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Defining Endoplasmic Reticulum Stress-Development Mitochondria Remodeling

Award Number: RF1NS125674
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Defining Endoplasmic Reticulum Stress-Development Mitochondria Remodeling - PROJECT SUMMARY Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are intricately linked in the onset and pathogenesis of numerous neurodegenerative diseases such as Alzheimer’s disease (AD) and related tauopathies including progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD). However, the pathologic relationship between ER stress and mitochondrial dysfunction in these diseases is currently poorly defined. Clinical, genetic, and biochemical evidence shows that imbalanced signaling through the PERK arm of the unfolded protein response (UPR) contributes to the neuronal dysfunction associated with many neurodegenerative diseases including those listed above. PERK integrates transcriptional and translational signaling to promote adaptive remodeling of mitochondrial proteostasis and function in response to acute ER stress. However, in response to chronic ER stress, PERK initiates apoptosis through complex mechanisms that involve mitochondrial dysfunction. This leads to the intriguing question: ‘How does PERK differentially regulate protective and pathologic aspects of mitochondrial function in response to varying levels of ER stress?’. We demonstrated that PERK-dependent translation attenuation promotes adaptive mitochondrial elongation in response to acute ER insults. Here, we will show that this change in mitochondrial morphology corresponds to PERK-dependent regulation of phospholipids within mitochondrial membranes. Intriguingly, changes in phospholipids are implicated in the pathogenesis of multiple neurodegenerative diseases. Further, mitochondrial phospholipids are key regulatory determinants for diverse aspects of mitochondrial biology including morphology, oxidative phosphorylation, and apoptosis. Here, we test the hypothesis that PERK-dependent regulation of mitochondrial phospholipids promotes adaptive remodeling of mitochondrial membranes during ER stress and that imbalances in this regulation contributes to the pathologic mitochondrial dysfunction observed during neurodegeneration. Using a combination of biochemical, metabolomic, and imaging-based approaches, we will define the molecular basis for PERK-dependent regulation of mitochondrial phospholipids and demonstrate the importance of this regulation in dictating mitochondrial morphology, cristae ultrastructure, and function in response to ER stress. Through these efforts, we will identify PERK-dependent regulation of mitochondrial phospholipids as a mechanism to adapt mitochondria in response to acute ER stress. Further, we will show that chronic PERK signaling induces pathologic alterations to mitochondrial phospholipids that contributes to the mitochondrial dysfunction associated with neurodegeneration. Collectively, our results will establish PERK-dependent remodeling of mitochondrial membrane phospholipids as a key determinant in dictating mitochondrial function in response to varying levels of ER stress. Further, our work will reveal new insights into the pathologic and therapeutic implications of PERK signaling on the mitochondrial dysfunction associated with the pathogenesis of neurodegenerative diseases including AD and related diseases.


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: 2026 ( Subtotal = $0 )
2026	2022	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/9/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/9/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $2,356,233 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/19/2022	NEW	$2,356,233
														Subtotal = $2,356,233

Grand Total All Awards = $2,356,233

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Defining Endoplasmic Reticulum Stress-Development Mitochondria Remodeling

Award Number: RF1NS125674

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/20/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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