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Secretion of mitochondria as a cellular quality control mechanism

Award Number: R01HL155281
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/20/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Secretion of mitochondria as a cellular quality control mechanism - Project summary In the heart, the primary function of mitochondria is to meet the high energy demand of the beating myocytes by providing ATP through oxidative phosphorylation. However, mitochondria can quickly change into death-promoting organelles. Not surprisingly, cells have developed multiple defense mechanisms against aberrant mitochondria that can cause harm to the cell. The ability to eliminate dysfunctional mitochondria and prevent unnecessary death is particularly important in post-mitotic myocytes that cannot be easily replaced. It is well established that dysfunctional mitochondria are rapidly sequestered by autophagosomes and subsequently delivered to lysosomes for degradation. Recent studies have identified cells that can also eliminate mitochondria via a Rab9-dependent alternative autophagy pathway or via a Rab5-dependent-early endosomal pathway. Mitochondria can also be directly taken up by lysosomes. Clearly, multiple pathways of mitochondrial elimination exist in cells to prevent their accumulation and ensure survival. However, these degradation pathways all converge at the level of the lysosomes and it is not clear whether alternative mitochondrial quality control pathways exists when lysosomal function is compromised. We have discovered that dysfunctional mitochondria can also be secreted from cells when internal degradation pathways are overwhelmed or impaired. Our preliminary data demonstrate that Rab7-/- and LAMP2-/- cells that have impaired lysosomal degradation are still able to efficiently eliminate depolarized mitochondria. We also found increased levels of circulating extracellular vesicles (EVs) containing mitochondria in plasma after a myocardial infarction, as well as in cardiac specific Rab7- and LAMP2-deficient mice at baseline. Proteomics analysis of EVs combined with Western blot analysis suggest that the mitochondria are in vesicles that originate from the endosomal pathway. In this proposal, we will investigate the hypothesis that dysfunctional mitochondria are secreted from cells in EVs and that this represent an important quality control pathway in the heart that can compensate when lysosomes are overwhelmed or compromised. This hypothesis will be tested with two specific aims. Specific aim 1 will identify the origin and fate of the extracellular vesicles containing mitochondria and determine the pathophysiological conditions that induce their release from myocytes. Specific aim 2 will dissect the molecular mechanisms regulating secretion of mitochondria in EVs. Overall, these studies will provide important new insights into a novel alternative mechanism of mitochondrial elimination in the myocardium. The studies will also provide insights into whether these EVs can potentially function as early diagnostic biomarkers of cardiac stress prior to development of disease.


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 = $0 )
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	4	4/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $554,393 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	4	6/13/2024	NON-COMPETING CONTINUATION	$45,257
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	4	11/9/2023	NON-COMPETING CONTINUATION	$509,136
														Subtotal = $554,393

Issue Date FY: 2023 ( Subtotal = $565,706 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	3	11/15/2022	NON-COMPETING CONTINUATION	$509,136
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	3	2/11/2023	NON-COMPETING CONTINUATION	$56,570
														Subtotal = $565,706

Issue Date FY: 2022 ( Subtotal = $565,706 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	2	6/8/2022	NON-COMPETING CONTINUATION	$56,571
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	2	11/5/2021	NON-COMPETING CONTINUATION	$509,135
														Subtotal = $565,706

Issue Date FY: 2021 ( Subtotal = $575,702 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	1	7/3/2021	NEW	$57,570
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	1	12/20/2020	NEW	$518,132
														Subtotal = $575,702

Grand Total All Awards = $2,261,507

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Secretion of mitochondria as a cellular quality control mechanism

Award Number: R01HL155281

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/20/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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