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Review
. 2023 Dec 15;24(24):17514.
doi: 10.3390/ijms242417514.

Mitochondrial Dysfunction in Metabolic Dysfunction Fatty Liver Disease (MAFLD)

Ying Zhao  1   2 , Yanni Zhou  1   2 , Dan Wang  1   2 , Ziwei Huang  1   2 , Xiong Xiao  1   2 , Qing Zheng  1   2 , Shengfu Li  1   3 , Dan Long  1   3 , Li Feng  1   2
Affiliations
Review

Mitochondrial Dysfunction in Metabolic Dysfunction Fatty Liver Disease (MAFLD)

Ying Zhao et al. Int J Mol Sci. .

Abstract

Nonalcoholic fatty liver disease (NAFLD) has become an increasingly common disease in Western countries and has become the major cause of liver cirrhosis or hepatocellular carcinoma (HCC) in addition to viral hepatitis in recent decades. Furthermore, studies have shown that NAFLD is inextricably linked to the development of extrahepatic diseases. However, there is currently no effective treatment to cure NAFLD. In addition, in 2020, NAFLD was renamed metabolic dysfunction fatty liver disease (MAFLD) to show that its pathogenesis is closely related to metabolic disorders. Recent studies have reported that the development of MAFLD is inextricably associated with mitochondrial dysfunction in hepatocytes and hepatic stellate cells (HSCs). Simultaneously, mitochondrial stress caused by structural and functional disorders stimulates the occurrence and accumulation of fat and lipo-toxicity in hepatocytes and HSCs. In addition, the interaction between mitochondrial dysfunction and the liver-gut axis has also become a new point during the development of MAFLD. In this review, we summarize the effects of several potential treatment strategies for MAFLD, including antioxidants, reagents, and intestinal microorganisms and metabolites.

Keywords: MAFLD; fatty acid metabolism; liver–gut axis; mitochondrial antioxidant; mitochondrial quality control; oxidative stress.

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Conflict of interest statement

No conflicts of interest exist in the review, and it was approved by all authors for publication. I would like to declare on behalf of my coauthors that the work described is original research that has not been published previously and is not under consideration for publication elsewhere, in whole or in part.

Figures

Figure 1
Figure 1
Oxidative stress caused by mitochondrial structures and mt-DNA mutations in MAFLD. Activation of the mitochondrial membrane permeability transition pore (MPTP) by factors such as mitochondrial mutant genes and the accumulation of fatty acids promotes the outflow of Ca2+ from the mitochondrial calcium pool and then stimulates the activity of inner membrane proteins to affect the ATP synthesis rate and form new transition pores. Mitochondrial gene mutation (mt-DNA) also stimulates the activation of MPTP and uncoupling proteins (UCPs). In addition, the reduction in the activity of inner membrane proteins leads to electron leakage in the ETC, which promotes the generation of mt-ROS and ultimately aggravates the degree of mitochondrial oxidative stress in MAFLD.
Figure 2
Figure 2
Mitochondrial quality control and oxidative stress in MAFLD.
Figure 3
Figure 3
Abnormal fatty acid oxidation in mitochondria. “↑” represents upregulated expression; “┬” represents downregulated expression. Carbohydrates in hepatocytes are initially metabolized into pyruvate, and then pyruvate forms free fatty acids (FFAs) through DNL. Finally, FFAs form triglycerides and VLDL in MAFLD. Upon stimulation such as the introduction of high sugar and fat, the activation of MPTP and decrease in PPARα leads to the abnormal structure of CPT1C and CPT2C, which transport FFAs on the mitochondrial membrane. FFAs flow into the mitochondrial matrix, causing lipotoxic accumulation and further affecting BAT consumption, which leads to obesity. FFAs in the matrix are decomposed into acyl-CoA via β-oxidation and then participate in oxidative phosphorylation. In MAFLD, PPARα can reduce the activity of β-oxidase and inhibit the decomposition of FFAs, while increasing the activity of PPAR-γ can promote the expression of FGF-21 and restore the oxidation of FFAs through the AMPK-mTOR pathway to inhibit the development of fibrosis. Moreover, mitochondrial oxidation imbalance causes the accumulation of mt-ROS, TNF, and LPS, aggravating the development of inflammation. At the same time, TNF can activate phosphorylated IKK to inhibit the NK-κB antioxidant response, including promoting the continuous accumulation of superoxide by reducing MnSOD activity and the Nf-κB/JNK reaction. In addition, Nrf2 mediates oxidation reaction efficiency and participates in fat metabolism. Nrf2 forms a ternary complex with Keap1 and PGAM5 to directly respond to mt-ROS and stimulates nuclear Nrf2 to be accelerated and transported into mitochondria. Nrf2 can eliminate excess mt-ROS accumulation and restore β-oxidation by enhancing the expression of Trx, GSR, Srx1, Prx3, and GPx. However, Nrf2 also participates in regulating the occurrence of mitophagy and aggravating ROS accumulation by reducing the expression of TXNIP and increasing the combination of Trx and ASK1.The abbreviations in Figure 3 are defined as follows: DNL (de novo lipogenesis); VLDL (very-low-density lipoprotein); MPTP (mitochondrial permeability transition pore); CPT1C (carnitine palmitoyl transferase 1C); CPT2C (carnitine palmitoyl transferase 2C); MCAD (medium-chain acyl-CoA dehydrogenase); LCAD (long-chain acyl-CoA dehydrogenase); VLCAD (very-long-chain acyl-CoA dehydrogenase); AMPT/MTOR (adenosine monophosphate-activated protein kinase/mammalian target of rapamycin); BAT (brown adipose tissue); NK-κB (nuclear factor kappa-light-chain-enhancer of activated B cells); LPS (lipopolysaccharide); IKK (IκB kinase); MnSOD (manganese superoxide dismutase); ETC (electron transport chain); TCA (tricarboxylic acid cycle): NADH/FADH2 (nicotinamide adenine dinucleotide (reduced form)/flavin adenine dinucleotide (reduced form)); Nrf2 (nuclear factor erythroid 2-related factor 2); PGAM5 (phosphoglycerate mutase family member 5); Prx3 (peroxiredoxin 3); TXNIP (thioredoxin-interacting protein); and ASK1 (apoptosis signal-regulating kinase).
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