Liver Cell Mitophagy in Metabolic Dysfunction-Associated Steatotic Liver Disease and Liver Fibrosis

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of the global population. MASLD and its advanced-stage liver fibrosis and cirrhosis are the leading causes of liver failure and liver-related death worldwide. Mitochondria are crucial organelles in liver cells for energy generation and the oxidative metabolism of fatty acids and carbohydrates. Recently, mitochondrial dysfunction in liver cells has been shown to play a vital role in the pathogenesis of MASLD and liver fibrosis. Mitophagy, a selective form of autophagy, removes and recycles impaired mitochondria. Although significant advances have been made in understanding mitophagy in liver diseases, adequate summaries concerning the contribution of liver cell mitophagy to MASLD and liver fibrosis are lacking. This review will clarify the mechanism of liver cell mitophagy in the development of MASLD and liver fibrosis, including in hepatocytes, macrophages, hepatic stellate cells, and liver sinusoidal endothelial cells. In addition, therapeutic strategies or compounds related to hepatic mitophagy are also summarized. In conclusion, mitophagy-related therapeutic strategies or compounds might be translational for the clinical treatment of MASLD and liver fibrosis.

Keywords: Kupffer cells (KCs); hepatic stellate cells (HSCs); hepatocytes; liver fibrosis; liver sinusoidal endothelial cells (LSECs); macrophages; metabolic dysfunction-associated steatohepatitis (MASH); metabolic dysfunction-associated steatotic liver disease (MASLD); mitochondria; mitophagy.

Figure 1

Processes of mitophagy. The process of mitophagy can be divided into five steps: (1) Initiation: ATG8 family proteins are anchored in the inner and outer membranes of the phagophores. (2) Recognition: SMRs or MMRs recognize impaired mitochondria and link the mitochondria to phagophores via the ATG8-LIR interaction. (3) Sequestration: Impaired mitochondria are sequestered, forming mitophagosomes. (4) Fusion: Mitophagosomes further fuse with lysosomes to form mitolysosomes. (5) Degradation: Impaired mitochondria are degraded and recycled in mitolysosomes. Abbreviations: Atg, autophagy-related gene; SMRs, soluble mitophagy receptors; MMRs, membrane-attached mitophagy receptors; UBDs, ubiquitin-binding domains; LIR, microtubule-associated protein 1A/1B light chain 3 (LC3)-interacting region (LIR); OMM, outer mitochondrial membrane.

Figure 2

Mitophagy signaling pathways. The mitophagy signaling pathways can be classified as PINK1/Parkin-dependent (a), PINK1/Parkin-independent (b), or other mitophagy signaling pathways (c). (a) In healthy mitochondria, PINK1 translocates into mitochondria through TOMM and TIMM and is proteolytically cleaved by PARL and MPP. Upon mitochondrial damage, PINK1 fails to enter and accumulates on the OMM, which recruits and phosphorylates Parkin. PINK1 and Parkin jointly generate p-Ub chains on the OMM. SMRs (e.g., p62, OPTN, and NDP52) recognize p-Ub signals and link damaged mitochondria to phagophores via the LIR-ATG8 interaction. (b) MMRs directly interact with lipidated ATG8. BNIP3, BNIP3L, and FUNDC1 are common in response to hypoxia. PHB2 localizes to the IMM. Upon proteasome-mediated rupture of the OMM, PHB2 interacts with ATG8. (c) Several ubiquitin ligases, MUL1, SIAH1, and ARIH1, ubiquitinate the OMM to promote mitophagy. Notably, MUL1 has an LIR motif that interacts with ATG8. Damaged mitochondria can be translocated to other cells (e.g., macrophages) through exospheres or EVs for mitophagy. MDVs derived from mitochondria fuse with lysosomes for degradation. Cardiolipin translocates from the IMM to the OMM to interact with ATG8. Abbreviations: TOMM/TIMM, translocase complex of the outer/inner mitochondrial membrane (OMM/IMM); PARL, presenilin-associated rhomboid-like protein; MPP, mitochondrial processing peptidase; p-Ub, phosphorylated ubiquitin; MDVs, mitochondria-derived vesicles; EVs, extracellular vesicles.

Figure 3

Hepatocyte mitophagy in MASLD and liver fibrosis. Many regulators and signaling pathways are involved in hepatocyte mitophagy in MASLD and liver fibrosis. In most cases, damaged hepatocyte mitophagy leads to the aggravation of inflammation, the accumulation of dysfunctional mitochondria, enhanced oxidative stress, lipid accumulation, and apoptosis. Notably, there is a crosstalk between hepatocytes and macrophages. A reduction in Miz1 results in increased levels of free PRDX6. PRDX6 interacts with Parkin and blocks Parkin autoubiquitination as well as downstream OMM ubiquitination. Impaired mitophagy caused hepatocyte inflammasome activation and stimulated macrophage TNF-α production. TNF-α further promotes Miz1 degradation in hepatocytes, forming a vicious feedback loop. Created with BioRender.com (accessed on 29 May 2024).

Figure 4

HSC mitophagy in MASLD and liver fibrosis. In response to CCl₄, downregulated SIRT3 fails to specifically deacetylate PINK1 and NIPSNAP1, resulting in impaired mitophagy. During the process of CCl₄ withdrawal, downregulation of BCL-B promotes HSC apoptosis by inducing Parkin-mediated mitophagy. Hepatocytes under nutritional stress release exosomal miR-27a to inhibit PINK1-mediated mitophagy in HSCs, leading to the activation of HSCs. Abbreviations: ECM, extracellular matrix. Created with BioRender.com (accessed on 30 March 2024).

Figure 5

Macrophage mitophagy in MASLD and liver fibrosis. During MASH progression, elevated PTPROt expression exacerbates inflammation. However, PTPROt enhances mitophagy to partially restrict ROS production and inflammation. In liver fibrosis, XBP1 binds directly to the Bnip3 promoter, suppressing the transcription of Bnip3. Impaired BNIP3-mediated mitophagy ultimately leads to increased release of pro-inflammatory and pro-fibrotic cytokines in macrophages. High TIM-4 levels contribute to increased levels of PINK1 and Parkin and the induction of TGF-β1. Created with BioRender.com (accessed on 29 May 2024).