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Mitochondrial malfunction perturbs lysosomal activities and cellular nutrient sensing pathways

Award Number: R56AG082790
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Mitochondrial malfunction perturbs lysosomal activities and cellular nutrient sensing pathways - PROJECT SUMMARY The hallmarks of aging are well established, and include mitochondrial malfunction, deregulated nutrient sensing, altered inter-cellular communication, and senescence, among others. These hallmarks have typically been studied independently, and it is unclear how they are coordinated. It remains poorly understood, particularly in mammals, how mitochondrial malfunction relates with the other hallmarks of aging. We have found that mitochondrial malfunction can affect lysosomal membrane composition, which in turn impacts lysosomal activity, and our preliminary data show that the combined effect of mitochondrial malfunction and lysosomal impairment perturbs nutrient sensing and inter-cellular communication through the secretion of cytokines akin to the senescence-associated secretory phenotype (SASP). Notably, the SASP-like signature is detectable long before senescence markers and is fully reversible. Therefore, we hypothesize that mitochondrial malfunction and its impact on mitochondria-lysosome crosstalk can trigger other cellular aging hallmarks thus unleashing a coordinated program of cellular aging. To test this hypothesis, we will first test how mitochondrial contents can be sensed by the lysosomes, and how different mechanisms of delivery of those contents impact the SASP-like signature. We will then test how the SASP-like signature triggers senescence via paracrine signaling. Next, we will test how lysosomes modified in response to mitochondrial malfunction cause aberrant nutrient signaling, and how this feature further contributes to SASP-like signature and senescence, both in vitro and in vivo. Finally, we will test how the changes in lysosomal membrane composition affect the physical contact sites between lysosomes, mitochondria and endoplasmic reticulum, and how this organelle rearrangement contributes to the aging phenotypes. Through this work, we will harness the mechanisms mitochondrial malfunction and the consequent lysosomal impairment trigger multiple aging hallmarks in a coordinated manner, through mechanisms that provide a window of opportunity for therapeutic interventions. These results are directly relevant to a more complete understanding of the processes leading to cellular and organismal aging in humans and other mammals.


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 = -$43 )
2025	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Aging Research	000	1	12/23/2024	NEW	-$43
														Subtotal = -$43

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Aging Research	000	1	11/2/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $418,500 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Aging Research	000	1	9/14/2023	NEW	$418,500
														Subtotal = $418,500

Grand Total All Awards = $418,457

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Mitochondrial malfunction perturbs lysosomal activities and cellular nutrient sensing pathways

Award Number: R56AG082790

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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