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The role of mito-nuclear communication in the adaptation to mitochondrial dysfunction and stress resistance

Award Number: R35GM150858
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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The role of mito-nuclear communication in the adaptation to mitochondrial dysfunction and stress resistance - PROJECT SUMMARY/ABSTRACT Interactions between mitochondrial (mtDNA) and nuclear (nDNA) genomes are essential for maintaining mitochondrial and cellular functions. However, an age- and disease-associated increase of heteroplasmic mtDNA (the presence of different mtDNA haplotypes) creates an inter-genomic mismatch that perturbs mitonuclear interaction efficiency. Disrupted mitonuclear interaction results in mitochondrial dysfunction, reduced organismal fitness, and initiation of various stress that has been associated with a plethora of many human diseases, such as Huntington's disease, Leber's hereditary optic neuropathy, and type 2 diabetes mellitus. In response to disrupted mitonuclear interactions, cells activate stress response pathways to remodel gene expression and metabolism, thereby maintaining mitochondrial function and alleviating cellular stress. However, a detailed molecular understanding of mitonuclear mechanisms linking activation of stress response pathways for maintaining mitochondrial function and stress resistance has been understudied, representing a significant knowledge gap. I hypothesize that distinct mismatched mitonuclear genomes maintain coordination of mitochondrial status with various stress response pathways to alleviate harmful consequences of suboptimal mitonuclear interactions. To test this hypothesis, we developed a novel yeast mitonuclear exchange model (cytoductants) by combining more than 100 mtDNA genotypes onto the same nDNA genetic background, thereby generating an elegant system with various degrees of perturbation in mitonuclear interaction and altered mitochondrial function. Overall, the main goal of our research is to mechanistically understand how perturbations in mitonuclear interaction are transduced into biological effects. My laboratory will build and sustain three research projects to accomplish this goal. We will first test the hypothesis that understanding mitonuclear communication at molecular level will uncover distinct mitonuclear responses to perturbed mitonuclear interactions. (Project 1). Secondly, we will identify the crosstalk between stress response pathways and their downstream effectors in protecting cells from various stress under the condition of perturbed mitonuclear interaction. Further, we will determine whether a specific type of stressor determines the specificity of the response or not (Project 2). Finally, with an innovative cell engineering approach, we will investigate the hypothesis that balancing cellular energy hemostasis can mitigate the effect of disrupted mitonuclear interaction (Project 3). The proposed research is significant because it will uncover how cells respond to disrupted mitonuclear interactions to maintain cellular homeostasis. Since many mitochondrial diseases are carried in heteroplasmy, this basic research into the maintenance of mitonuclear interaction will likely identify modulators of efficient mitochondrial interaction. It might be targeted pharmacologically to treat human pathologies associated with mitonuclear dysfunction, such as neurodegeneration and aging.


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 = $403,750 )
2026	2026	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	5	5/26/2026	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2025 ( Subtotal = $408,877 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	004	4	7/14/2025	NON-COMPETING CONTINUATION	$403,750
2025	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	002	2	5/22/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	003	2	6/11/2025	NON-COMPETING CONTINUATION	$0
2025	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	2	5/7/2025	NON-COMPETING CONTINUATION	-$163,043
2025	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	001	3	5/7/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$168,170
														Subtotal = $408,877

Issue Date FY: 2024 ( Subtotal = $619,982 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	2	6/4/2024	SUPPLEMENT FOR EXPANSION	$231,857
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	2	6/3/2024	NON-COMPETING CONTINUATION	$388,125
														Subtotal = $619,982

Issue Date FY: 2023 ( Subtotal = $369,340 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	1	7/12/2023	NEW	$369,340
														Subtotal = $369,340

Grand Total All Awards = $1,801,949

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The role of mito-nuclear communication in the adaptation to mitochondrial dysfunction and stress resistance

Award Number: R35GM150858

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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