The goal of this proposal is to understand how mutations and inhibitors that disrupt general mitochondrial functions can cause syndromes with marked tissue specificity. This team is developing new experimental models in which they can exploit the powerful genetic tools in Drosophila to bear on this question. The intent is to test whether tissue specificity of genetic and chemical stressors occurs because they target interactions between general mitochondrial functions and tissue specific genes. A particular mutant of Drosophila Cytochrome oxidase subunit 1 is male sterile, and otherwise normal. It is hypothesized that this highly specific phenotype is the result of failure by this allele to work in conjunction with a testis specific isoform of one of the other respiratory chain proteins. Indeed, ectopic expression of the somatic version of Cytochrome c in testis suppresses the sterility phenotype. The proposed experiments will rigorously test whether this sterility is due to a specific deficit in the partnership of the mutant Cytochrome oxidase and the testis specific isoform of Cytochrome c. Additionally, the fly eye will be engineered as a biosensor for disruption of isoform-specific interactions of mitochondrial functions, and will be applied to identify mutations and chemicals interfering with these interactions. Tissue specificity resulting from synergy of two defects will also be examined, where a tissue specific alteration sensitizes the tissue to diverse genetic and chemical stressors. Eye specific knockdown of E2F compromised growth to produce a slightly reduced eye. It also sensitized the eye to mitochondrial stress. A low dose of oligomycin that is without notable effect in other tissues, synergizes with E2F:RNAi in the eye to produce tissue transformations (e.g. antennae growing out of the eye) and hypertrophy. It is hypothesized that this dysgenesis/hypertrophy relies on two inputs with a biologically universal relationship. Any mutation that inhibits growth of a specific tissue creates a selective environment favoring cells that can escape the growth limitation by transforming to another cell type (transdetermination). A second stress that destabilizes developmental fate would produce the fodder for this selection. Mitochondrial stress appears to provide this destabilizing input. This model will be tested and screened for natural mutations and environmental chemicals contributing to the synergizing inputs. Since mammals express numerous proteins as tissue-specific isoforms, they carry many genes that can mutate to create a selection for transdetermination. Without synergizing input, these mutations would have little impact and could accumulate. Thus, it is suspected that the human population has a large and insidious pool of """"""""polymorphisms"""""""" that creates a diversity of chemical sensitivities. Recognition of sensitizing mutations should empower application of DNA sequencing to personalized health-care.
Project Narrative Chemicals or mutations that prevent mitochondria from fulfilling their role as the primary providers of cellular energy cause death, whereas mild mitochondrial stress causes surprisingly complex disruptions in human health. We have developed powerful experimental model in which we will investigate the basis for the complexity of the health defects, and in which we can explore the possibility that chemical perturbation of mitochondrial function has more pervasive influence on human health than is generally recognized.
|Yu, Zhongsheng; O'Farrell, Patrick H; Yakubovich, Nikita et al. (2017) The Mitochondrial DNA Polymerase Promotes Elimination of Paternal Mitochondrial Genomes. Curr Biol 27:1033-1039|
|Ma, Hansong; O'Farrell, Patrick H (2016) Selfish drive can trump function when animal mitochondrial genomes compete. Nat Genet 48:798-802|
|O'Farrell, Patrick H (2015) Growing an Embryo from a Single Cell: A Hurdle in Animal Life. Cold Spring Harb Perspect Biol 7:|
|Ma, Hansong; O'Farrell, Patrick H (2015) Selections that isolate recombinant mitochondrial genomes in animals. Elife 4:|
|Ma, Hansong; Xu, Hong; O'Farrell, Patrick H (2014) Transmission of mitochondrial mutations and action of purifying selection in Drosophila melanogaster. Nat Genet 46:393-7|
|DeLuca, Steven Z; O'Farrell, Patrick H (2012) Barriers to male transmission of mitochondrial DNA in sperm development. Dev Cell 22:660-8|