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Moonlighting in Mitochondria: A Non-Canonical Role for Cardiac Troponin I in Inherited Cardiomyopathies

Award Number: K08HL171896
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Moonlighting in Mitochondria: A Non-Canonical Role for Cardiac Troponin I in Inherited Cardiomyopathies - PROJECT SUMMARY: Cardiovascular disease is a leading cause of death, and mitochondrial dysfunction is implicated in the pathogenesis of cardiomyopathy. Cardiac troponin I (cTnI) is a regulator of myocyte contraction, and mutations in cTnI lead to hypertrophic, dilated, and restrictive cardiomyopathies and sudden death. It is not known why cTnI mutations have such heterogeneous phenotypes, and there are no targeted therapies for cardiomyopathies caused by cTnI mutations. cTnI is regulated by phosphorylation and proteolytic truncation. We recently showed that selectively inhibiting phosphorylation of cTnI by delta protein kinase C (δPKC) during myocardial infarction using a lab-designed peptide inhibitor attenuates cardiac injury and prevents mitochondrial dysfunction. My preliminary data show a novel role of cTnI in inhibiting mitochondrial function, and a therapeutic benefit of preventing cTnI’s binding to mitochondrial ATP synthase using a peptide inhibitor in ischemic injury. The objective of this application is to identify the mechanisms by which cTnI inhibits mitochondrial function and to define the interplay between cTnI mutations and mitochondrial dysfunction in genetic cardiomyopathies. My central hypothesis is that cTnI phosphorylation and truncation directly inhibit mitochondrial function, and mutations in cTnI impair mitochondrial function to cause cardiomyopathy. This hypothesis will be tested in two specific aims: 1) Determine the effect of cTnI phosphorylation and truncation on mitochondrial function and 2) determine the effect of pathogenic cTnI mutations on mitochondrial function. In Aim 1, I will test the effect of recombinant cTnI with phospho-mimetic amino acid substitutions and N-terminal truncation on ATP synthase binding/activity and mitochondrial respiration. I will also express phospho-mimetic cTnI and N-terminal truncated cTnI in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) to examine their effects on mitochondrial structure/function and myocyte contractility/relaxation kinetics. In Aim 2, I will use hiPSC-CM and transgenic mice with cTnI mutations to establish the effect of pathogenic mutations (causing hypertrophic, dilated and restrictive cardiomyopathy) on mitochondrial function and test the effect of lab-designed peptide inhibitors of cTnI phosphorylation and mitochondrial binding on mitochondrial function and contractility/relaxation in vivo. This research is expected to identify a novel and therapeutically targetable role of cTnI in inhibiting mitochondrial function and exacerbating myocardial remodeling in genetic cardiomyopathies. To successfully complete this project, Dr. Elezaby’s educational goals include training in 1) rational drug design; 2) hiPSC-CM biology; 3) genotype-specific mechanisms in genetic cardiomyopathies; 4) scientific communication; and 5) professional development. His mentorship team includes world-renowned experts in mitochondrial and stem cell biology, drug development, myocyte physiology, and cardiovascular genetics. His career development plan has been designed to ultimately achieve his long-term goal of becoming a leading clinician-scientist investigating the mechanistic underpinnings, therapeutic targets, and interplay between cardiac metabolism and cardiomyopathy.


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 = $165,672 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	2	6/27/2025	NON-COMPETING CONTINUATION	$165,672
														Subtotal = $165,672

Issue Date FY: 2024 ( Subtotal = $165,672 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	1	7/26/2024	NEW	$165,672
														Subtotal = $165,672

Grand Total All Awards = $331,344

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Moonlighting in Mitochondria: A Non-Canonical Role for Cardiac Troponin I in Inherited Cardiomyopathies

Award Number: K08HL171896

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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