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Mitochondrial Energy Sensing and Neuronal Function

Award Number: R01NS115906
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: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2029

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Mitochondrial Energy Sensing and Neuronal Function - Neurons integrate multiple inputs and coordinate a series of molecular events to drive cellular function. During neurotransmission, electrical depolarization at the pre-synaptic axon is transduced to chemical signals that affect post-synaptic dendrites. Neurons depend on mitochondrial function for survival. At the center of mitochondrial function is the protonmotive force (PMF), an electrochemical proton gradient that coordinates metabolic signaling and energetic responses. The PMF acts like a ‘bioenergetic battery’ and the stored electrical energy is used to uptake metabolites, make ATP, alter reactive oxygen species production, and buffer cellular calcium signaling. The PMF is dynamic and fluctuates in biology to drive cellular differentiation and autophagy, while the loss of PMF is associated with neurodegeneration and cell death. Maintaining PMF is required for neuronal function, and the neuronal architecture offer unique cellular environments. Distinct neuronal regions have unique biological constraints and mitochondrial energetic demands. Likewise, mitochondrial morphology and function are also specialized in a compartment-dependent manner. How neurons fuel cellular processes and how individual mitochondrial populations modulate energetics in each neuronal compartment remains poorly understood in part due to the lack of tools offering cell-specific and spatiotemporal control of the PMF. This R01 renewal addresses this gap in the field by leveraging discoveries from the previous funding period, where we developed a novel optogenetic approach to independently control, both spatially and temporally, the PMF in vivo. The neuronal cell membrane potential integrates and regulates numerous facets of neuronal signaling and health. Much like the neuronal membrane potential, we propose that the mitochondrial PMF acts as a central integrator to transduce signaling and power a wide array of cellular pathways and functions. We hypothesize that neuronal responses to mitochondrial energetics are highly dependent on the timing, duration, and location of the mitochondrial perturbation. Controlling the PMF has been a long-standing challenge in mitochondrial biology. Here, we propose to use light to increase or decrease the PMF in distinct neuronal compartments and dissect the effects on neuronal function. Accumulating evidence demonstrates that altering energy status has wide ranging effects on neuronal function. We will determine the spatiotemporal tenets defining mitochondrial PMF signaling across neuronal compartments and how these signals affect neuronal activity and in vivo behavior. Addressing the neuropathologic heterogeneity of mitochondrial function in neurons will advance the field and define novel, targeted approaches to guide therapeutic strategies targeting neurodegeneration.


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 = $543,486 )
2025	2025	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	5/13/2025	COMPETING CONTINUATION	$101,843
2025	2025	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	12/13/2024	COMPETING CONTINUATION	$543,486
2025	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	5/13/2025	NON-COMPETING CONTINUATION	-$101,843
2025	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $543,486

Issue Date FY: 2024 ( Subtotal = $372,125 )
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/30/2024	NON-COMPETING CONTINUATION	$26,854
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/1/2023	NON-COMPETING CONTINUATION	$345,271
														Subtotal = $372,125

Issue Date FY: 2023 ( Subtotal = $383,632 )
2023	2023	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	1/30/2023	NON-COMPETING CONTINUATION	$38,361
2023	2023	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/25/2022	NON-COMPETING CONTINUATION	$345,271
														Subtotal = $383,632

Issue Date FY: 2022 ( Subtotal = $383,632 )
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/31/2022	NON-COMPETING CONTINUATION	$38,362
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/10/2021	NON-COMPETING CONTINUATION	$345,270
														Subtotal = $383,632

Issue Date FY: 2021 ( Subtotal = $396,385 )
2021	2021	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/11/2020	NON-COMPETING CONTINUATION	$356,749
2021	2021	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/11/2021	NON-COMPETING CONTINUATION	$39,636
														Subtotal = $396,385

Issue Date FY: 2020 ( Subtotal = $396,385 )
2020	2020	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/28/2020	NEW	$396,385
														Subtotal = $396,385

Grand Total All Awards = $2,475,645

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Mitochondrial Energy Sensing and Neuronal Function

Award Number: R01NS115906

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: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2029

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