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Determining the role of ROS and calcium within the mPTP and mitochondrial UPR nexus

Award Number: F31HL179975
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/18/2026
PERIOD OF PERFORMANCE END DATE: 12/17/2027

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Determining the role of ROS and calcium within the mPTP and mitochondrial UPR nexus - ABSTRACT Age-related ischemia/reperfusion (I/R) injuries trigger catastrophic mitochondrial dysfunction through the opening of the detrimental mitochondrial permeability transition pore (mPTP). Patients who suffer I/R injuries experience insufficient levels of oxygen to vital tissues. Oxygen restoration elevates cytosolic calcium (Ca2+) and reactive oxygen species (ROS), leading to the formation of the mPTP, a channel formed in the inner mitochondrial membrane that is thought to be composed primarily of F-ATP synthase. ROS and Ca2+ are known activators of the mPTP, as well as intracellular signaling molecules expelled from the mPTP. When cytosolic Ca2+ levels are elevated, mitochondria sequester the excess Ca2+, which is subsequently forcibly released back into the cytosol through the opening of the mPTP. Continuous mPTP opening contributes to mitochondrial toxicity via mitochondrial swelling, outer membrane rupture, and downstream cell death cascades. Oxidative stress further sensitizes mitochondria to Ca2+, reducing the amount of Ca2+ needed for mPTP formation and promoting ROS amplification through mPTP propagation. The Angeli lab at the University of Maine has developed a novel C. elegans model of the mPTP via destabilization of the F-ATP synthase via loss of one of its subunits, OSCP/atp-31. This model provides an innovative solution for investigating the fundamental mechanisms of the mPTP in vivo and its relationship to aging. The Angeli lab previously identified that the opening of the mPTP leads to the induction of a maladaptive mitochondrial unfolded protein response (malUPRmt) in C. elegans1. However, it is unknown how the mPTP induces the malUPRmt. We hypothesize that ROS and/or Ca2+ expelled from the mPTP induce the malUPRmt via the master UPRmt transcription factor ATFS-1. In support of this hypothesis, our preliminary data demonstrates that antioxidant administration reduces malUPRmt activation, and separately, that loss of calmodulin (CaM/cmd-1), a cytoplasmic and nuclear Ca2+ binding and signaling protein, also inhibits the malUPRmt. Additionally, we have identified that ATFS-1 contains a predicted CaM/cmd-1 binding domain. Here, we propose to examine the roles of ROS (Aim 1) and Ca2+ (Aim 2) in our F-ATP synthase mPTP/malUPRmt model. We will also examine whether F-ATP synthase destabilization induces the UPRmt in mammalian cell culture (Aim 3). Understanding the regulatory roles of ROS and Ca²⁺ in the context of the mPTP/malUPRmt within enhance our basic understanding of their relationship to aging and age-related diseases, such as heart attack and stroke, which is of high biomedical importance.


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 = $39,097 )
2026	2026	UNIVERSITY OF MAINE SYSTEM	5717 CORBETT HALL	ORONO	ME	04469	PENOBSCOT	USA	Cardiovascular Diseases Research	000	1	6/25/2026	NEW	$39,097
														Subtotal = $39,097

Grand Total All Awards = $39,097

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Determining the role of ROS and calcium within the mPTP and mitochondrial UPR nexus

Award Number: F31HL179975

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/18/2026

PERIOD OF PERFORMANCE END DATE: 12/17/2027

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