Altered Mitochondrial Function in MASLD: Key Features and Promising Therapeutic Approaches

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), encompasses a range of liver conditions from steatosis to nonalcoholic steatohepatitis (NASH). Its prevalence, especially among patients with metabolic syndrome, highlights its growing global impact. The pathogenesis of MASLD involves metabolic dysregulation, inflammation, oxidative stress, genetic factors and, notably, mitochondrial dysfunction. Recent studies underscore the critical role of mitochondrial dysfunction in MASLD's progression. Therapeutically, enhancing mitochondrial function has gained interest, along with lifestyle changes and pharmacological interventions targeting mitochondrial processes. The FDA's approval of resmetirom for metabolic-associated steatohepatitis (MASH) with fibrosis marks a significant step. While resmetirom represents progress, further research is essential to understand MASLD-related mitochondrial dysfunction fully. Innovative strategies like gene editing and small-molecule modulators, alongside lifestyle interventions, can potentially improve MASLD treatment. Drug repurposing and new targets will advance MASLD therapy, addressing its increasing global burden. Therefore, this review aims to provide a better understanding of the role of mitochondrial dysfunction in MASLD and identify more effective preventive and treatment strategies.

Keywords: MASH; MASLD; metabolic syndrome; mitochondria; mitochondrial dysfunction; mitochondrial quality control; oxidative stress.

Figure 1

Progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Created with BioRender.com. Accessed on 22 July 2024.

Figure 2

Mitochondrial quality control (MQC) mechanisms. Abbreviations: TFAM, mitochondrial transcription factor A; mtDNA, mitochondrial DNA; PINK1, PTEN-induced kinase 1; FIS1, fission protein 1; MFF, mitochondrial fission factor; DRP1, dynamin-related protein 1; OPA1, optic atrophy 1; MFN1, mitofusin 1; MFN2, mitofusin 2. Created with BioRender.com. Accessed on 22 July 2024.

Figure 3

Mechanisms of mitochondrial dysfunction in MASLD. Abbreviations: FFAs, free fatty acids; ROS, reactive oxygen species; ETC, electron transport chain; Cyt C, cytochrome c; mtDNA, mitochondrial DNA; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator 1α; NF-κB, nuclear factor-kappa B; NLRP3, nucleotide-binding oligomerization domain-like receptor 3; TNF-α, tumor necrosis factor-alpha; IL-1β, interleukin-1 beta; IL-6, interleukin-6; PINK1, PTEN-induced kinase 1; FIS1, fission protein 1; MFF, mitochondrial fission factor; DRP1, dynamin-related protein 1; OPA1, optic atrophy 1; MFN1, mitofusin 1; MFN2, mitofusin 2. Created with BioRender.com. Accessed on 23 July 2024.

Figure 4

Mitochondria-targeted agents and lifestyle changes in MASLD. Abbreviations: AMPK, AMP-activated protein kinase; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator 1α; SIRTs, sirtuins; PPAR, peroxisome proliferator-activated receptor; TZDs, thiazolidinediones; SGLT2, sodium–glucose co-transporter 2; MitoQ, Mito-quinone; MPC, mitochondrial pyruvate carrier; Cyt C, cytochrome c; mtDNA, mitochondrial DNA; CL, cardiolipin; ROS, reactive oxygen species; SOD, superoxide dismutase; GSH, glutathione. Created with BioRender.com. Accessed on 22 July 2024.