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 ¿ (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.