Basic Concepts
The incidence of common, metabolic diseases thought to have complex genetic etiologies have steadily increased worldwide for the past few decades. Consequently, identification and pursuit of genetic models that explain disease risk and mechanisms for development are required, and yet no clear paradigm has been identified that can sufficiently and consistently explain the genetic basis of these diseases.
The evolution of the eukaryotic cell involved a symbiotic interaction between the antecedents of the mitochondrion and nucleus. This history provides a basis for investigating whether genetic interaction and co-evolution of the nuclear and mitochondrial genomes exists, and moreover, provides a logical means for explaining aspects of disease development and risk from a genetic perspective.
Our laboratory investigates both mitochondrial and Mendelian genetics (Mito-Mendelian) in the role of programming and regulating cell function associated with common disease. The Mito-Mendelian paradigm contemplates the natural variation and co-evolution of both mitochondrial and nuclear DNA backgrounds on multiple mitochondrial functions, including energy production, cell signaling and immunity, and how these processes respond to changes in the cellular environment – our hypothesis is that alterations in these systems due to different mitochondrial – nuclear DNA pairings can collectively influence disease development. At the nexus of these systems is the economy of mitochondrial metabolism (how efficient the organelle converts electron flow into heat, ATP and oxidants) which is programmed by Mito-Mendelian genetics.
Current Disease and Focus Areas
- The role of mitochondrial metabolism in chronic heart disease and recovery from acute (myocardial infarction) cardiac events.
- Mitochondrial – Nuclear genetic interactions (Mito-Mendelian genetics) and its role in programming metabolism that influences fundamental pathways important in disease susceptibility.
- The role of mitochondrial metabolism in initiating innate immune response when challenged by cardiovascular/cardiometabolic risk factors that drive metabolic disease development.
The overall goal of these studies is to understand the fundamental genetic basis for common disease development, which we hypothesize is the result of interactions between the nuclear (Mendelian) and mitochondrial metabolic program (influenced by the mtDNA) that interface with changing environmental stressors.
Research Overview: Rationale
Because the genetic selection processes for mitochondrial – nuclear interaction are influenced by survival and reproductive success, the changing environmental challenges from original prehistoric conditions to contemporary (along with increased lifespan) have significantly affected cell function. In this regard, our work explores the influence of mito-Mendelian genetics upon bioenergetics, inflammation, metabolism, and nuclear gene expression. For these studies, we invented and developed Mitochondrial – Nuclear eXchange (MNX) animal models that enable unambiguous testing of mitochondrial and nuclear genetic backgrounds upon cell function and disease development. From this research, it is becoming clear that mito-Mendelian genetics influences cell function and response to acute and chronic stimuli.
These findings are consistent with the hypothesis that the genetic basis for most common diseases is not based solely upon Mendelian or Mitochondrial genetics, but is the consequence of mito-Mendelian genetics. Current laboratory projects investigate the role for mito-Mendelian genetics in the metabolic programming of the cell, and its role in determining how the cell responds to a variety of known disease risk factors.
Research Overview: Original Reports
Our laboratory has published several reports supporting the concept that mito-Mendelian genetics significantly impacts common disease susceptibility using MNX mouse models.
Fetterman et al, 2013, Biochemical Journal https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807257/
This was the first report that directly tested and documented the role of different nuclear – mitochondrial genetic combinations on disease susceptibility. In this manuscript, different mtDNAs on the same nuclear background are shown to increase or decrease individual susceptibility to cardiac volume overload – a characteristic often associated with mitral or aortic regurgitation. The main findings of this work were that different nuclear – mitochondrial genetic combinations changed features of mitochondrial metabolism that significantly influenced individual response to left ventricular overload. These studies were among the first to provide direct evidence for a “mito-Mendelian” basis of disease.
Feeley et al, 2015, Cancer Research
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610037/
This report tested the impact of different mtDNA backgrounds on the same nuclear background using a mouse model of metastatic cancer. The main findings were that different mtDNA backgrounds on the same nuclear background changed tumor latency and metastatic load.
Dunham-Snary and Ballinger, 2015, Science
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238407/
This report discusses the need for accounting individual nuclear and mitochondrial genome combinations in gene therapy approaches and general consideration of “mito-Mendelian” genetics in the development of common disease.
Kesterson et al., 2016, Bioprotocol
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100744/
This report describes in detail, the approach, methods, and considerations in making Mitochondrial – Nuclear eXchange (MNX) mouse models.
Krzywanski et al., 2016, Circulation Cardiovascular Genetics
https://pubmed.ncbi.nlm.nih.gov/26787433/
This report characterized mitochondrial function and measures of mitochondrial stress in endothelial cells having distinct mitochondrial genetic backgrounds. Results showed that differences in mitochondrial genetics and mitochondrial DNA damage was associated with maternal ancestry, which also associated with differences in vascular function, remodeling, and age of cardiovascular disease onset in patients.
Dunham-Snary et al., 2019 EBioMedicine
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197375/
This report showed that different nuclear-mitochondrial genetic combinations significantly altered whole body metabolism, metabolic efficiency, body composition, and importantly gene expression in response to diet. The main findings were that mito-Mendelian genetics has significant impact upon stress induced metabolism, body composition, and changes in gene expression.
Kandasamy et al., 2019, AJP-Lung Cell Mol Physiol
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962596/
This report examined whether different nuclear-mitochondrial genetic combinations significantly influenced the impact of hyperoxia therapy on neonates with premature lung development, in terms of mitochondrial function, pulmonary function and histology. The main findings were that mtDNA haplogroup variation induced differences in mitochondrial function that could modify neonatal alveolar development and brochopulmonary dysplasia susceptibility.
Brown et al., 2020 Redox Biology
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281786/
This is a comprehensive review that articulates the basis for a mito-Mendelian genetic perspective for disease risk and development.
Sammy et al., 2021, AJP-Endocrinol Metab.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560378/
This report showed that different mitochondrial genetic backgrounds on the same nuclear background significantly altered glucose metabolism and insulin sensitivity, which also directly associated with age-related changes in body composition.
