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Novel roles of PDK4 in regulating mitochondrial protein phosphorylation, carbon flux and metabolic resilience

Award Number: R01DK129488
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Novel roles of PDK4 in regulating mitochondrial protein phosphorylation, carbon flux and metabolic resilience - ABSTRACT This project aims to understand of how mitochondrial carbon trafficking and bioenergetics are regulated by pyruvate dehydrogenase kinase 4 (PDK4), a protein that is highly responsive to nutrient and energetic cues and one that has received much attention as a potential therapeutic target. PDK4 is a member of a family of pyruvate dehydrogenase kinase enzymes (PDK1-4) that phosphorylate and inactive the mitochondrial pyruvate dehydrogenase complex (PDC). By converting pyruvate to acetyl-CoA, the PDC connects glycolysis to the tricarboxylic acid cycle (TCAC), which generates reducing equivalents needed for ATP synthesis. Notably, PDK4 is one of the most robustly induced genes/proteins in response to acute energy stresses–such as fasting, exercise and consumption of a high fat meal. PDK4 is also strongly induced by acute exposure to fatty acids and/or other ligands that activate the PPAR family of transcription factors. This remarkable level of nutrient/energy-induced regulation is unique to PDK4 (as compared with PDKs1-3), raising the possibility that PDK4 has distinct metabolic functions. The major conceptual innovation and central premise of this proposal stems from new and exciting evidence from our laboratory that PDK4 phosphorylates and regulates proteins beyond the PDC. Preliminary studies used mass spectrometry-based proteomics to assess the phospho- proteome of hearts and/or skeletal muscles from mice in which the PDK4 gene was overexpressed or ablated. In aggregate, the findings support a working model wherein PDK4 phosphorylates and regulates multiple mitochondrial enzymes and proteins in response to lipid stress. Accordingly, the project seeks to test hypothesis that PDK4 plays a central role in mediating lipid-induced phosphorylation of mitochondrial proteins beyond the PDC, which in turn modulates carbon trafficking and bioenergetics in manner that confers metabolic resilience. To test this hypothesis, we will combine gain- and loss-of-function mouse models with several state-of-the-art molecular profiling tools (mass spectrometry-based proteomics, phospho-proteomics, metabolomics and stable isotope metabolic flux analysis), a sophisticated mitochondrial diagnostics platform, and comprehensive physiological assessments to delineate the PDK4 interactome and its critical physiological functions.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $571,434 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/18/2025	NON-COMPETING CONTINUATION	$571,434
														Subtotal = $571,434

Issue Date FY: 2024 ( Subtotal = $617,385 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/8/2024	NON-COMPETING CONTINUATION	$38,587
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/12/2024	NON-COMPETING CONTINUATION	$578,798
														Subtotal = $617,385

Issue Date FY: 2023 ( Subtotal = $651,498 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/31/2023	NON-COMPETING CONTINUATION	$651,498
														Subtotal = $651,498

Issue Date FY: 2022 ( Subtotal = $660,100 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/6/2022	NEW	$660,100
														Subtotal = $660,100

Grand Total All Awards = $2,500,417

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Novel roles of PDK4 in regulating mitochondrial protein phosphorylation, carbon flux and metabolic resilience

Award Number: R01DK129488

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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