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Antioxidants
Volume 14
Issue 6
10.3390/antiox14060618
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

A Defective Circulating Mitochondrial Bioenergetics Profile Reflects the Hepatic One and Outlines Genetic MASLD

by
Erika Paolini
1,
Miriam Longo
1,
Marica Meroni
1,
Paola Podini
2,
Marco Maggioni
3,
Angelo Quattrini
2,
Anna Ludovica Fracanzani
1,4 and
Paola Dongiovanni
1,*
1
Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
2
Neuropathology Unit, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
3
Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
4
Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
*
Author to whom correspondence should be addressed.
Antioxidants 2025, 14(6), 618; https://doi.org/10.3390/antiox14060618
Submission received: 11 April 2025 / Revised: 9 May 2025 / Accepted: 20 May 2025 / Published: 22 May 2025
(This article belongs to the Special Issue Oxidative Stress and Liver Disease)
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Abstract

Genetics and mitochondrial (mt) dysfunction contribute to metabolic dysfunction-associated steatotic liver disease (MASLD). Recently, we demonstrated that the co-presence of PNPLA3, TM6SF2 and MBOAT7 polymorphisms predisposes to disease progression in MASLD patients and that their deletion triggers mt maladaptation in vitro. Here, we deepened the impact of the silencing of these genes on mt dynamism and respiration by reintroducing TM6SF2 and/or MBOAT7 wild-type proteins in deleted cells through lentiviral infection. Since hepatic mt bioenergetics is impaired in MASLD, in the attempt to identify a non-invasive signature, we then compared the enzymatic mt activity of seahorses, which was assessed in liver biopsies and peripheral blood mononuclear cells (PBMCs) of biopsy-proven MASLD patients (n = 44; Discovery cohort) stratified according to the number of the three at-risk variants (3NRV). Concerning the in vitro results, the rescue of MBOAT7 and/or TM6SF2 wild-type proteins resulted in the assembly of spaghetti-shaped mitochondria with improved oxidative phosphorylation (OXPHOS) capacity. In the Discovery cohort, the hepatic bioenergetic profile fully reflected that in PBMCs and was impaired especially in 3NRV carriers. A lowered serum respiration rate was confirmed in noninvasively assessed MASLD (n = 45; Fibroscan-MASLD cohort), while it did not change in unrelated liver disease patients (n = 45). In summary, we firstly demonstrated that mt circulating respirometry reflects that in liver and is specific in defining genetic MASLD.
Keywords: MASLD; genetics; mitochondria; non-invasive biomarker MASLD; genetics; mitochondria; non-invasive biomarker
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MDPI and ACS Style

Paolini, E.; Longo, M.; Meroni, M.; Podini, P.; Maggioni, M.; Quattrini, A.; Fracanzani, A.L.; Dongiovanni, P. A Defective Circulating Mitochondrial Bioenergetics Profile Reflects the Hepatic One and Outlines Genetic MASLD. Antioxidants 2025, 14, 618. https://doi.org/10.3390/antiox14060618

AMA Style

Paolini E, Longo M, Meroni M, Podini P, Maggioni M, Quattrini A, Fracanzani AL, Dongiovanni P. A Defective Circulating Mitochondrial Bioenergetics Profile Reflects the Hepatic One and Outlines Genetic MASLD. Antioxidants. 2025; 14(6):618. https://doi.org/10.3390/antiox14060618

Chicago/Turabian Style

Paolini, Erika, Miriam Longo, Marica Meroni, Paola Podini, Marco Maggioni, Angelo Quattrini, Anna Ludovica Fracanzani, and Paola Dongiovanni. 2025. "A Defective Circulating Mitochondrial Bioenergetics Profile Reflects the Hepatic One and Outlines Genetic MASLD" Antioxidants 14, no. 6: 618. https://doi.org/10.3390/antiox14060618

APA Style

Paolini, E., Longo, M., Meroni, M., Podini, P., Maggioni, M., Quattrini, A., Fracanzani, A. L., & Dongiovanni, P. (2025). A Defective Circulating Mitochondrial Bioenergetics Profile Reflects the Hepatic One and Outlines Genetic MASLD. Antioxidants, 14(6), 618. https://doi.org/10.3390/antiox14060618

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