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. 2022 May;43(5):1141-1155.
doi: 10.1038/s41401-022-00864-z. Epub 2022 Feb 1.

Mitochondria homeostasis: Biology and involvement in hepatic steatosis to NASH

Yu-Feng Li #  1 , Zhi-Fu Xie #  1 , Qian Song  1   2 , Jing-Ya Li  3   4   5
Affiliations

Mitochondria homeostasis: Biology and involvement in hepatic steatosis to NASH

Yu-Feng Li et al. Acta Pharmacol Sin. 2022 May.

Abstract

Mitochondrial biology and behavior are central to the physiology of liver. Multiple mitochondrial quality control mechanisms remodel mitochondrial homeostasis under physiological and pathological conditions. Mitochondrial dysfunction and damage induced by overnutrition lead to oxidative stress, inflammation, liver cell death, and collagen production, which advance hepatic steatosis to nonalcoholic steatohepatitis (NASH). Accumulating evidence suggests that specific interventions that target mitochondrial homeostasis, including energy metabolism, antioxidant effects, and mitochondrial quality control, have emerged as promising strategies for NASH treatment. However, clinical translation of these findings is challenging due to the complex and unclear mechanisms of mitochondrial homeostasis in the pathophysiology of NASH.

Keywords: NASH; liver; metabolism; mitochondria; mitochondrial homeostasis.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. The regulations of hepatic mitochondria homeostasis by nuclear and mitochondrial genomes.
Mitochondria arose from an ancestral bacterium and contain their own genome (mtDNA), which encodes 13 proteins involved in the respiratory chains. However, greater than 98% of the total protein complement of the organelle is encoded by the nuclear genome and plays a crucial role in mitochondrial function. An overview of the regulation of mitochondrial and nuclear genomes in mitochondrial gene expression and the signaling pathways is summarized in this figure. MtDNA gene replication, transcription, and translation regulations are all involved in the assembly of OXPHOS complexes, which play an important role in mitochondrial function. The nuclear genomes encoded mitochondrial function-related proteins via transcription (chromatin remodeling, DNA methylation, transcription factors) and posttranscription (miRNA interference, alternative splicing, RNA stability) regulation and control the mitochondrial function, such as OXPHOS, FAO, TCA cycle, mitochondrial biogenesis, mitochondrial fission/fusion, and mitophagy (see text for additional information).
Fig. 2
Fig. 2. Hepatic mitochondrial dysfunction is tightly associated with NASH development.
Western diet drives the mitochondrial TCA cycle and induces lipogenesis and lipid droplet formation. Hepatic lipid accumulation accelerates insulin resistance in the liver and adipose tissue, which results in a massive flux of FFAs into the liver from adipose tissue. FFAs overload in the liver and hepatic insulin resistance results in inefficient β-oxidation and uncouples mitochondrial TCA cycle activity from OXPHOS, which leads to excessive ROS generation. Hepatic ROS accumulation and lipotoxicity caused by lipid overload promote hepatocyte cell death via apoptosis or necrosis. Dysfunctional hepatocytes secrete microparticles containing chemotactic signals (inflammatory or necrosis factor) into the extracellular matrix, which induce hepatic resistant immune cells (macrophages) or recruit immune cells from bone marrow activation. The fibrogenic signal derived from dysfunctional hepatocytes and/or inflammatory cells activates HSCs and promotes the development of liver fibrosis. Overnutrition or intestinal microbiota-derived signal stimulation induces mitochondrial metabolic remodeling in macrophages and HSCs, which further accelerates the development of NASH directly or indirectly. Abbreviations: ROS reactive oxygen species, TCA cycle tricarboxylic acid cycle, FFA free fatty acid, OXPHOS oxidative phosphorylation system, mtDNA mitochondrial DNA, HSCs hepatic stellate cell, NASH nonalcoholic steatohepatitis.
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