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Establishing a Novel Instrumental Model for Elucidating Mitochondrial DNA-Associated Dysfunction and Pathogenicity

Award Number: R35GM143048
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract The Shao group at Iowa State University aims to leverage their expertise in genetic tool development to assemble a comprehensive mitochondrial genetic toolkit. The causative role of mitochondrial DNA is implicated in a myriad of human diseases and disorders. However, human mitochondrial dysfunction studies suffer from the absence of an ideal eukaryotic model. The well-studied model yeast, S. cerevisiae, is unsuitable due to its mitochondrial physiology deviating too far from humans. We propose developing a new promising model to heighten knowledge of human mtDNA, yielding new insights on mitochondrial dysfunction and pathogenicity. We have identified that Yarrowia lipolytica strikes a perfect balance between practicality (i.e., low cost and quick timescale of genetic manipulations as a low eukaryote) and tractability (i.e., mirroring human's obligate aerobic needs). In addition, the overwhelming majority of current mitochondrial dysfunction studies focus solely on nuclear-encoded mitochondrial gene abnormalities. This is mainly attributed to the fact that the explosive progression of nuclear genome editing technology in the epoch of “post-CRISPR” has yet to translate to mtDNA editing. We propose leveraging a recently discovered stem-loop RNA motif to overcome nucleic acid import limitations – the largest technical barrier to the development of CRISPR-associated technologies. If this strategy proves effective, we envision that many mtDNA manipulation tools will be developed by research labs around the globe, following the same trajectory as the CRISPR nuclear genome manipulation revolution. Over the next five years, in addition to the foundational tool development, we will strive for elucidating mtDNA-phenotype relationships in the new model. The ability of Y. lipolytica to accumulate lipids makes it a particularly suitable model for human adipocytes. Mitochondrial dysfunction in adipose tissue is involved in a broad spectrum of epidemics plaguing human health. Mediated by our development of a mitochondrial genetic toolkit, we will reconstitute mtDNA-associated human pathologies in a precise manner, enabling tailored drug development and all the subsequent mechanistic studies. Moreover, we propose studying the impact of modulating the fluidity of the inner mitochondrial membrane on altering mitochondrial physiology, which will lead to the discovery of potential treatments of obesity-related diseases in the future. Lastly, along a side research branch, we will integrate the developed mitochondrial genetic toolkit with our previous efforts in metabolic engineering. We will leverage the multiplicity of mitochondria in a single cell as well as the high copy number of mtDNA in a single mitochondrion to boost the dosage of the gene encoding the rate-limiting step in a biochemical pathway. This strategy will revolutionize the metabolic engineering design of eukaryotic hosts to produce a wide variety of compounds derived from TCA cycle or whose biosynthetic mechanism requires a high ATP input. Altogether, this MIRA for ESI project will enable me to move into research areas distinct from my existing ones and grant me the flexibility to follow important new research directions as opportunities arise.


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: 2024 ( Subtotal = $366,763 )
2024	2024	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Biomedical Research and Research Training	000	4	6/3/2024	NON-COMPETING CONTINUATION	$366,763
														Subtotal = $366,763

Issue Date FY: 2023 ( Subtotal = $367,397 )
2023	2023	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Biomedical Research and Research Training	000	3	7/11/2023	NON-COMPETING CONTINUATION	$367,397
														Subtotal = $367,397

Issue Date FY: 2022 ( Subtotal = $368,006 )
2022	2022	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Biomedical Research and Research Training	000	2	5/16/2022	NON-COMPETING CONTINUATION	$368,006
														Subtotal = $368,006

Issue Date FY: 2021 ( Subtotal = $350,210 )
2021	2021	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Biomedical Research and Research Training	000	1	6/17/2021	NEW	$350,210
														Subtotal = $350,210

Grand Total All Awards = $1,452,376

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Establishing a Novel Instrumental Model for Elucidating Mitochondrial DNA-Associated Dysfunction and Pathogenicity

Award Number: R35GM143048

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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