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Determining the Role of Mitochondrial Hydrogen Peroxide in the Regulation of Neuronal Mitochondrial Networks

Award Number: F30NS143384
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Determining the Role of Mitochondrial Hydrogen Peroxide in the Regulation of Neuronal Mitochondrial Networks - ABSTRACT The brain consumes nearly 20% of the body’s ATP despite accounting for only 2% of body weight, highlighting its disproportionate energy demand. As the cells of the brain also exhibit a limited regenerative capacity, sustained bioenergetic failure often results in a permanent loss of cognitive, sensorimotor, and autonomic function. While neurodegenerative and neurodevelopmental conditions are often multifactorial, one common theme observed across these diseases is altered metabolic homeostasis. To meet the tremendous energetic demands of intercellular communication, neurons rely on highly efficient ATP production via mitochondrial oxidative phosphorylation (OxPhos). In addition to ATP, OxPhos yields reactive oxygen species (ROS) shown to oxidize cellular lipids, proteins, and nucleic acids. While decades of research have investigated the consequences of ROS accumulation in various pathologies and aging, the role of ROS in healthy neuronal function is incompletely understood. Membrane-diffusible mitochondrial hydrogen peroxide (mtH2O2), a specific form of ROS, has become the focus of recent research due to its reported interactions with redox modifiable cysteine residues – coined redox switches. As mtH2O2 is produced in the mitochondrial matrix in a metabolic performance dependent manner, it likely exhibits direct influence on local mitochondrial dynamics to shape metabolism and maintain a healthy mitochondrial network. Our preliminary data in primary mouse cortical neurons suggests that mtH2O2 serves a regulatory role in mitochondrial fission/fusion balance. Following attenuation of mtH2O2 via depletion of superoxide dismutase 2 (SOD2), we observed a reduction in mitochondrial size within neuronal dendrites. To ascertain if this change in size is a result of impaired mitochondrial fission/fusion balance, we performed time lapse fluorescent microscopy on live primary neurons and found that while SOD2 ablation decreases the frequency of both fission and fusion events, it preferentially inhibits fusion. Thus, we hypothesize that mtH2O2 dictates local neuronal mitochondrial dynamics. We have devised two independent aims to test this hypothesis. In the first aim, we will determine the compartment- specific signaling capacity of mtH2O2 by visualizing H2O2 spatial abundance in the mitochondrial matrix and at the outer mitochondrial membrane in neuronal dendrites, somas and axons using a novel genetically encoded H2O2 reporter, HyPer7. In the second aim, we will quantify changes in mitochondrial fission and fusion following genetic manipulation of mitochondrial antioxidants – resulting in physiologically relevant changes in mtH2O2 levels – then employ targeted proteomics to identify differences in the oxidation profiles of known fission and fusion proteins. If successful, our work will characterize an essential role of mtH2O2 in mitochondrial health by its direct regulation of proteins involved in mitochondrial remodeling.


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 = $39,242 )
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 560	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	4/15/2026	NEW	$576
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 560	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	2/17/2026	NEW	$0
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/17/2026	NEW	$38,666
														Subtotal = $39,242

Grand Total All Awards = $39,242

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Determining the Role of Mitochondrial Hydrogen Peroxide in the Regulation of Neuronal Mitochondrial Networks

Award Number: F30NS143384

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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