Mitochondrial are integral to many aspects of cellular function.
We continue to discover new essential roles for mitochondria in
cell physiology. Therefore, it is not surprising that mitochondrial
dysfunction is associated with an ever-increasing number of human
diseases such as cancer, diabetes, infertility, and underlies aging
and neurodegenerative disorders. However, despite their importance,
fundamental questions regarding mitochondrial biology and disease
The Patel Lab uses a unique combination of evolutionary framework and functional experimentation to study the biology of mitochondrial DNA (mtDNA). While mtDNA encode genes that are essential for the eukaryotic cell, they can also be viewed as 'selfish' genetic entities trying to maximize their own short- and long-term evolutionary success, often at a great cost to their hosts. The Patel Lab studies the cellular and molecular mechanisms that mtDNA employ to behave 'selfishly' and their consequences on organismal development and physiology. We also study the defense mechanisms that eukaryotic host cells have evolved to detect and curb proliferation of 'selfish' mutant mtDNA, and to deal with their detrimental effects.
mtDNA can behave 'selfishly' in two ways. First, mutant mtDNA variants can directly compete with wildtype mtDNA. Most mutant mtDNA co-exist with wildtype mtDNA in a state of heteroplasmy, and only become pathogenic when their levels exceed a certain threshold. Using the developing germline in C. elegans as a model system, we aim to understand how mutant mtDNA can outcompete their wild type counterparts and can even expand at the expense of host fitness.
Second, mtDNA can behave 'selfishly' by directly competing with the interests of the nuclear genome. Mitochondria are maternally transmitted in most animals including humans. Lack of inheritance through males renders natural selection ineffective at removing mtDNA mutations that are deleterious to males but neutral or beneficial in females. Using powerful genetic tools in Drosophila and Caenorhabditis species, we seek to identify such male-harming mtDNA mutants and characterize their functional consequences. Because decreased male fitness is detrimental for the evolutionary success of the nuclear genome, nuclear-encoded suppressors are predicted to evolve. As with host-pathogen interactions, antagonistic evolution of mtDNA with nuclear suppressors is expected to result in a molecular arms race. We are interested in studying the dynamics of this arms race and its consequences on organismal biology.
Our ultimate aim is to gain fundamental insights into not only how mitochondrial dysfunction causes disease, but to also learn the general evolutionary principles that have the power to explain why and under what circumstances mitochondrial function breaks down. This approach promises to provide a unifying theory to explain origins of many diseases, which are currently viewed as a disparate set of disorders.
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