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Mitochondrial amido...
Mitochondrial amidoxime-reducing component 1 p.Ala165Thr increases protein degradation mediated by the proteasome.
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- Dutta, Tanmoy, 1998 (author)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Sasidharan, Kavitha (author)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Ciociola, Ester (author)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Pennisi, Grazia, 1990 (author)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Noto, Francesca R, 1995 (author)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Kovooru, Lohitesh, 1993 (author)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine
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Kroon, Tobias (author)
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Lindblom, Anna (author)
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Du, Yue (author)
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Pirmoradian, Mohammad (author)
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Wallin, Simonetta (author)
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- Mancina, Rosellina Margherita (author)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Lindén, Daniel, 1971 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology
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- Romeo, Stefano, 1976 (author)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine
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(creator_code:org_t)
- 2024
- 2024
- English.
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In: Liver international. - 1478-3223. ; 44:5, s. 1219-1232
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https://doi.org/10.1...
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Abstract
Subject headings
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- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern with no effective and specific drug treatment available. The rs2642438 minor allele in mitochondrial amidoxime-reducing component 1 (MARC1) results in an aminoacidic substitution (p.Ala165Thr) and associates with protection against MASLD. However, the mechanisms behind this protective effect are unknown. In this study, we examined the consequences of this aminoacidic substitution on protein stability and subcellular localization.We overexpressed the human MARC1 A165 (wild-type) or 165T (mutant) invivo in mice and invitro in human hepatoma cells (HepG2 and HuH-7), generated several mutants at position 165 by insitu mutagenesis and then examined protein levels. We also generated HepG2 cells stably overexpressing MARC1 A165 or 165T to test the effect of this substitution on MARC1 subcellular localization.MARC1 165T overexpression resulted in lower protein levels than A165 both invivo and invitro. Similarly, any mutant at position 165 showed lower protein levels compared to the wild-type protein. We showed that the 165T mutant protein is polyubiquitinated and its degradation is accelerated through lysine-48 ubiquitin-mediated proteasomal degradation. We also showed that the 165T substitution does not affect the MARC1 subcellular localization.This study shows that alanine at position 165 in MARC1 is crucial for protein stability, and the threonine substitution at this position leads to a hypomorphic protein variant due to lower protein levels. Our result supports the notion that lowering hepatic MARC1 protein level may be a successful therapeutic strategy for treating MASLD.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Keyword
- Animals
- Fatty Liver* / metabolism
- Humans
- Mice
- Mitochondrial Proteins* / genetics
- Mitochondrial Proteins* / metabolism
- Oxidoreductases* / genetics
- Oxidoreductases* / metabolism
- Proteasome Endopeptidase Complex* / metabolism
- Proteolysis
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Dutta, Tanmoy, 1 ...
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Sasidharan, Kavi ...
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Ciociola, Ester
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Pennisi, Grazia, ...
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Noto, Francesca ...
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Kovooru, Lohites ...
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show more...
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Kroon, Tobias
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Lindblom, Anna
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Du, Yue
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Pirmoradian, Moh ...
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Wallin, Simonett ...
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Mancina, Roselli ...
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Lindén, Daniel, ...
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Romeo, Stefano, ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cardiac and Card ...
- Articles in the publication
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Liver internatio ...
- By the university
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University of Gothenburg