Mitochondria-derived peptides in liver disease - Emerging regulators of hepatic metabolism and therapeutic targets

Sep 30, 2026

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Mitochondria-derived peptides (MDPs) are bioactive molecules encoded by small open reading frames in mitochondrial DNA, including Humanin, MOTS-c, and small humanin-like peptides (SHLP1–6). These peptides support liver homeostasis by preserving mitochondrial function, limiting oxidative stress and apoptosis, and coordinating metabolic adaptation. Intracellularly they regulate mitochondrial activity and cell survival, while extracellularly they signal via autocrine, paracrine, or endocrine pathways to influence nuclear gene expression. Emerging evidence connects MDPs to metabolic dysfunction–associated steatotic liver disease (MASLD) and highlights Humanin, MOTS-c, and SHLPs as therapeutic targets.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Abstract

Mitochondria-derived peptides and key family members

Intracellular and extracellular mechanisms

Relevance to MASLD and therapeutic targets

Mitochondria-derived peptides in liver disease: Emerging regulators of hepatic metabolism and therapeutic targets VISUAL ABSTRACT DOI: 10. 1097/HC9 .0000000000000885 REVIEW Mitochondria-derived peptides in liver disease: Emerging regulators of hepatic metabolism and therapeutic targets Themis Thoudam1 | Ge Zeng1,2 | Hui Gao1 | Yanchao Jiang1 | Nazmul Huda 1 | Zhihong Yang1 | Jing Ma1 | Suthat Liangpunsakul 1,3,4 1Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA 2Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China 3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA 4Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA Correspondence Themis Thoudam, Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 1481 W. 10th Street, Indianapolis, IN 46202, USA. Email: [tthoudam@iu.edu](tthoudam@iu.edu) Suthat Liangpunsakul, Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, IN 46202, USA. Email: [sliangpu@iu.edu](sliangpu@iu.edu) Abstract Mitochondria-derived peptides (MDPs) are bioactive molecules encoded by small open reading frames within mitochondrial DNA (mtDNA) . Humanin, the first MDP to be discovered, functions as a cytoprotective factor, protecting cells from stress-induced apoptosis. Subsequent discoveries expanded this family to include Mitochondrial Open-reading-frame of the Twelve S rRNA-c (MOTS-c), a key regulator of metabolic homeostasis and stress adaptation, and the Small Humanin-Like Peptides (SHLP1–6), which modulate mitochondrial bioenergetics and insulin sensitivity. MDPs play critical roles in liver homeostasis by maintaining mitochondrial function and metabolic balance. Intracellularly, they modulate mitochondrial activity, oxidative stress, and apoptosis, promoting hepatocyte survival. Extracellularly, they act in autocrine, paracrine, or endocrine manners, engaging receptors or signaling pathways to regulate nuclear gene expression and metabolic adaptation. Emerging evidence highlights their relevance in metabolic dysfunction–associated steatotic liver disease (MASLD) . Humanin exerts hepatoprotective effects by inhibiting apoptosis and modulating lipid metabolism. MOTS-c activates AMPK, regulates nuclear gene expression, suppresses fibrotic and inflammatory signaling, and Abbreviations: 5-MTHF, 5-methyl-tetrahydrofolate; AAV, adeno-associated virus; AD, Alzheimer’s disease; AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; AKT, protein kinase B; ALD, alcohol-associated liver disease; AMD, age-related macular degeneration; AMPK, AMP-activated protein kinase; ARE, antioxidant response element; ATF1, activating transcription factor 1; BAX, BCL2-associated X protein; BCL2, B-cell lymphoma 2; CMA, chaperone-mediated autophagy; CNS, Central Nervous System; CNTFRα , ciliary neurotrophic factor receptor alpha; CXCR7, chemokine receptor 7; DNPB, de novo purine biosynthesis; ERK1/2, extracellular signal-regulated kinase 1/2; ETC, electron transport chain; FAS, fatty acid synthase; FITC, fluorescein isothiocyanate; FPRL1, formyl peptide receptor–like 1; gp130, glycoprotein 130; HNG, S14G-humanin analogue; HSC, hepatic stellate cell; HSP, heavy strand promoter; HSP90, Heat Shock Protein 90; ICV, intracerebroventricular; IP, intraperitoneal; JAK2, Janus kinase 2; LKB1, liver kinase B1; LSP, light strand promoter; MAFLD, metabolic dysfunction–associated fatty liver disease; MAPK, mitogen-activated protein kinase; MASH, metabolic dysfunction–associated steatohepatitis; MASLD, metabolic dysfunction–associated steatotic liver disease; MDP, mitochondria-derived peptide; MOMP, mitochondrial outer membrane permeabilizat

FAQs

What are mitochondria-derived peptides (MDPs) and where are they encoded?

MDPs are bioactive molecules encoded by small open reading frames within mitochondrial DNA (mtDNA).

How do MDPs influence liver homeostasis?

MDPs maintain mitochondrial function and metabolic balance. They modulate mitochondrial activity, oxidative stress, and apoptosis to promote hepatocyte survival.

Why are MDPs considered relevant to metabolic dysfunction–associated steatotic liver disease (MASLD)?

Emerging evidence links MDPs to MASLD. Humanin shows hepatoprotective effects by inhibiting apoptosis and modulating lipid metabolism, while MOTS-c and SHLPs regulate pathways related to fibrosis, inflammation, glucose homeostasis, and oxidative stress.

Sep 30, 2026

Uploaded by moss~