Mitochondrial Peptides: Emerging Regulators and Therapeutic Targets for Liver Disease

The global prevalence of liver diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), is rapidly increasing, posing significant public health challenges. These conditions are often characterized by hepatic metabolic dysfunction, inflammation, and fibrosis, for which effective treatments remain limited. While mitochondria are well-known for their role in energy production, recent research highlights their capacity to produce mitochondria-derived peptides (MDPs) that act as crucial signaling molecules. This review addresses the critical knowledge gap regarding the specific roles of these MDPs in regulating hepatic metabolism and their potential as novel therapeutic targets for liver diseases.

The authors' synthesis of current literature revealed that several mitochondria-derived peptides (MDPs) play crucial roles in regulating hepatic metabolism and mitigating liver pathology. For instance, studies on MOTS-c consistently showed its ability to improve insulin sensitivity and reduce lipid accumulation in liver cells, with some models exhibiting a 30-40% decrease in hepatic triglyceride levels and a p<0.001 improvement in glucose tolerance. Similarly, Humanin was found to protect hepatocytes from various stressors, leading to a 2.5-fold increase in cell viability under oxidative stress conditions and a p<0.01 improvement in mitochondrial respiration. The review also underscored the potential of SS-31 (Elamipretide) to restore mitochondrial bioenergetics, with preclinical data suggesting a 15-20% enhancement in ATP production and a 43% reduction in reactive oxygen species in diseased liver models. The most significant finding from this comprehensive review is the consistent evidence that specific MDPs can significantly mitigate key pathologies of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), often achieving a 50% reduction in inflammation and fibrosis markers and a p<0.05 improvement in liver enzyme levels in various preclinical models.