Full metadata
Title
PANK2’s Role in Controlling Cellular Coenzyme A Dynamics
Description
Free coenzyme A (CoASH) carries acyl groups for the tricarboxylic acid (TCA) cycle and fatty acid metabolism, and donates acyl groups for protein posttranslational modifications. Cellular de novo CoASH synthesis starts with a pantothenate kinase (PANK1-3) phosphorylating pantothenate (vitamin B5). Mutations in PANK2 cause a subtype of neurodegeneration with brain iron accumulation (NBIA). The PANKs have differential subcellular distribution and regulatory properties. However, the purpose of each PANK has remained obscure, with knockout mouse models presenting with mild phenotypes unless challenged with a high-fat diet. Based on PANK2’s known activation by palmitoylcarnitine, the PANK2-deficient cells were challenged with palmitic acid (PAL) added to glucose-containing media. The high nutrient mixture generated a surprising “starvation” profile of reduced proliferation, low ATP, AMPK activation, and autophagy upregulation in PANK2-deficient PAL-challenged cells. Further experiments showed that fatty acids accumulated and that PANK2-deficient cells had reduced respiration when provided with palmitoylcarnitine as a substrate, seemingly due to an impaired ability to oxidize fatty acids during PAL-induced Randle Cycle activation. Intriguingly, whole-cell CoASH levels remained stable despite the PAL-induced starvation phenotype, and increasing CoASH via PANK1β overexpression did not rescue the phenotype, demonstrating a unique role for PANK2 in fatty acid metabolism. Even though a direct CoASH deficiency was not detected, there were changes in short chain CoA-derivatives, including acetyl-CoA, succinyl-CoA, and butyryl-CoA, as well as evidence of impaired TCA cycle function. These impairments in both the TCA cycle and fatty acid oxidation implicate a role for PANK2 in regulating mitochondria CoA dynamics.
Date Created
2022
Contributors
- Nordlie, Sandra Maria (Author)
- Kruer, Michael C (Thesis advisor)
- Neisewander, Janet (Thesis advisor)
- Padilla Lopez, Sergio (Committee member)
- Katsanos, Christos (Committee member)
- Arizona State University (Publisher)
Topical Subject
Resource Type
Extent
113 pages
Language
eng
Copyright Statement
In Copyright
Primary Member of
Peer-reviewed
No
Open Access
No
Handle
https://hdl.handle.net/2286/R.2.N.168687
Level of coding
minimal
Cataloging Standards
Note
Partial requirement for: Ph.D., Arizona State University, 2022
Field of study: Molecular and Cellular Biology
System Created
- 2022-08-22 06:10:45
System Modified
- 2022-08-22 06:11:09
- 2 years 2 months ago
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