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From mtDNA stress to cellular immunity: Triggers, Mechanisms and Effectors

Award Number: R35GM147191
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: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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From mtDNA stress to cellular immunity: Triggers, Mechanisms and Effectors - PROJECT SUMMARY: Mitochondria are the evolutionary product of the endosymbiosis between the ancestral eukaryotic cell and an obligate aerobe bacterium, which brought new functionalities to eukaryotic cells. During their evolution, mitochondria transferred more than 99% of their known genetic material to the nucleus – with the exception of a small, multi-copy genome referred to as mtDNA. In Homo sapiens, the 16.6 Kbp of mtDNA is circular and encodes for 13 members of the oxidative phosphorylation chain (OXPHOS) and other structural RNAs. Beyond their canonical role in the generation of ATP through OXPHOS, the mitochondria are also critical stakeholders in several cellular processes from metabolite fluxes and calcium signaling to cell death and aging. Recently, mitochondrial stress has been implicated in the aberrant activation of innate immunity, mediated by the release of organellar components, such as mitochondrial nucleic acids, recognized by cytosolic sensors as foreign and potentially dangerous. Aberrant immunity has deep implications in human health and is a driver of human diseases, such as neuroinflammation and autoimmunity. Mitochondrial immunity has been studied both in vitro and in vivo, but the complete repertoire of its triggers and effectors has yet to be characterized. I recently uncovered a previously unknown source of stress conducive to aberrant immunity: stress to the mtDNA in the form of double-stranded breaks (mtDSBs). The presence of this stressor is relayed to the cytosolic compartment via mitochondrial herniation, a recently described form of Bax/Bak mediated organelle permeabilization, that exposes mitochondrial contents to the cytosol. After mtDSBs, mitochondrial RNA – rather than the recipient of the stress, mtDNA – initiated the innate immunity cascade by activating the sensor RIG-I. Our proposed research plan builds on this past work to ask essential questions: (1) which sources of mtDNA stress are conducive to aberrant immunity and what is the impact of dysfunctional mitochondrial transcription or translation; (2) how is mitochondrial herniation regulated and how does it differ from other forms of mitochondrial permeabilization; and (3) what are the distinctive features of mitochondrial RNA activation of RIG-I and where do they originate? Our goal is to understand how mitochondria integrate and translate stress signals, particularly in the context of innate immunity. My lab will probe different sources of mtDNA stress and interrogate the mechanisms, effectors, and mitochondrial moieties engaging the cytosolic sensors of immunity. RIG-I is a key protein for the defense against viruses, but its aberrant activation is involved in both autoimmune conditions and the beneficial anti-tumor responses elicited by cancer treatments. By building upon our recent findings and prior experience, as well as by establishing collaborations and seeking the assistance of senior investigators with advanced expertise in both mitochondrial biology and the key technologies proposed, our research program aims to have long-lasting impacts on the foundational and translational knowledge of cellular stress responses going beyond mitochondrial biology into a pathway with further implications in human health and disease: innate immunity.


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 = $390,000 )
2026	2026	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	4/24/2026	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2025 ( Subtotal = $390,000 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	4	4/8/2025	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2024 ( Subtotal = $390,000 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	001	3	7/29/2024	NON-COMPETING CONTINUATION	$39,000
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	4/17/2024	NON-COMPETING CONTINUATION	$351,000
														Subtotal = $390,000

Issue Date FY: 2023 ( Subtotal = $632,050 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	001	2	7/18/2023	SUPPLEMENT FOR EXPANSION	$242,050
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	2	4/21/2023	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $632,050

Issue Date FY: 2022 ( Subtotal = $390,000 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	6/21/2022	NEW	$390,000
														Subtotal = $390,000

Grand Total All Awards = $2,192,050

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From mtDNA stress to cellular immunity: Triggers, Mechanisms and Effectors

Award Number: R35GM147191

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: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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