Abstract: Disclosed is an RNA allotopic strategy to complement and genetically rescue mitochondrial gene defects. This approach can permit rescue of a mitochondrial DNA mutant by allotopic expression of a full-length recoded mitochondrial RNA that is transcribed in the nucleus, successfully imported into the mitochondria, and expressed there.

Abstract: Mitochondrial disease genetic diagnostics and methods of use thereof.

Abstract: Mitochondrial disease genetic diagnostics and methods of use thereof are provided.

Abstract: A microfluidic sensor device includes a substrate having patterned thereon at least one Ag/AgCl electrode (working electrode) and an inner chamber overlying the at least one Ag/AgCl electrode. The device includes an ion selective permeable membrane permeable to TPP+ disposed on one side of the first chamber and a sensing chamber overlying the ion selective permeable membrane. A separate reference electrode is inserted into the sensing chamber. The working electrode and reference electrode are coupled to a voltmeter to measure voltage. This voltage can then be translated into a TPP+ concentration which is used to determine the mitochondrial membrane potential (??m).

Abstract: A microfluidic sensor device includes a substrate having patterned thereon at least one Ag/AgCl electrode (working electrode) and an inner chamber overlying the at least one Ag/AgCl electrode. The device includes an ion selective permeable membrane permeable to TPP+ disposed on one side of the first chamber and a sensing chamber overlying the ion selective permeable membrane. A separate reference electrode is inserted into the sensing chamber. The working electrode and reference electrode are coupled to a voltmeter to measure voltage. This voltage can then be translated into a TPP+ concentration which is used to determine the mitochondrial membrane potential (??m).

Abstract: Animal models and methods wherein homoplasmic and heteroplasmic mtDNA mutation(s) are induced in an animal (e.g., a mouse) to cause or facilitate the development of a disorder (e.g., disease, malformation, defect, abnormality or other disorder). In at least some embodiments, the mtDNA mutation(s) will cause or facilitate the development of an age-related disorder, such as a cardiac disease, cardiomyopathy, muscle disease, cancer, abnormaly in tissues of high cellular turnover, heart dysfunction, graying of hair, alopecia, auditory function loss, cochlear degeneration, immune cell loss, anemia, male germ cell loss leading to lack of sperm and infertility, skeletal muscle mass loss (sarcopenia), neurodegeneration, increased presence of apoptotic markers, and loss of bone mass.

Abstract: Methods of treating disorders such as neurofibromatosis-1 are provided, including methods in which catalytic antioxidants such as metalloporphyrins are administered. Methods of regulating longevity, and methods and systems for screening for modulators of aging or longevity, are also provided. In addition, related transgenic animals are described.

Abstract: Animal models and methods wherein homoplasmic and heteroplasmic mtDNA mutation(s) are induced in an animal (e.g., a mouse) to cause or facilitate the development of a disorder (e.g., disease, malformation, defect, abnormality or other disorder). In at least some embodiments, the mtDNA mutation(s) will cause or facilitate the development of an age-related disorder, such as a cardiac disease, cardiomyopathy, muscle disease, cancer, abnormaly in tissues of high cellular turnover, heart dysfunction, graying of hair, alopecia, auditory function loss, cochlear degeneration, immune cell loss, anemia, male germ cell loss leading to lack of sperm and infertility, skeletal muscle mass loss (sarcopenia), neurodegeneration, increased presence of apoptotic markers, and loss of bone mass.

Abstract: Methods, compositions and apparatus (e.g., test kits, test systems, reagents, related computer software, calculators, etc.) for pre-symptomatic or post-symptomatic diagnosis of Alzheimer's Disease or other disorders associated with the formation of ?-amyloid deposits (e.g., plaques) and/or ?-amyloid fibrils. Also, methods, compositions and apparatus assessing the efficacy of treatments for such disorders. Sample cells, tissue or body fluid are obtained from a human or animal subject and analyzed to determine whether or to what extent certain mitochondrial DNA control region (mtDNA CR). Significantly elevated numbers of these mtDNA CR mutations may indicate that the subject suffers from, or is at increased risk for development of, Alzheimer's Disease or other disorders associated with the formation of ?-amyloid deposits (e.g., plaques) and/or ?-amyloid fibrils. A significant decrease in the numbers of these mtDNA CR mutations during treatment for the disorder may indicate that the treatment is effective.

Abstract: Provided are methods of identifying Metabolic Syndrome phenotypes for an organism or a biological sample derived therefrom which methods are based on detecting a polymorphism, haplotype, haplotype group, or haplotype subgroup in the mitochondrial genome of the organism and correlating the polymorphism or haplotype to a Metabolic Syndrome phenotype. Also provided are systems or kits for the detection of such polymorphisms or haplotypes and the correlation of the polymorphisms or haplotypes to a Metabolic Syndrome phenotype. Provided are methods of identifying a modulator of a Metabolic Syndrome phenotype and kits for the treatment of a Metabolic Syndrome phenotype.

Abstract: Methods of treating disorders such as neurofibromatosis-1 are provided, including methods in which catalytic antioxidants such as metalloporphyrins are administered. Methods of regulating longevity, and methods and systems for screening for modulators of aging or longevity, are also provided. In addition, related transgenic animals are described.

