Mitochondrial Inborn Errors in Metabolism View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

1984-2019

FUNDING AMOUNT

6504144 USD

ABSTRACT

DESCRIPTION (provided by applicant): Leber Hereditary Optic Neuropathy (LHON), the first inherited mtDNA disease identified, stereotypically presents as acute onset blindness in midlife and is one of the most common mtDNA mitochondrial disease phenotypes, >1 in 7000. LHON commonly results from missense mutations in mtDNA complex I (ND) genes, though rarer LHON mutations can occur in any mtDNA gene. LHON complex I gene mutations result in progressive retinal ganglion cell (RGC) and optic nerve degeneration with males being 2 to 5 times more likely to be affected than females and with a highly variable penetrance. Because of the unique tissue specificity of LHON, an animal model is required to investigate the neuronal, RGC and optic nerve physiology and pathology and to develop and test pharmacological and genetic therapies. After twenty years of development we have succeeded in isolating in the mouse mtDNA a mutation that is known to cause optic atrophy in humans (ND6 P25L) and in introducing this mtDNA mutation into the mouse female germ line in the homoplasmic state. This mouse manifests all of the features of LHON possible given the anatomical differences human and mice eyes. Analysis of synaptosomal ND6 P25L mitochondria has revealed a unique complex I defect in which ROS production is chronically elevated while ATP production is only minimally impaired. Hence, the primary causal factor in LHON appears to be chronic RGC oxidative stress. We now propose to use this pathophysiological insight and mouse model to further clarify the physiological consequences of LHON mutations for the RGC and optic nerve. We will then investigate the importance of nuclear-cytoplasmic interactions in generating the variable penetrance of LHON by combining the ND6 P25L mtDNA with a knockin missense mutation in an X- linked complex I gene and with an inducible mitochondrially-targeted catalase (mCAT). The former combination will permit investigation of the genetics of male bias and the later will allow confirmation of the importance of mitochondrial ROS in RGC and optic nerve toxicity and the role of nDNA antioxidant gene variation in modulating mutant mtDNA pathology. Our mouse model will also be used to test the efficacy of antioxidant drugs in inhibiting the onset of LHON and of benzofibrate in repairing mitochondrial and RGC oxidative damage through induction of mitochondrial biogenesis. Finally, we will prepare an AAV-mCAT vector for intra-orbital injection to transduce the mCAT catalytic antioxidant enzyme into the ND6 P25L RGC mitochondria in hopes of inhibiting RGC ROS production and optic atrophy. The AAV-mCAT experiments will be complemented by AAV transduction of allotopic mtDNA ND6 genes with either the universal genetic code or the mtDNA code. The former mRNAs will be translated on cytosolic ribosomes and the protein imported into the mitochondrion while the latter will carry RNA import signals to induce the uptake of the mRNA by the mitochondria and translation on mitochondrial ribosomes. Thus our mtDNA mutant mouse model of LHON has provided new insight into the pathophysiology of LHON and new avenues for therapeutics. More... »

URL

http://projectreporter.nih.gov/project_info_description.cfm?aid=9253451

Related SciGraph Publications

  • 2018-10-29. Mitochondrial genetic medicine in NATURE GENETICS
  • 2017. Leber Hereditary Optic Neuropathy: Exemplar of an mtDNA Disease in PHARMACOLOGY OF MITOCHONDRIA
  • 2016-12. Cristae remodeling causes acidification detected by integrated graphene sensor during mitochondrial outer membrane permeabilization in SCIENTIFIC REPORTS
  • 2016-07-06. Genetics: Mitochondrial DNA in evolution and disease in NATURE
  • 2015-12. Trans-mitochondrial coordination of cristae at regulated membrane junctions in NATURE COMMUNICATIONS
  • 2015-12. Corrigendum: Landscape of the mitochondrial Hsp90 metabolome in tumours in NATURE COMMUNICATIONS
  • 2013-12. Landscape of the mitochondrial Hsp90 metabolome in tumours in NATURE COMMUNICATIONS
  • 2013-02. Mitochondrial genome instability resulting from SUV3 haploinsufficiency leads to tumorigenesis and shortened lifespan in ONCOGENE
  • 2012-10. Mitochondria and cancer in NATURE REVIEWS CANCER
  • 2011-06. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss in NATURE GENETICS
  • 2011-02. Mitochondrial cardiomyopathies: how to identify candidate pathogenic mutations by mitochondrial DNA sequencing, MITOMASTER and phylogeny in EUROPEAN JOURNAL OF HUMAN GENETICS
  • 2007-04. Life extension through neurofibromin mitochondrial regulation and antioxidant therapy for neurofibromatosis-1 in Drosophila melanogaster in NATURE GENETICS
  • 2006-11. Detection of Low Levels of the Mitochondrial tRNALeu(UUR) 3243A>G Mutation in Blood Derived from Patients with Diabetes in MOLECULAR DIAGNOSIS & THERAPY
  • 2006-08. Mitochondrial mutations in cancer in ONCOGENE
  • 2005-04. Adeno-associated virus-mediated gene transfer of the heart/muscle adenine nucleotide translocator (ANT) in mouse in GENE THERAPY
  • 2004-12. TGF-β1 induction of the adenine nucleotide translocator 1 in astrocytes occurs through Smads and Sp1 transcription factors in BMC NEUROSCIENCE
  • 2002-04-02. Animal Models for Mitochondrial Disease in MITOCHONDRIAL DNA
  • 2002-02. The role of mtDNA background in disease expression: a new primary LHON mutation associated with Western Eurasian haplogroup J in HUMAN GENETICS
  • 2001-07. Novel mtDNA mutations and oxidative phosphorylation dysfunction in Russian LHON families in HUMAN GENETICS
  • 1999-04. Transfer of chloramphenicol‐resistant mitochondrial DNA into the chimeric mouse in TRANSGENIC RESEARCH
  • 1998-02. A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase in NATURE GENETICS
  • 1997-09. Y chromosome polymorphisms in Native American and Siberian populations: identification of Native American Y chromosome haplotypes in HUMAN GENETICS
  • 1997-07. A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator in NATURE GENETICS
  • 1996-01. Production of transmitochondrial mouse cell lines by cybrid rescue of rhodamine-6G pre-treated L-cells in SOMATIC CELL AND MOLECULAR GENETICS
  • 1995-04. Renal amino acid transport in adults with oxidative phosphorylation diseases in KIDNEY INTERNATIONAL
  • 1994-06. Mitochondrial DNA mutations in diseases of energy metabolism in JOURNAL OF BIOENERGETICS AND BIOMEMBRANES
  • 1994-06. Molecular basis of mitochondrial DNA disease in JOURNAL OF BIOENERGETICS AND BIOMEMBRANES
  • 1990-11. Mitochondrial DNA Mutations Associated with Neuromuscular Diseases: Analysis and Diagnosis Using the Polymerase Chain Reaction in PEDIATRIC RESEARCH
  • 1987-06. Sequence analysis of cDNAs for the human and bovine ATP synthase β subunit: mitochondrial DNA genes sustain seventeen times more mutations in CURRENT GENETICS
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