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Mitochondria, oxidative stress and nonalcoholic fatty liver disease: A complex relationship

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Agnieszka Karkucinska-Wieckowska, Ines C.M. Simoes, Piotr Kalinowski, Magdalena Lebiedzinska-Arciszewska, Krzysztof Zieniewicz, Piotr Milkiewicz, Magdalena Górska-Ponikowska, Paolo Pinton, Afshan N. Malik, Marcin Krawczyk, Paulo J. Oliveira, Mariusz R. Wieckowski

Original languageEnglish
JournalEuropean Journal of Clinical Investigation
Issue number3
Early online date15 Jun 2021
Accepted/In press2021
E-pub ahead of print15 Jun 2021

Bibliographical note

Funding Information: MRW and ICMS are supported by the National Science Centre, Poland (UMO‐2018/29/B/NZ1/00589, UMO‐2020/36/T/NZ1/00004). M.L‐A. is supported by National Science Centre, Poland (UMO‐2015/17/D/NZ1/00030). M.G‐P. is supported by Polish Ministry of Science and Higher Education (Iuventus Plus No IP2015 022074 and ST 46 grants). PJO is supported by FEDER funds through the Operational Program Competitiveness Factors COMPETE and national funds by the Foundation for Science and Technology (FCT) (Grants PTDC/ASP‐HOR/29152/2017, POCI‐01‐0145‐FEDER‐029152 and UIDB/04539/2020). ICMS, PJO, ANM and MRW gratefully acknowledge the financial support for this research from the FOIE GRAS and mtFOIE GRAS projects. These projects received funding from the European Union's Horizon 2020 Research and Innovation Program under the Marie Skłodowska‐Curie Grant Agreement No. 722619 (FOIE GRAS) and Grant Agreement No. 734719 (mtFOIE GRAS). PM was supported by European Reference Network on Hepatological Diseases (ERN RARE‐LIVER). Publisher Copyright: © 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


According to the ‘multiple-hit’ hypothesis, several factors can act simultaneously in nonalcoholic fatty liver disease (NAFLD) progression. Increased nitro-oxidative (nitroso-oxidative) stress may be considered one of the main contributors involved in the development and risk of NAFLD progression to nonalcoholic steatohepatitis (NASH) characterized by inflammation and fibrosis. Moreover, it has been repeatedly postulated that mitochondrial abnormalities are closely related to the development and progression of liver steatosis and NAFLD pathogenesis. However, it is difficult to determine with certainty whether mitochondrial dysfunction or oxidative stress are primary events or a simple consequence of NAFLD development. On the one hand, increasing lipid accumulation in hepatocytes could cause a wide range of effects from mild to severe mitochondrial damage with a negative impact on cell fate. This can start the cascade of events, including an increase of cellular reactive nitrogen species (RNS) and reactive oxygen species (ROS) production that promotes disease progression from simple steatosis to more severe NAFLD stages. On the other hand, progressing mitochondrial bioenergetic catastrophe and oxidative stress manifestation could be considered accompanying events in the vast spectrum of abnormalities observed during the transition from NAFL to NASH and cirrhosis. This review updates our current understanding of NAFLD pathogenesis and clarifies whether mitochondrial dysfunction and ROS/RNS are culprits or bystanders of NAFLD progression.

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