Mitochondrial diseases caused by mutations in the mitochondrial DNA (mtDNA) are an important source of morbidity and mortality, yet only supportive care is available to affected patients. Mouse models of human disease are instrumental in the developing and testing new therapeutic modalities. So far, the lack of characterized mouse cell lines with mtDNA mutations and technologies to produce such mutations has made impossible routine development of mouse models for the diseases caused by mtDNA mutations. Therefore, the long-term GOAL of this application is to enable routine modeling of human mitochondrial diseases in mice. We propose to achieve this GOAL through (1) refining the methodology developed in the course of preliminary studies;(2) through the use of this methodology to generate a collection of mouse cell lines (3) through the characterization of this collection by sequencing and functional assays, and (4) through the generation of transmitochondrial mice carrying mtDNA mutations generated and characterized in aims 1-3. If successful, these studies will enable routine mouse modeling of mitochondrial disease. Moreover, the outcome of aims 1-3 should generate resources, which will facilitate the structure-function studies of mammalian respiratory complexes. This outcome will also enable generation of a collection of mouse cell lines containing all possible single-nucleotide substitutions in their mtDNA. Candidate: The candidate is a new investigator who received a tenure-track Assistant Professor position in the Department of Cell Biology and Neuroscience, University of South Alabama in 2004. Since then he has authored or co-authored 23 publications in peer-reviewed journals and one book chapter. Most recently, the candidate was invited and wrote a single-author, 20-page review for FEBS journal on the role of mitochondrial DNA in aging process. The candidate's immediate career goal is to secure RO1-level funding for upcoming tenure review. The long-term career goals involve developing a vigorous research program around two main research focused in his lab: the nature of diversity of genotype-phenotype correlations in mitochondrial diseases and mechanisms for the maintenance of mitochondrial DNA integrity. Environment: College of Medicine, University of South Alabama represents a vibrant mitochondrial research environment with 10 faculty members involved in mitochondrial research. Of those, four are senior level researchers (full Professors) and 6 are junior researchers. Both the Chairman and the Vice-Chair of the applicant's Department as well as four junior faculty are mitochondrial researchers. Mitochondrial research in the applicant's Department is supported by three RO1s and one R21.

Public Health Relevance

Animal (mouse) models of human disease are instrumental in developing and testing new therapeutic modalities, yet they are not available for mitochondrial diseases caused by mtDNA mutations. In this application we propose to generate transmitochondrial mice with mtDNA mutations to model human disease.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Research Project (R01)
Project #
5R01OD010944-04
Application #
8442897
Study Section
Therapeutic Approaches to Genetic Diseases (TAG)
Program Officer
O'Neill, Raymond R
Project Start
2010-06-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$341,303
Indirect Cost
$70,457
Name
University of South Alabama
Department
Biology
Type
Schools of Medicine
DUNS #
172750234
City
Mobile
State
AL
Country
United States
Zip Code
36688
Khozhukhar, Natalya; Spadafora, Domenico; Rodriguez, Yelitza et al. (2018) Elimination of Mitochondrial DNA from Mammalian Cells. Curr Protoc Cell Biol 78:20.11.1-20.11.14
Pei, Liming; Wallace, Douglas C (2018) Mitochondrial Etiology of Neuropsychiatric Disorders. Biol Psychiatry 83:722-730
Ferreira, C R; Goorden, S M I; Soldatos, A et al. (2018) Deoxysphingolipid precursors indicate abnormal sphingolipid metabolism in individuals with primary and secondary disturbances of serine availability. Mol Genet Metab 124:204-209
Zand, Katayoun; Pham, Ted D A; Li, Jinfeng et al. (2017) Resistive flow sensing of vital mitochondria with nanoelectrodes. Mitochondrion 37:8-16
Balczon, Ron; Morrow, K Adam; Zhou, Chun et al. (2017) Pseudomonas aeruginosa infection liberates transmissible, cytotoxic prion amyloids. FASEB J 31:2785-2796
Shokolenko, Inna N; Alexeyev, Mikhail F (2017) Mitochondrial transcription in mammalian cells. Front Biosci (Landmark Ed) 22:835-853
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
Wallace, Douglas C (2017) A Mitochondrial Etiology of Neuropsychiatric Disorders. JAMA Psychiatry 74:863-864
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
Barel, Ortal; Malicdan, May Christine V; Ben-Zeev, Bruria et al. (2017) Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy. Brain 140:568-581

Showing the most recent 10 out of 55 publications