Research Project: Deciphering and reversing the consequences of mitochondrial DNA damage
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Contributors
Funders
ID
EC.00073
Authors
Dunn, Cory David
Other
Publications
Reduced glucose sensation can increase the fitness of saccharomyces cerevisiae Lacking mitochondrial DNA
(Public Library of Science, 2016) Dunn, Cory David; Kavaklı, İbrahim Halil; Akdoğan, E.; Tardu, M.; Garipler, G.; Baytek, G.; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Yes; College of Engineering; College of Sciences
Damage to the mitochondrial genome (mtDNA) can lead to diseases for which there are no clearly effective treatments. Since mitochondrial function and biogenesis are controlled by the nutrient environment of the cell, it is possible that perturbation of conserved, nutrient-sensing pathways may successfully treat mitochondrial disease. We found that restricting glucose or otherwise reducing the activity of the protein kinase A (PKA) pathway can lead to improved proliferation of Saccharomyces cerevisiae cells lacking mtDNA and that the transcriptional response to mtDNA loss is reduced in cells with diminished PKA activity. We have excluded many pathways and proteins from being individually responsible for the benefits provided to cells lacking mtDNA by PKA inhibition, and we found that robust import of mitochondrial polytopic membrane proteins may be required in order for cells without mtDNA to receive the full benefits of PKA reduction. Finally, we have discovered that the transcription of genes involved in arginine biosynthesis and aromatic amino acid catabolism is altered after mtDNA damage. Our results highlight the potential importance of nutrient detection and availability on the outcome of mitochondrial dysfunction.
A bacteria-derived tail anchor localizes to peroxisomes in yeast and mammalian cells
(Nature Publishing Group (NPG), 2018) Akdoğan, Emel; Dunn, Cory David; Keskin, Abdurrahman; Lutfullahoglu-Bal, Guleycan; Seferoğlu, Ayşe Bengisu; Department of Molecular Biology and Genetics; Yes; College of Sciences
Prokaryotes can provide new genetic information to eukaryotes by horizontal gene transfer (HGT), and such transfers are likely to have been particularly consequential in the era of eukaryogenesis. Since eukaryotes are highly compartmentalized, it is worthwhile to consider the mechanisms by which newly transferred proteins might reach diverse organellar destinations. Toward this goal, we have focused our attention upon the behavior of bacteria-derived tail anchors (TAs) expressed in the eukaryote Saccharomyces cerevisiae. In this study, we report that a predicted membrane-associated domain of the Escherichia coli YgiM protein is specifically trafficked to peroxisomes in budding yeast, can be found at a pre-peroxisomal compartment (PPC) upon disruption of peroxisomal biogenesis, and can functionally replace an endogenous, peroxisome-directed TA. Furthermore, the YgiM(TA) can localize to peroxisomes in mammalian cells. Since the YgiM(TA) plays no endogenous role in peroxisomal function or assembly, this domain is likely to serve as an excellent tool allowing further illumination of the mechanisms by which TAs can travel to peroxisomes. Moreover, our findings emphasize the ease with which bacteria-derived sequences might target to organelles in eukaryotic cells following HGT, and we discuss the importance of flexible recognition of organelle targeting information during and after eukaryogenesis.
The endoplasmic reticulum-mitochondria encounter structure complex coordinates coenzyme q biosynthesis
(Sage, 2019) Dunn, Cory David; Eisenberg-Bord, Michal; Tsui, Hui S.; Antunes, Diana; Fernández-Del-Río, Lucía; Bradley, Michelle C; Nguyen, Theresa; Rapaport, Doron; Clarke, Catherine F; Schuldiner, Maya; Department of Molecular Biology and Genetics; No; College of Sciences
Loss of the endoplasmic reticulum (ER)-mitochondria encounter structure (ERMES) complex that resides in contact sites between the yeast ER and mitochondria leads to impaired respiration; however, the reason for that is not clear. We find that in ERMES null mutants, there is an increase in the level of mRNAs encoding for biosynthetic enzymes of coenzyme Q6 (CoQ6), an essential electron carrier of the mitochondrial respiratory chain. We show that the mega complexes involved in CoQ6 biosynthesis (CoQ synthomes) are destabilized in ERMES mutants. This, in turn, affects the level and distribution of CoQ6 within the cell, resulting in reduced mitochondrial CoQ6. We suggest that these outcomes contribute to the reduced respiration observed in ERMES mutants. Fluorescence microscopy experiments demonstrate close proximity between the CoQ synthome and ERMES, suggesting a spatial coordination. The involvement of the ER-mitochondria contact site in regulation of CoQ6 biogenesis highlights an additional level of communication between these two organelles.
Some liked it hot: a hypothesis regarding establishment of the proto-mitochondrial endosymbiont during eukaryogenesis
(Springer, 2017) Dunn, Cory David; Department of Molecular Biology and Genetics; No; College of Sciences
Eukaryotic cells are characterized by a considerable increase in subcellular compartmentalization when compared to prokaryotes. Most evidence suggests that the earliest eukaryotes consisted of mitochondria derived from an alpha-proteobacterial ancestor enclosed within an archaeal host cell. However, what benefits the archaeal host and the proto-mitochondrial endosymbiont might have obtained at the beginning of this endosymbiotic relationship remains unclear. In this work, I argue that heat generated by the proto-mitochondrion initially permitted an archaeon living at high temperatures to colonize a cooler environment, thereby removing apparent limitations on cellular complexity. Furthermore, heat generation by the endosymbiont would have provided phenotypic flexibility not available through fixed alleles selected for fitness at specific temperatures. Finally, a role for heat production by the proto-mitochondrion bridges a conceptual gap between initial endosymbiont entry to the archaeal host and a later role for mitochondrial ATP production in permitting increased cellular complexity.
Bacterial tail anchors can target to the mitochondrial outer membrane
(BioMed Central, 2017) Dunn, Cory David; Keskin, Abdurrahman; Lutfullahoglu-Bal, Guleycan; Seferoğlu, Ayşe Bengisu; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; Yes; College of Sciences; GRADUATE SCHOOL OF SCIENCES AND ENGINEERING
Background: During the generation and evolution of the eukaryotic cell, a proteobacterial endosymbiont was re-fashioned into the mitochondrion, an organelle that appears to have been present in the ancestor of all present-day eukaryotes. Mitochondria harbor proteomes derived from coding information located both inside and outside the organelle, and the rate-limiting step toward the formation of eukaryotic cells may have been development of an import apparatus allowing protein entry to mitochondria. Currently, a widely conserved translocon allows proteins to pass from the cytosol into mitochondria, but how proteins encoded outside of mitochondria were first directed to these organelles at the dawn of eukaryogenesis is not clear. Because several proteins targeted by a carboxyl-terminal tail anchor (TA) appear to have the ability to insert spontaneously into the mitochondrial outer membrane (OM), it is possible that self-inserting, tail-anchored polypeptides obtained from bacteria might have formed the first gate allowing proteins to access mitochondria from the cytosol. Results: Here, we tested whether bacterial TAs are capable of targeting to mitochondria. In a survey of proteins encoded by the proteobacterium Escherichia coli, predicted TA sequences were directed to specific subcellular locations within the yeast Saccharomyces cerevisiae. Importantly, TAs obtained from DUF883 family members ElaB and YqjD were abundantly localized to and inserted at the mitochondrial OM. Conclusions: Our results support the notion that eukaryotic cells are able to utilize membrane-targeting signals present in bacterial proteins obtained by lateral gene transfer, and our findings make plausible a model in which mitochondrial protein translocation was first driven by tail-anchored proteins.
