Novel Knock-in mtDNA Mouse Model to Study Mitochondrial Dysfunction - PROJECT SUMMARY / ABSTRACT
Mitochondrial dysfunction (MD) plays a central role in the pathophysiology of many human diseases
commonly referred as non-communicable diseases (NCDs). NCDs are non-infectious, non-transmissible
disorders characterized by low-grade chronic inflammation, among which the most common are obesity, insulin
resistance, diabetes, forms of cancer, cardiovascular diseases, and nonalcoholic fatty liver disease. NCDs affect
an estimated 41 million people each year. Additionally, MD has also been implicated in aging and age-related
diseases, including neurological disorders such as Alzheimer's disease and related dementias, which represent
the sixth-leading cause of death in the United States, with cost for long-term and hospice care calculated to be
around 200 billion dollars per year. One cause of MD is an increase in mitochondrial DNA (mtDNA) mutations
resulting in impaired oxidative phosphorylation that leads to loss of bioenergetic homeostasis, increased cell
apoptosis, and senescence. To address the role of mtDNA mutations on tissue/organ homeostasis, two
independent groups developed a knock-in mouse expressing a proofreading-deficient version of the nucleus-
encoded catalytic subunit of mtDNA polymerase-γ (PolgA). The mtDNA mutator mouse model demonstrates a
cause-and-effect relationship between slowly increasing somatic mtDNA mutation levels and several phenotypes
associated with aging that manifest much earlier in life, including reduced lifespan, weight loss, alopecia, anemia,
kyphosis, osteoporosis, sarcopenia, and loss of subcutaneous fat. Although this mouse model has been key to
understand the effect of mtDNA mutations driven MD on organismal health, the global MD results in overall
tissue/organ dysfunction and makes it difficult to dissect how different tissues are affected and compensate for
MD, since it has not possible to separate single organ dysfunction from other organs equally affected by MD.
Moreover, due to the overall marked and severe progeroid phenotypes that affect the auditory, visual, and
ambulatory systems in this model, it has not been possible to test how MD affects brain health and cognition. To
overcome this limitation, we have generated a novel knock-in inducible mtDNA mutator mouse (RJA-
PolgACDS/CDS) with both spatial and temporal regulation capabilities that will allow us to study the effect of mtDNA
mutation-induced MD in single tissues at different time-points. The overall goal of this proposal is to validate this
new mouse model and demonstrate its utility in studying the role of MD in a broad range of human diseases. We
will test its temporal and spatial inducibility by crossing it with a whole-body expressing Cre mouse (Aim 1) as
well as inducible (CreERT2) and muscle-specific (ACTA1-Cre) Cre-expressing mouse lines (Aim 2). The
proposed work is highly responsive in addressing important knowledge gaps in understanding the role of MD on
organ homeostasis, including its role on onset and progression of many human diseases. Successful completion
of this work will provide a novel and unique animal model to investigate the relationship between MD and several
diseases and will provide a novel platform to investigate therapeutic strategies to target these pathologies.
