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. 2024 Feb:151:155762.
doi: 10.1016/j.metabol.2023.155762. Epub 2023 Dec 19.

Loss of mitochondrial adaptation associates with deterioration of mitochondrial turnover and structure in metabolic dysfunction-associated steatotic liver disease

Theresia Sarabhai  1 , Sabine Kahl  1 , Sofiya Gancheva  1 , Lucia Mastrototaro  2 , Bedair Dewidar  2 , Dominik Pesta  3 , Jacqueline M Ratter-Rieck  2 , Pavel Bobrov  4 , Kay Jeruschke  2 , Irene Esposito  5 , Matthias Schlensak  6 , Michael Roden  7
Affiliations

Loss of mitochondrial adaptation associates with deterioration of mitochondrial turnover and structure in metabolic dysfunction-associated steatotic liver disease

Theresia Sarabhai et al. Metabolism. 2024 Feb.

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Abstract

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 ~1.5fold lower mitochondrial number, but ~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-eIF2α-S51/eIF2α; 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. ClinGovTrial:NCT01477957.

Keywords: Fatty liver; Insulin resistance; MASH; Mitochondrial function; Mitophagy; Obesity; Ultrastructure.

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Conflict of interest statement

Declaration of competing interest M.R. received personal fees from Allergan, Astra-Zeneca, Boehringer-Ingelheim, Eli Lilly, Fishawack Group, Gilead Sciences, Novo Nordisk, Pfizer, Prosciento and Target RWE and investigator-initiated research support from Boehringer-Ingelheim, Nutricia/Danone and Sanofi-Aventis. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

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