease-related care. Genome mapping, one technique used to create genome map scaffolds, has now been combined with long read sequencing. New technologies have led to improved variation detection, including cryptic structural variation and diverse variants with different degrees of disease association. Combined with advances in automated and medical interpretations, variation detection is increasingly being applied in healthcare. These advances promise to make disease diagnostics more rapid, and potentially more accessible, to those with medical needs. Consequentially, the need for medical genetics and genomics experts is increasing. Here, the opportunities and potential challenges for application of genome-scale variation detection in disease are examined. (<300 words).
    Keywords:  genomic structural variation; inheritance patterns; integrative techniques; medical informatics; rare diseases (3-5, alphabetical order, MeSH)
    DOI:  https://doi.org/10.1016/j.pedneo.2022.10.002
  49. Front Oncol. 2022 ;12 1048746
    Acquired and hereditary bone marrow failure: A mitochondrial perspective.
    Waseem Nasr, Marie-Dominique Filippi.
      The disorders known as bone marrow failure syndromes (BMFS) are life-threatening disorders characterized by absence of one or more hematopoietic lineages in the peripheral blood. Myelodysplastic syndromes (MDS) are now considered BMF disorders with associated cellular dysplasia. BMFs and MDS are caused by decreased fitness of hematopoietic stem cells (HSC) and poor hematopoiesis. BMF and MDS can occur de novo or secondary to hematopoietic stress, including following bone marrow transplantation or myeloablative therapy. De novo BMF and MDS are usually associated with specific genetic mutations. Genes that are commonly mutated in BMF/MDS are in DNA repair pathways, epigenetic regulators, heme synthesis. Despite known and common gene mutations, BMF and MDS are very heterogenous in nature and non-genetic factors contribute to disease phenotype. Inflammation is commonly found in BMF and MDS, and contribute to ineffective hematopoiesis. Another common feature of BMF and MDS, albeit less known, is abnormal mitochondrial functions. Mitochondria are the power house of the cells. Beyond energy producing machinery, mitochondrial communicate with the rest of the cells via triggering stress signaling pathways and by releasing numerous metabolite intermediates. As a result, mitochondria play significant roles in chromatin regulation and innate immune signaling pathways. The main goal of this review is to investigate BMF processes, with a focus mitochondria-mediated signaling in acquired and inherited BMF.
    Keywords:  TGF beta; bone marrow failure (BMF); innate immune signaling; mitochondria; myelodysplastic disorder (MDS)
    DOI:  https://doi.org/10.3389/fonc.2022.1048746
  50. Int J Mol Sci. 2022 Nov 11. pii: 13933. [Epub ahead of print]23(22):
    Mitochondrial Fatty Acid β-Oxidation Disorders: From Disease to Lipidomic Studies-A Critical Review.
    Inês M S Guerra, Helena B Ferreira, Tânia Melo, Hugo Rocha, Sónia Moreira, Luísa Diogo, Maria Rosário Domingues, Ana S P Moreira.
      Fatty acid oxidation disorders (FAODs) are inborn errors of metabolism (IEMs) caused by defects in the fatty acid (FA) mitochondrial β-oxidation. The most common FAODs are characterized by the accumulation of medium-chain FAs and long-chain (3-hydroxy) FAs (and their carnitine derivatives), respectively. These deregulations are associated with lipotoxicity which affects several organs and potentially leads to life-threatening complications and comorbidities. Changes in the lipidome have been associated with several diseases, including some IEMs. In FAODs, the alteration of acylcarnitines (CARs) and FA profiles have been reported in patients and animal models, but changes in polar and neutral lipid profile are still scarcely studied. In this review, we present the main findings on FA and CAR profile changes associated with FAOD pathogenesis, their correlation with oxidative damage, and the consequent disturbance of mitochondrial homeostasis. Moreover, alterations in polar and neutral lipid classes and lipid species identified so far and their possible role in FAODs are discussed. We highlight the need of mass-spectrometry-based lipidomic studies to understand (epi)lipidome remodelling in FAODs, thus allowing to elucidate the pathophysiology and the identification of possible biomarkers for disease prognosis and an evaluation of therapeutic efficacy.
    Keywords:  CPT2D; FAOD; LCHADD; MCADD; VLCADD; inborn errors of metabolism; lipid changes; lipidomics; mass spectrometry; oxidative stress
    DOI:  https://doi.org/10.3390/ijms232213933
  51. BMC Biol. 2022 Nov 23. 20(1): 261
    Folate regulates RNA m5C modification and translation in neural stem cells.
    Xiguang Xu, Zachary Johnson, Amanda Wang, Rachel L Padget, James W Smyth, Hehuang Xie.
