Mitochondrial diseases caused by mutations in mitochondrial DNA (mtDNA) are a significant source of morbidity and mortality, yet only supportive care is available to affected patients. This lack of effective therapies can be partly attributed to the lack of faithful animal models for mitochondrial diseases caused by mutations in mtDNA. Two critical obstacles to the availability of mouse models of these diseases are 1) the lack of mouse mtDNA mutations homologous to those found in human disease, and 2) the lack of a method to efficiently generate such mutations. Therefore, the long-term goals of the proposed studies are 1) to overcome these obstacles in order to enable routine modeling of human diseases caused by mtDNA mutations, and 2) to provide mouse models of mitochondrial disease to the research community. In this application, we propose to leverage expertise developed at the University of South Alabama (mutagenesis of mouse mtDNA) and Children's Hospital of Philadelphia (transmitochondrial mouse models) towards generating models of human diseases caused by mutations in mitochondrially-encoded tRNA genes. Using the tools and techniques developed in the previous funding cycle and in preliminary studies, we will 1) generate an arrayed library of mouse clones carrying mutations in mtDNA, 2) use it to perform a targeted screening for mutations in tRNALeuUUR and in tRNALys, and 3) use these mutations as well as tRNA mutations isolated by us previously for the generation and characterization of transmitochondrial animals. It is anticipated that, if successful, the proposed studies will deliver a powerful impetus to mitochondrial research in general and to research on mitochondrial disease in particular by providing the mitochondrial research community with (1) mouse model(s) for mitochondrial disease caused by mutations in tRNA genes, (2) an arrayed library of mouse clones suitable for targeted screening for mtDNA mutations of interest as well as tools and protocols for generating and screening such libraries, and (3) cell line(s) carrying mouse homolog(s) of human pathogenic mtDNA mutations.

Public Health Relevance

Mouse models of human disease are instrumental for the development and testing of new therapeutic modalities, yet faithful models are not available for diseases caused by mutations in mitochondrial DNA. In order to fulfill this unmet need, we aim to leverage our combined expertise in mtDNA mutagenesis and transmitochondrial animals, respectively, towards mouse modeling of mitochondrial disease.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
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Therapeutic Approaches to Genetic Diseases Study Section (TAG)
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Mirochnitchenko, Oleg
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University of South Alabama
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Barel, Ortal; Christine V Malicdan, May; Ben-Zeev, Bruria et al. (2017) Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy. Brain 140:568-581
Zand, Katayoun; Pham, Ted D A; Li, Jinfeng et al. (2017) Resistive flow sensing of vital mitochondria with nanoelectrodes. Mitochondrion 37:8-16
Shokolenko, Inna N; Alexeyev, Mikhail F (2017) Mitochondrial transcription in mammalian cells. Front Biosci (Landmark Ed) 22:835-853
Kim, Chul; Potluri, Prasanth; Khalil, Ahmed et al. (2017) An X-chromosome linked mouse model (Ndufa1S55A) for systemic partial Complex I deficiency for studying predisposition to neurodegeneration and other diseases. Neurochem Int 109:78-93
Balczon, Ron; Morrow, K Adam; Zhou, Chun et al. (2017) Pseudomonas aeruginosa infection liberates transmissible, cytotoxic prion amyloids. FASEB J 31:2785-2796
Morrow, Ryan M; Picard, Martin; Derbeneva, Olga et al. (2017) Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity. Proc Natl Acad Sci U S A 114:2705-2710
Angelin, Alessia; Gil-de-Gómez, Luis; Dahiya, Satinder et al. (2017) Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments. Cell Metab 25:1282-1293.e7
Chalkia, Dimitra; Singh, Larry N; Leipzig, Jeremy et al. (2017) Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders. JAMA Psychiatry 74:1161-1168
Kandel, Judith; Picard, Martin; Wallace, Douglas C et al. (2017) Mitochondrial DNA 3243A>G heteroplasmy is associated with changes in cytoskeletal protein expression and cell mechanics. J R Soc Interface 14:
Wallace, Douglas C (2016) Genetics: Mitochondrial DNA in evolution and disease. Nature 535:498-500

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