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Dynamic adaptation of liver mitochondria to alcohol

Award Number: R21AA026944
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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Dynamic adaptation of liver mitochondria to alcohol - ABSTRACT The overarching goal of this proposal is to elucidate the role that mitochondrial remodeling in the liver plays in alcoholic liver disease (ALD). Our recent exciting findings suggest that chronic alcohol feeding causes dynamic mitochondrial remodeling in the liver that enhances mitochondrial bioenergetic activity as an adaptation to alcohol. We observed two major types of mitochondrial remodeling following alcohol feeding: 1) increased biogenesis of key mitochondrial constituents (e.g. expression of respiratory complex proteins, pyridine nucleotide levels) and, 2) alterations in liver mitochondrial morphology through changes in mitochondrial fusion-fission rates. Our findings add new insights to the established dogma that ALD primarily involves mitochondrial dysfunction. While this paradigm of mitochondrial dysfunction in ALD has been widely accepted for decades, it represents an incomplete picture of mitochondrial dynamics in the liver. Chronic alcohol feeding causes some mitochondrial dysfunction, but it also induces a great deal of mitochondrial remodeling in the liver as an adaptation to the stress induced by alcohol intake. In this proposal, we will examine the significance of mitochondrial remodeling in ALD by modulating two distinct pathways in the liver. Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is the master regulator of mitochondrial biogenesis, and our preliminary data suggests that it plays a role in alcohol- induced mitochondrial biogenesis, particularly of respiratory complexes in the liver. Consequently, we will silence PGC-1α using antisense (ASO) to determine if mitochondrial biogenesis plays a beneficial (i.e. adaptation) or deleterious role in the liver with chronic alcohol feeding. During ALD, like in many pathologies, mitochondrial fusion-fission alters to increase mitochondrial heterogeneity, which produces subpopulations of mitochondria that may have different properties (respiration, reactive oxygen species generation, JNK binding). We will modulate mitochondrial fusion-fission rates using ASO (e.g. Mfn-2 - produces fragmented mitochondria; Opa-1 - produces larger mitochondria) to alter mitochondrial heterogeneity to determine its significance in the pathogenesis of ALD. The proposal has two specific aims: 1) Determine the significance of mitochondrial biogenesis in the pathogenesis of ALD, and 2) Determine the extent and significance of mitochondrial heterogeneity that occurs in the liver with alcohol feeding. Overall, by modulating two different aspects of mitochondrial remodeling (biogenesis and fusion-fission), our proposal should provide new insights on the role mitochondrial remodeling plays in ALD. Although our proposal focuses on alcohol, we believe the findings of this study will have broader implications in liver pathophysiology, since many liver diseases, such as non-alcoholic fatty liver disease, are also associated with mitochondrial remodeling.


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: 2023 ( Subtotal = $0 )
2023	2020	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Alcohol Research Programs	000	2	2/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $181,981 )
2020	2020	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Alcohol Research Programs	000	2	8/19/2020	NON-COMPETING CONTINUATION	$181,981
														Subtotal = $181,981

Issue Date FY: 2019 ( Subtotal = $231,335 )
2019	2019	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Alcohol Research Programs	000	1	8/26/2019	NEW	$231,335
														Subtotal = $231,335

Grand Total All Awards = $413,316

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Dynamic adaptation of liver mitochondria to alcohol

Award Number: R21AA026944

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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