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Novel mitochondria-to-lysosome crosstalk contributes to lysosomal dysfunction during aging

Award Number: R01AG082824
ORGANIZATION: NATIONAL INSTITUTE ON AGING
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: 06/30/2028

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Novel mitochondria-to-lysosome crosstalk contributes to lysosomal dysfunction during aging - PROJECT SUMMARY/ABSTRACT Aging is accompanied by the gradual deterioration within each individual cellular compartments/organelles as well as the collapse of the interconnections among them, leading to the establishment of different hallmarks of aging. However, these hallmarks of aging, including loss of proteostasis, mitochondrial dysfunction, and cellular senescence, are traditionally studied separately and leave the connections among these hallmarks largely un- known. With a growing understanding of these inter-organelle interactions within young cells, it has become of interest to explore how losses in compartmental crosstalk contribute to the age-associated degeneration of or- ganelle function and the establishment/connection of hallmarks of aging. We recently discovered an unexpected crosstalk between mitochondria and the lysosome (vacuole in yeast) that explains age-associated vacuole/lysosome de-acidification, a process conserved from yeast to human cells and which contributes to the loss of proteostasis during aging and in many age-related diseases. We found that mitochondria contribute to the acidification of lysosome/vacuole via membrane contact sites. Moreover, our pre- liminary studies suggest that the collapse of mitochondria-vacuole contact during the replicative aging of yeast causes age-dependent de-acidification of vacuole. Similarly, we observed a close correlation between mitochon- dria and lysosome acidification in cultured human cells and in C. elegans, suggesting evolutionary conservation of this process. To address how aging affects the mitochondria-lysosome/vacuole contact and whether this mi- tochondria-to-lysosome axis plays a critical role in lysosome acidification in cellular senescence and animals, we here propose to investigate the mitochondria-lysosome/vacuole contact and lysosome/vacuole acidification dur- ing aging and in different longevity paradigms. Specifically, we will combine the expertise of our different model systems to (1) dissect the mechanism(s) underlying the age-related loss of mitochondria-vacuole connection in yeast; (2) determine mitochondrial contribution to lysosome acidification in human cells; and (3) dissect the roles of mitochondria-lysosome connection in lysosome acidification in C. elegans. Our studies will investigate a novel, possibly evolutionarily conserved inter-organelle communication connect- ing mitochondrial dysfunction and lysosome/vacuole de-acidification across different organisms and longevity paradigms. Although traditional thinking has held that age-associated lysosome/vacuole dysfunction is respon- sible for inducing mitochondrial dysfunction in a uni-directional manner, our study will determine whether mito- chondrial dysfunction may conversely impact on lysosome/vacuole dysfunction during aging revealing a here- to-fore unappreciated two-way crosstalk between these tightly connected organelles which may together con- tribute to several important hallmarks of aging. As such, the long-term implications of this study could be the identification of novel conserved therapeutic targets for age-related diseases with lysosome defects.


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 = $475,300 )
2025	2025	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	3	7/7/2025	NON-COMPETING CONTINUATION	$475,300
														Subtotal = $475,300

Issue Date FY: 2024 ( Subtotal = $485,000 )
2024	2024	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	2	7/26/2024	NON-COMPETING CONTINUATION	$485,000
														Subtotal = $485,000

Issue Date FY: 2023 ( Subtotal = $485,000 )
2023	2023	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	1	7/25/2023	NEW	$485,000
														Subtotal = $485,000

Grand Total All Awards = $1,445,300

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Novel mitochondria-to-lysosome crosstalk contributes to lysosomal dysfunction during aging

Award Number: R01AG082824

ORGANIZATION: NATIONAL INSTITUTE ON AGING

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: 06/30/2028

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