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Review
. 2022 Sep;11(3):126-143.
doi: 10.1007/s13679-022-00473-1. Epub 2022 May 2.

Hepatocyte Mitochondrial Dynamics and Bioenergetics in Obesity-Related Non-Alcoholic Fatty Liver Disease

Aigli-Ioanna Legaki  1 , Ioannis I Moustakas  1 , Michalina Sikorska  1 , Grigorios Papadopoulos  1 , Rallia-Iliana Velliou  1 , Antonios Chatzigeorgiou  2   3
Affiliations
Review

Hepatocyte Mitochondrial Dynamics and Bioenergetics in Obesity-Related Non-Alcoholic Fatty Liver Disease

Aigli-Ioanna Legaki et al. Curr Obes Rep. 2022 Sep.

Abstract

Purpose of the review: Mitochondrial dysfunction has long been proposed to play a crucial role in the pathogenesis of a considerable number of disorders, such as neurodegeneration, cancer, cardiovascular, and metabolic disorders, including obesity-related insulin resistance and non-alcoholic fatty liver disease (NAFLD). Mitochondria are highly dynamic organelles that undergo functional and structural adaptations to meet the metabolic requirements of the cell. Alterations in nutrient availability or cellular energy needs can modify their formation through biogenesis and the opposite processes of fission and fusion, the fragmentation, and connection of mitochondrial network areas respectively. Herein, we review and discuss the current literature on the significance of mitochondrial adaptations in obesity and metabolic dysregulation, emphasizing on the role of hepatocyte mitochondrial flexibility in obesity and NAFLD.

Recent findings: Accumulating evidence suggests the involvement of mitochondrial morphology and bioenergetics dysregulations to the emergence of NAFLD and its progress to non-alcoholic steatohepatitis (NASH). Most relevant data suggests that changes in liver mitochondrial dynamics and bioenergetics hold a key role in the pathogenesis of NAFLD. During obesity and NAFLD, oxidative stress occurs due to the excessive production of ROS, leading to mitochondrial dysfunction. As a result, mitochondria become incompetent and uncoupled from respiratory chain activities, further promoting hepatic fat accumulation, while leading to liver inflammation, insulin resistance, and disease's deterioration. Elucidation of the mechanisms leading to dysfunctional mitochondrial activity of the hepatocytes during NAFLD is of predominant importance for the development of novel therapeutic approaches towards the treatment of this metabolic disorder.

Keywords: Energy metabolism; Liver; Mitochondrial bioenergetics; Mitochondrial dysfunction; NAFLD; NASH.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Mitochondrial dynamics: the process of fission and fusion. Mitochondrial fission is regulated by Drp1 and FIS1, which compress and separate mitochondrial tubules. Under conditions of low energy demand, fission facilitates uncoupled respiration, resulting to reduced ATP synthesis. Oppositely, during fusion, Mfn1/2 and OPA1 integrate the OMMs and IMMs. Mitochondrial fusion is stimulated by energy demand and stress and leads to upregulation of metabolic competence. Drp1, dynamin-like/related protein 1; FIS1, mitochondrial fission 1 protein; Mfn1, mitofusin 1; Mfn2, mitofusin 2; OPA1, optic atrophy 1; OMM; outer mitochondrial membrane; IMM, inner mitochondrial membrane
Fig. 2
Fig. 2
Hepatic mitochondrial adaptations in non-alcoholic fatty liver disease (NAFLD). In NAFLD, rapid accumulation of triglycerides (TGs) in the liver, due to high availability of free fatty acids (FFAs), and/or de novo lipogenesis (DNL) is associated with an elevated mitochondrial oxidative activity. The cytoplasmic FFAs are first converted into fatty acyl-CoA which is relocated to mitochondria to be decomposed via β-oxidation and produce acetyl-CoA. Increased FFA influx leads to insufficient hepatic β-oxidation and therefore, lipotoxic intermediates accumulate, triggering inflammation and disrupting insulin signaling. In contrast, the utilization of acetyl-CoA by the mitochondrial tricarboxylic acid (TCA) cycle continues unabated to meet the energetic demands of gluconeogenesis. Mitochondrial β-oxidation generates NADH and flavine-adenine dinucleotide (FADH2), the electrons (e-) of which are transferred to the electron transport chain (ETC). Disruption of the electron flow within the ETC induces leakage of electrons and the generation of reactive oxygen species (ROS), contributing to NAFLD progression, mainly by triggering hepatocyte stress and damage. Furthermore, when hepatocytes are exposed to excessive nutrient overload and FFAs, mitochondria become disintegrated through increased fission. DNL, de novo lipogenesis; TGs, triglycerides; OMM; outer mitochondrial membrane; IMM, inner mitochondrial membrane; ATP, adenosine triphosphate; Drp1, dynamin-like/related protein 1. Pathways and procedures that are increased are designated by ↑
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