Dissection of COQ8 Signaling with Mass Spectrometry and Chemical Genetics Mitochondrial dysfunction contributes to the aging process, and properly functioning mitochondria can play a role in the defense against aging. Mitochondrial signaling in response to stress can increase lifespan, but the underling mechanisms are poorly defined. The long-term objectives of the proposed research are to define the mechanisms of mitochondrial signaling in aging and the defense against aging, and to develop methods to manipulate mitochondrial signaling pathways. By elucidating mitochondrial signaling that affects aging, we hope to contribute knowledge that will lead to the development of new therapeutic strategies to help people age well. The immediate objective of the proposed research is to dissect a crucial part of a mitochondrial signaling pathway that regulates coenzyme Q biosynthesis. Severe disruption of coenzyme Q biosynthesis can cause human disease, but mild disruption of coenzyme Q biosynthesis extends lifespan in model organisms. Coenzyme Q abundance decreases with age in human mitochondria, but it is not known if this change protects mitochondria from age-related decay, or potentiates the mitochondrial dysfunction known to be involved in aging. Gaps in our understanding of the link between coenzyme Q and aging call for further research into the regulation of coenzyme Q biosynthesis. COQ8 is a mitochondrial protein that is essential for coenzyme Q biosynthesis and the focus of this proposal. COQ8 is predicted to be an atypical kinase, and its signaling mechanisms are undefined. The proposed research will dissect COQ8 signaling with targeted proteomic and metabolomic mass spectrometry after manipulation of COQ8 through a combination of chemical and genetic perturbation.
The specific aims are to (Aim 1) identify the endogenous substrate(s) of COQ8, and (Aim 2) define the downstream effects of COQ8 signaling on the coenzyme Q biosynthesis pathway. Successful completion of these aims will provide new insight into coenzyme Q biosynthesis and mitochondrial signaling, both of which play prominent roles in aging and age-related diseases. Furthermore, the proposed research will develop analog-sensitive COQ8, a broadly applicable and valuable tool that will accelerate research on the relationship between coenzyme Q abundance and lifespan. This research will be carried out as part of a broader training program characterized by (a) a dynamic, interdisciplinary research group (b) a campus with a wide range of cutting-edge clinical and basic science aging research, (c) a commitment to mentorship from leaders in aging research, (d) excellent medical and graduate coursework, and (e) outstanding opportunities for clinical experiences in geriatric internal medicine.
As we age, changes in metabolism can cause significant disabilities, diseases, and a generally decreased quality of life. The proposed research will investigate the mechanisms by which mitochondria (centers of metabolic activity in cells) and coenzyme Q (a lipid that is central to metabolism) affect the aging process and age-related diseases. By studying mitochondria and coenzyme Q at the molecular level, we hope to gain knowledge that will lead to a better understanding of aging and generate new strategies to help people age well.
|Stefely, Jonathan A; Reidenbach, Andrew G; Ulbrich, Arne et al. (2015) Mitochondrial ADCK3 employs an atypical protein kinase-like fold to enable coenzyme Q biosynthesis. Mol Cell 57:83-94|
|Lohman, Danielle C; Forouhar, Farhad; Beebe, Emily T et al. (2014) Mitochondrial COQ9 is a lipid-binding protein that associates with COQ7 to enable coenzyme Q biosynthesis. Proc Natl Acad Sci U S A 111:E4697-705|
|Khadria, Ambalika S; Mueller, Benjamin K; Stefely, Jonathan A et al. (2014) A Gly-zipper motif mediates homodimerization of the transmembrane domain of the mitochondrial kinase ADCK3. J Am Chem Soc 136:14068-77|
|Hebert, Alexander S; Merrill, Anna E; Stefely, Jonathan A et al. (2013) Amine-reactive neutron-encoded labels for highly plexed proteomic quantitation. Mol Cell Proteomics 12:3360-9|