Abstract: A method is provided for identifying a subject likely to have, or at risk of developing a disease condition correlated with increased reactive oxygen species (ROS), including cancer, by identifying in the subject a missense mutation in a nucleic acid of Complex III, IV and/or V of the OXPHOS system. This invention also provides a method of identifying a likelihood of having a heritable predisposition to cancer by detecting a homoplasmic missense mutation in non-tumor tissue of an OXPHOS system gene. This invention also provides a method for detecting likelihood of having cancer, predisposition to cancer, and likelihood of passing a predisposition to cancer to progeny involving identifying in non-tumor tissue of the subject a missense mutation in a complex III, IV and/or V gene of the mitochondrial OXPHOS system. The mutation may be a nuclear or mitochondrial mutation. The invention has been exemplified with respect to prostate cancer.

Abstract: Described are methods for inactivating adenine nucleotide transporter proteins in specific tissues of a transgenic nonhuman animal using a conditional knockin/knockout technology such as the Cre-LoxP, Flip-FLP recombinase, or Tet-on/off technologies. Specifically, the Ant2 gene is functionally inactivated in a mouse in liver, with or without the concurrent inactivation of the Ant1 gene. The result is an animal in which the Ant2 gene and accompanying ANT 2 protein is absent in one or more tissues, either in the presence or absence of the Ant1 gene and accompanying protein. The resulting animals, cells, mitochondria, and subcelluar fractions such as the mitochondrial permeability transition pore can then be used to identify agents that affect animal and/or subcellular function via a direct or indirect interaction with the ANT2 protein and/or its Ant2 gene.

Abstract: The present application describes methods for the testing of compounds of potential usefulness as therapeutic antioxidants and/or as therapeutic free radical scavengers. The animal model for testing such compounds is the Sod2CJE homozygous Manganese Superoxide Dismutase-deficient mouse. When pups of these mice are treated with certain antioxidants, they survive past about 7 days of age, and later develop characteristic histological changes and characteristic neurobehavioral disorders. Those treated mice can be further treated with test compounds which may or may not cross the blood brain barrier, and the life span and physical and neurobehavioral characteristics of those mice provide information about the potential utility of the test compound as a therapeutic antioxidant. Phenotypes of the treated mice allow conclusions regarding targeted areas of the brain and thus, applications to particular disorders such as Parkinsonism.

Abstract: The present application describes methods for the testing of compounds of potential usefulness as therapeutic antioxidants and/or as therapeutic free radical scavengers. The animal model for testing such compounds is the Sod2CJE homozygous Manganese Superoxide Dismutase-deficient mouse. When pups of these mice are treated with certain antioxidants, they survive past about 7 days of age, and later develop characteristic histological changes and characteristic neurobehavioral disorders. Those treated mice can be further treated with test compounds which may or may not cross the blood brain barrier, and the life span and physical and neurobehavioral characteristics of those mice provide information about the potential utility of the test compound as a therapeutic antioxidant. Phenotypes of the treated mice allow conclusions regarding targeted areas of the brain and thus, applications to particular disorders such as Parkinsonism.

Abstract: Provided are transgenic mice genetically engineered for a deficiency of the heart-skeletal muscle isoform of the adenine nucleotide translocator protein (Ant1). These mice exhibit histological, biochemical and physiological signs of deficiency in oxidative phosphorylation and energy generation, and these mice provide the first animal model for mitochondrial myopathy and hypertrophic cardiomyopathy. This animal model is used in methods for testing compounds for therapeutic value in treating failure to exchange ATP and ADP across the mitochondrial inner membrane, OXPHOS deficiency and in treating cardiac hypertrophy.

Abstract: The present invention provides an assay for diagnosing or predicting a predisposition to dystonia and/or Leber's Hereditary Optic Neuropathy by detecting the presence of a mutation in mitochondrial DNA, in the oxidative phosphorylation (OXPHOS) gene ND6, that causes a substitution in amino acid 72 of the ND6 polypeptide. In particular, the mutation can be at mtDNA position 14459. Also provided are therapeutic treatments for dystonia and/or Leber's Hereditary Optic Neuropathy, as well as methods of screening compounds for effectiveness in treating these diseases and an animal model.

Abstract: This invention provides a method of Alzheimer's disease and/or Parkinson's Disease. The method comprises detecting in a sample from a subject the presence of a mutation, for example, in nucleotide position 4,336, 3,397, 3,196 or an insertion between positions 956 and 965, of mitochondrial DNA. The presence of the mutation indicates the presence of or a predisposition to Alzheimer's and Parkinson's disease. Since each mutation increases the likelihood of developing or having Alzheimer's and Parkinson's disease, the detection of more than one of the mutations in an individual can increase the probability of having or developing the disease. The invention also provides a method of determining mutations associated with the presence of or predisposition to Alzheimer's and/or Parkinson's disease.

Abstract: The present invention relates to a method and manufacture for detecting neuromuscular disease, particularly Myoclonic Epilepsy and Ragged Red Fiber disease, by ascertaining whether a transition mutation has occurred at the 8344 nucleotide position in the mitochondrial DNA of a patient. The invention provides methods to detect this mutation including digestion of the patient's mtDNA with restriction endonucleases followed by analysis of the resulting fragments, differential hybridization of oligonucleotides, direct PCR sequencing and denaturing gradient gel electrophoresis.

Abstract: The present invention relates a method and manufacture for detecting neuromuscular disease, particularly Leber's hereditary optic neuropathy, by ascertaining whether a point mutation has occurred at the 11778 nucleotide position in the mitochondrial DNA of a patient. The invention provides methods to detect this mutation including digestion of the patient's mtDNA with restriction endonucleases followed by analysis of the resulting fragments, differential hybridization of oligonucleotides procedures, and differential PCR techniques.