mtDNA depleter mouse for decoding mitochondrial regulation of diverse organs

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This application is responsive to PAR-19-369 “Development of Animal Models and Related Biological Materials for Research R21,” which seeks application to develop animal models that are applicable to the research interests of multiple NIH institutes. It addresses one of the objective “Characterization of new and significantly improved genetically modified animal models that are applicable to diseases that impact multiple body systems, e.g., animal models with mitochondrial defects.” Impaired mitochondrial function is associated with many primary mitochondrial diseases in which mitochondrial dysfunction is the primary cause of the disease. Notably, mtDNA depletion syndromes (MDS) are characterized by a severe reduction in mtDNA content leading to impaired mitochondrial function in affected tissues and organs. Secondary mitochondrial diseases in which mitochondria are secondarily involved include cardiovascular, diabetes, obesity, neurological disorders, and cancer. Moreover, a general decline in mitochondrial function is extensively reported during aging and is known to be a driving force underlying age-related human diseases. Despite the enormous importance of mitochondria in the optimal function of various organs, the in vivo role of mitochondria in the vast majority of mammalian organs remain unknown. Mitochondrial DNA polymerase γ (POLG1) is the only DNA polymerase involved in the synthesis of mtDNA. We developed an inducible mouse expressing, in the polymerase domain of POLG1, a dominant-negative (DN) mutation (an aspartic acid to alanine (D to A) mutation at position 1135, that induces depletion of mtDNA in the whole animal. Our preliminary studies suggest that impaired mitochondrial function in the whole animal results in multisystem dysfunction. These include the development of skin wrinkles and hypertrophy of the liver, kidney, heart and spleen. Furthermore, mtDNA depleter mice show atrophy of male and female reproductive organs. Based on these observations, we hypothesize that the characterization of mtDNA depleter mice will facilitate the understanding of the vital function of mitochondria in the development and function of multiple organ systems. We propose two specific aims to test this hypothesis: Aim 1: Determine the organ-specific hypertrophic and atrophic pathology associated with mitochondrial dysfunction in mtDNA depleter mouse Aim 2: Identify organ specific mitochondrial stress response mechanisms underlying hypertrophy and atrophy. Our long-term goal is to enable the widespread use of this mouse model, which will accelerate mitochondrial research across various organs and diseases. The mouse will be useful in diverse research areas relevant to the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, the National Heart, Lung and Blood Institute, the National Institute of Child and Human Development, and the National Institute of Neurological Disorders and Stroke, the National Cancer Institute, the National Institute of Allergy and Infectious Diseases and Center for Women’s health.