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Mechanisms of mitochondrial dynamics, quality control and mtDNA-mediated inflammation in alcohol-associated liver disease

Award Number: R01AA031230
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: 08/20/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Mechanisms of mitochondrial dynamics, quality control and mtDNA-mediated inflammation in alcohol-associated liver disease - Project Summary/Abstract Despite recent progress on understanding the mechanisms of alcohol-associated liver disease (ALD), no successful treatment for ALD is available. Alcohol metabolism in the liver leads to decreased levels of nicotinamide adenine dinucleotide (NAD+) and increased NADH/ NAD+ ratio resulting in impaired alcohol metabolism, mitochondrial dysfunction and oxidative stress. The widely accepted notion that alcohol induces mitochondrial dysfunction is largely derived from the results on chronic alcohol-fed rats. However, we and others recently demonstrated that chronic alcohol-fed mice have increased mitochondrial respiration with increased number of megamitochondria in the liver. Increased mitochondrial respiration regenerates NAD+, which can be further used for alcohol metabolism via alcohol dehydrogenase and aldehyde dehydrogenase 2, suggesting alcohol induces an adaptive response to facilitate alcohol metabolism by increasing mitochondria respiration. It has long been known that accumulation of hepatic megamitochondria is associated with better outcomes in human ALD although the exact role and mechanisms of megamitochondria in the pathogenesis of ALD are unknown. We recently showed that alcohol decreases mitochondria fission protein dynamin-related protein 1 (DRP1) (gene name DNM1L) in mouse livers and human alcohol-associated hepatitis resulting in increased megamitochondria formation. We further demonstrated that chronically accumulated megamitochondria are maladaptive resulting in impaired NAD+ regeneration, increased mtDNA release and cGAS-STING-mediated innate immune response in alcohol-fed mice. Liver-specific Dnm1l knockout (L-Dnm1l KO) mice developed spontaneous liver tumors and was further exacerbated by alcohol feeding. Deletion of mitochondrial fusion protein (mitofusin 1 and 2) to regain liver mitochondrial “stasis” remarkably abolished cGAS-STING-mediated innate immune response and tumorigenesis in L-Dnm1l KO mice. The goal of this proposal is to understand the mechanisms for how megamitochondria are maladaptive to promote mtDNA release and how cGAS-STING pathway contributes to the pathogenesis of ALD and liver cancer. The central hypothesis is that chronically accumulated megamitochondria impair mitophagy and increase BAX/BAK pore formation to promote mtDNA release and cGAS-STING-mediated innate immune response resulting in alcohol- induced liver injury and tumorigenesis, all of which can be restrained by re-establishing hepatic mitochondrial stasis. The study will identify novel mechanisms of mitochondrial dynamics and homeostasis in regulating hepatic inflammation and liver tumorigenesis in ALD, which may help develop new therapeutic options by targeting mitochondria for ALD.


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 = $386,542 )
2025	2025	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	000	2	5/29/2025	NON-COMPETING CONTINUATION	$386,542
														Subtotal = $386,542

Issue Date FY: 2024 ( Subtotal = $386,196 )
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	000	1	8/20/2024	NEW	$386,196
														Subtotal = $386,196

Grand Total All Awards = $772,738

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Mechanisms of mitochondrial dynamics, quality control and mtDNA-mediated inflammation in alcohol-associated liver disease

Award Number: R01AA031230

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: 08/20/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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