Mitochondria are centers of metabolism and signaling whose function is essential to all but a few eukaryotic cell types. General dysfunction of these organelles is implicated in a wide range of inborn errors of metabolism, and in an increasing number of common human diseases. Elucidation of the biochemical functions of these disease-related proteins has become a bottleneck in understanding mitochondrial pathophysiology. This proposal initially focuses on one such protein, ADCK3, a predicted kinase with a poorly understood connection to the biosynthesis of coenzyme Q, an integral part of the mitochondrial electron transport chain. Mutations in this protein can cause a form of cerebellar ataxia, one of numerous mitochondrial respiratory chain disorders. More broadly, ADCK3 is part of a large and ancient family of predicted atypical kinases-the UbiB family-that has no structural or functional characterization reported to date. This proposal will establish the fundamental enzymatic properties of this archetypal member of the UbiB family, identify its direct endogenous substrate(s), and test the hypothesis that it functions to remodel the protein infrastructure of th inner mitochondrial membrane through alterations in the local phospholipid environment. Leveraging the depth and breadth of expertise available through the investigators of this program project, the proposed work incorporates a diverse range of tools to address these goals, including: a robust, high mass-accuracy lipidomics platform and yeast, mammalian cell culture and mouse knockout models of ADCK3 deficiency. As the characterization of ADCK3 progresses, the approaches and techniques established here will subsequently be applied to the other ADCK kinases that are generally conserved from yeast through metazoans. These kinases include four in human mitochondria (ADCK1, 2, 4 and 5), which have now been associated both with lipid metabolism and with specific cancers, including glioblastoma multiforme (GBM) and estrogen receptor-positive (ER+) breast tumors. Thus, in addition to the direct insights that will be generate regarding the specific function of ADCK3, this work sets the stage for an extensive analysis of a unique mitochondrial kinase family of mounting biomedical importance.

Public Health Relevance

Mitochondrial dysfunction is implicated in a wide range of rare and common human diseases, yet the biological functions of the mutated proteins underlying these diseases are predominantly unknown. This proposal aims to elucidate the basic enzymatic functions and direct substrate(s) of ADCK3, an archetypal member of the large and uncharacterized UbiB family of predicted atypical kinases, which is mutated in human cerebellar ataxias. Completion of these goals will be important first steps toward establishing the molecular etiology of a mitochondrial disease and understanding the biochemical functions of a unique kinase family of mounting biomedical importance.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM112057-04
Application #
9054123
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Anderson, Vernon
Project Start
2014-08-01
Project End
2018-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Morgridge Institute for Research, Inc.
Department
Type
DUNS #
012420082
City
Madison
State
WI
Country
United States
Zip Code
53715
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Reidenbach, Andrew G; Kemmerer, Zachary A; Aydin, Deniz et al. (2018) Conserved Lipid and Small-Molecule Modulation of COQ8 Reveals Regulation of the Ancient Kinase-like UbiB Family. Cell Chem Biol 25:154-165.e11
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