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Regulation of Mitochondrial Function by Orphan Protein Phosphatases

Award Number: R01DK098672
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2013
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Regulation of Mitochondrial Function by Orphan Protein Phosphatases - PROJECT SUMMARY/ABSTRACT Mitochondria are centers of metabolism whose activities need to be calibrated to meet changing cellular needs. General dysfunction of these organelles is implicated in many common human disorders, including metabolic syndrome, type 2 diabetes, obesity, non-alcoholic fatty liver disease, heart failure, various cancers and neurodegenerative diseases, and general metabolic inflexibility, most often through unclear means. Defining the pathogenic mitochondrial alterations that contribute to these metabolic disorders and devising new therapeutic strategies to rectify them represent principal challenges in mitochondrial medicine. A potential contributor to this dysfunction is aberrant intra-mitochondrial protein phosphorylation—a process recognized as critical for pyruvate dehydrogenase regulation for more than 50 years, but relatively unexplored otherwise. Recent efforts from our laboratory and others have now revealed that mitochondrial proteins are replete with dynamic phosphorylation that changes reproducibly between healthy and diseased states, and that phosphorylation can alter the activities of proteins involved in core metabolic pathways. Furthermore, we have connected select protein dephosphorylation events to the poorly characterized matrix protein phosphatase PPTC7 and discovered that PPTC7 disruption in mice causes profound metabolic defects and neonatal death. Given these emerging findings, the premise of this project is that reversible phosphorylation may be widely important in calibrating mitochondrial metabolism, and that its mismanagement could contribute to the pathophysiology of mitochondria- related disorders. Rigorous new efforts to reveal how phosphorylation affects mitochondrial protein function and to define the phosphatases that target each site may ultimately enable a new therapeutic strategy focused on manipulation of the mitochondrial phosphorylation network. To this end, we have now extended our phosphoproteomic analyses to 10 mitochondrial phosphatase knockdown lines using a CRISPRi system. This rich dataset forges many unique connections between phosphatases and phosphoproteins and forms the foundation for the further work proposed here. Based on these findings, we propose 1) to establish the functional impact of phosphorylation on putative PPTC7 and HDHD5 substrates involved in core mitochondrial catabolic pathways, including branched chain amino acid and fatty acid catabolism, and 2) to define the role of PGAM5 in regulating mitochondrial cristae architecture by managing an extensive set of phosphorylation events on subunits of the mitochondrial contact site and cristae organizing system (MICOS). Altogether, through a comprehensive approach that combines mammalian physiology, omics-level analyses, and rigorous biochemistry, we aim to make definitive connections between mitochondrial phosphatases and their substrates, establish a broad framework for understanding the role of this post-translation modification in calibrating mitochondrial activities, and ultimately pave the way for a new therapeutic strategy to rectify mitochondrial dysfunction.


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 = $451,295 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	11	5/16/2025	NON-COMPETING CONTINUATION	$451,295
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	3/31/2025	COMPETING CONTINUATION	$249
2025	2022	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	3/31/2025	NON-COMPETING CONTINUATION	-$249
														Subtotal = $451,295

Issue Date FY: 2024 ( Subtotal = $451,295 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	8/3/2024	COMPETING CONTINUATION	$451,295
														Subtotal = $451,295

Issue Date FY: 2022 ( Subtotal = $431,047 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	5/25/2022	NON-COMPETING CONTINUATION	$431,047
														Subtotal = $431,047

Issue Date FY: 2021 ( Subtotal = $443,874 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	5/14/2021	NON-COMPETING CONTINUATION	$443,874
2021	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	7/31/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$124,299
2021	2019	MORGRIDGE INSTITUTE FOR RESEARCH, INC., THE	330 N ORCHARD ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	7/31/2021	COMPETING CONTINUATION	-$124,299
														Subtotal = $443,874

Issue Date FY: 2020 ( Subtotal = $465,365 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	7/22/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$465,365
2020	2019	MORGRIDGE INSTITUTE FOR RESEARCH, INC., THE	330 N ORCHARD ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	7/21/2020	COMPETING CONTINUATION	$0
														Subtotal = $465,365

Issue Date FY: 2019 ( Subtotal = $518,632 )
2019	2019	MORGRIDGE INSTITUTE FOR RESEARCH, INC., THE	330 N ORCHARD ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	6/18/2019	COMPETING CONTINUATION	$518,632
2019	2019	MORGRIDGE INSTITUTE FOR RESEARCH, INC., THE	330 N ORCHARD ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	6/20/2019	COMPETING CONTINUATION	$13
2019	2017	MORGRIDGE INSTITUTE FOR RESEARCH, INC., THE	330 N ORCHARD ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	6/20/2019	NON-COMPETING CONTINUATION	-$13
														Subtotal = $518,632

Issue Date FY: 2017 ( Subtotal = $301,611 )
2017	2017	MORGRIDGE INSTITUTE FOR RESEARCH, INC., THE	330 N ORCHARD ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/17/2017	NON-COMPETING CONTINUATION	$271,449
2017	2017	MORGRIDGE INSTITUTE FOR RESEARCH, INC., THE	330 N ORCHARD ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	6/15/2017	NON-COMPETING CONTINUATION	$30,162
														Subtotal = $301,611

Issue Date FY: 2016 ( Subtotal = $306,381 )
2016	2016	THE MORGRIDGE INSTITUTE FOR RESEARCH INC	330 NORTH ORCHARD STREET	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	2/29/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$301,611
2016	2016	THE MORGRIDGE INSTITUTE FOR RESEARCH INC	330 NORTH ORCHARD STREET	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	6/9/2016	SUPPLEMENT FOR EXPANSION	$4,770
2016	2015	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/26/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $306,381

Issue Date FY: 2015 ( Subtotal = $323,823 )
2015	2015	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/27/2015	NON-COMPETING CONTINUATION	$323,823
														Subtotal = $323,823

Issue Date FY: 2014 ( Subtotal = $323,823 )
2014	2014	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/3/2014	NON-COMPETING CONTINUATION	$323,823
														Subtotal = $323,823

Issue Date FY: 2013 ( Subtotal = $323,823 )
2013	2013	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/4/2013	NEW	$323,823
														Subtotal = $323,823

Grand Total All Awards = $4,340,969

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Regulation of Mitochondrial Function by Orphan Protein Phosphatases

Award Number: R01DK098672

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2013

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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