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Loss of mitochondrial adaptation associates with deterioration of mitochondrial turnover and structure in metabolic dysfunction-associated steatotic liver disease.
Metabolism 151, 12 (2024)
Background: Obesity and type 2 diabetes frequently have metabolic dysfunction-associated steatotic liver disease (MASLD) including steatohepatitis (MASH). In obesity, the liver may adapt its oxidative capacity, but the role of mitochondrial turnover in MASLD remains uncertain.Methods: This cross-sectional study compared individuals with class III obesity (n = 8/group) without (control, OBE CON; NAFLD activity score: 0.4 +/- 0.1) or with steatosis (OBE MASL, 2.3 +/- 0.4), or MASH (OBE MASH, 5.3 +/- 0.3, p < 0.05 vs. other groups). Hepatic mitochondrial ultrastructure was assessed by transmission electron microscopy, mitochondrial respiration by high-resolution respirometry, biomarkers of mitochondrial quality control and endoplasmic reticulum (ER) stress by Western Blot.Results: Mitochondrial oxidative capacity was 31 % higher in OBE MASL, but 25 % lower in OBE MASH (p < 0.05 vs. OBE CON). OBE MASH showed similar to 1.5fold lower mitochondrial number, but similar to 1.2-1.5fold higher diameter and area (p < 0.001 vs. other groups). Biomarkers of autophagy (p62), mitophagy (PINK1, PARKIN), fission (DRP-1, FIS1) and fusion (MFN1/2, OPA1) were reduced in OBE MASH (p < 0.05 vs. OBE CON). OBE MASL showed lower p62, p-PARKIN/PARKIN, and p-DRP-1 (p < 0.05 vs. OBE CON). OBE MASL and MASH showed higher ER stress markers (PERK, ATF4, p-eIF2 alpha-S51/eIF2 alpha; p < 0.05 vs. OBE CON). Mitochondrial diameter associated inversely with fusion/fission biomarkers and with oxidative capacity, but positively with H2O2.Conclusion: Humans with hepatic steatosis already exhibit impaired mitochondrial turnover, despite upregulated oxidative capacity, and evidence for ER stress. In MASH, oxidative stress likely mediates progressive decline of mitochondrial turnover, ultrastructure and respiration indicating that mitochondrial quality control is key for energy metabolism and may have potential for targeting MASH.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Fatty liver; MASH; Obesity; Insulin resistance; Mitochondrial function; Mitophagy; Ultrastructure; Nonalcoholic Fatty Liver; Endoplasmic-reticulum Stress; Insulin-resistance; Crystalline Inclusions; Steatohepatitis; Deficiency; Mechanisms; Pathology
ISSN (print) / ISBN
0026-0495
e-ISSN
1532-8600
Zeitschrift
Metabolism: clinical and experimental
Quellenangaben
Band: 151,
Seiten: 12
Verlag
Elsevier
Verlagsort
1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa
Begutachtungsstatus
Peer reviewed
Institut(e)
Helmholtz AI - DLR (HAI - DLR)
Förderungen
Schmutzler-Stiftung
German Diabetes Association (DDG)
Federal Ministry for Research (BMBF)
German Federal Ministry of Health (BMG)
German Diabetes Center (DDZ) - Ministry of Culture and Science of the State of Northrhine Westphalia
German Diabetes Association (DDG)
Federal Ministry for Research (BMBF)
German Federal Ministry of Health (BMG)
German Diabetes Center (DDZ) - Ministry of Culture and Science of the State of Northrhine Westphalia