       BACKGROUND: Folate is an essential B-group vitamin and a key methyl donor with important biological functions including DNA methylation regulation. Normal neurodevelopment and physiology are sensitive to the cellular folate levels. Either deficiency or excess of folate may lead to neurological disorders. Recently, folate has been linked to tRNA cytosine-5 methylation (m5C) and translation in mammalian mitochondria. However, the influence of folate intake on neuronal mRNA m5C modification and translation remains largely unknown. Here, we provide transcriptome-wide landscapes of m5C modification in poly(A)-enriched RNAs together with mRNA transcription and translation profiles for mouse neural stem cells (NSCs) cultured in three different concentrations of folate.
    RESULTS: NSCs cultured in three different concentrations of folate showed distinct mRNA methylation profiles. Despite uncovering only a few differentially expressed genes, hundreds of differentially translated genes were identified in NSCs with folate deficiency or supplementation. The differentially translated genes induced by low folate are associated with cytoplasmic translation and mitochondrial function, while the differentially translated genes induced by high folate are associated with increased neural stem cell proliferation. Interestingly, compared to total mRNAs, polysome mRNAs contained high levels of m5C. Furthermore, an integrative analysis indicated a transcript-specific relationship between RNA m5C methylation and mRNA translation efficiency.
    CONCLUSIONS: Altogether, our study reports a transcriptome-wide influence of folate on mRNA m5C methylation and translation in NSCs and reveals a potential link between mRNA m5C methylation and mRNA translation.
    Keywords:  Folic acid; Mouse neural stem cell; Polysome profiling; RNA bisulfite sequencing; RNA cytosine-5 methylation
    DOI:  https://doi.org/10.1186/s12915-022-01467-0
  52. Biomicrofluidics. 2022 Dec;16(6): 064101
    Mechanical characterization of isolated mitochondria under conditions of oxidative stress.
    Yesaswini Komaragiri, Muzaffar H Panhwar, Bob Fregin, Gayatri Jagirdar, Carmen Wolke, Stefanie Spiegler, Oliver Otto.
      Mechanical properties have been proven to be a pivotal parameter to enhance our understanding of living systems. While research during the last decades focused on cells and tissues, little is known about the role of organelle mechanics in cell function. Here, mitochondria are of specific interest due to their involvement in numerous physiological and pathological processes, e.g., in the production and homeostasis of reactive oxygen species (ROS). Using real-time fluorescence and deformability cytometry, we present a microfluidic technology that is capable to determine the mechanical properties of individual mitochondria at a throughput exceeding 100 organelles per second. Our data on several thousands of viable mitochondria isolated from rat C6 glial cells yield a homogenous population with a median deformation that scales with the applied hydrodynamic stress. In two proof-of-principle studies, we investigated the impact of exogenously and endogenously produced ROS on mitochondria mechanics. Exposing C6 cells to hydrogen peroxide (H2O2) triggers superoxide production and leads to a reduction in mitochondria size while deformation is increased. In a second study, we focused on the knockout of tafazzin, which has been associated with impaired remodeling of the mitochondrial membrane and elevated levels of ROS. Interestingly, our results reveal the same mechanical alterations as observed after the exposure to H2O2, which points to a unified biophysical mechanism of how mitochondria respond to the presence of oxidative stress. In summary, we introduce high-throughput mechanical phenotyping into the field of organelle biology with potential applications for understanding sub-cellular dynamics that have not been accessible before.
    DOI:  https://doi.org/10.1063/5.0111581
  53. Bioessays. 2022 Nov 22. e2200190
    Ancient endosymbiont-mediated transmission of a selfish gene provides a model for overcoming barriers to gene transfer into animal mitochondrial genomes.
    Gaurav G Shimpi, Bastian Bentlage.
      In contrast to bilaterian animals, non-bilaterian mitochondrial genomes contain atypical genes, often attributed to horizontal gene transfer (HGT) as an ad hoc explanation. Although prevalent in plants, HGT into animal mitochondrial genomes is rare, lacking suitable explanatory models for their occurrence. HGT of the mismatch DNA repair gene (mtMutS) from giant viruses to octocoral (soft corals and their kin) mitochondrial genomes provides a model for how barriers to HGT to animal mitochondria may be overcome. A review of the available literature suggests that this HGT was mediated by an alveolate endosymbiont infected with a lysogenic phycodnavirus that enabled insertion of the homing endonuclease containing mtMutS into octocoral mitochondrial genomes. We posit that homing endonuclease domains and similar selfish elements play a crucial role in such inter-domain gene transfers. Understanding the role of selfish genetic elements in HGT has the potential to aid development of tools for manipulating animal mitochondrial DNA.
    Keywords:  Phycodnaviridae; endosymbiont gene transfer; giant viruses; horizontal gene transfer; mitochondrial genome; mtMutS; octocorals
    DOI:  https://doi.org/10.1002/bies.202200190
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