Cardiolipin deficiency disrupts CoQ redox state and induces steatohepatitis.

Autor: Brothwell MJ; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA., Cao 曹国燊 G; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Biochemistry; University of Utah; Salt Lake City, UT; USA., Maschek JA; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA.; Metabolomics Core Research Facility; University of Utah; Salt Lake City, UT; USA., Poss AM; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA., Peterlin AD; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA., Wang 汪立平 L; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA., Baker TB; Huntsman Cancer Institute; University of Utah, Salt Lake City, UT; USA.; Division of Transplantation and Advanced Hepatobiliary Surgery, Department of Surgery; University of Utah; Salt Lake City, UT; USA., Shahtout JL; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Physical Therapy and Athletic Training; University of Utah; Salt Lake City, UT; USA., Siripoksup P; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Physical Therapy and Athletic Training; University of Utah; Salt Lake City, UT; USA., Pearce QJ; Metabolomics Core Research Facility; University of Utah; Salt Lake City, UT; USA., Johnson JM; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA., Finger FM; Novo Nordisk Foundation Center for Basic Metabolic Research; University of Copenhagen; Copenhagen; DK.; Center for Adipocyte Signaling (ADIPOSIGN); University of Southern Denmark; Odense; DK., Prola A; Laboratory of Fundamental and Applied Bioenergetics; University of Grenoble Alpes, Inserm U1055; Grenoble; FR., Pellizzari SA; Department of Biochemistry; University of Utah; Salt Lake City, UT; USA.; Department of Pathology; University of Utah; Salt Lake City, UT; USA., Hale GL; Huntsman Cancer Institute; University of Utah, Salt Lake City, UT; USA.; Department of Pathology; University of Utah; Salt Lake City, UT; USA., Manuel AM; Metabolomics Core Research Facility; University of Utah; Salt Lake City, UT; USA., Watanabe 渡邉真也 S; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA., Miranda ER; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA.; Molecular Medicine Program; University of Utah; Salt Lake City, UT; USA., Affolter KE; Huntsman Cancer Institute; University of Utah, Salt Lake City, UT; USA.; Laboratory of Fundamental and Applied Bioenergetics; University of Grenoble Alpes, Inserm U1055; Grenoble; FR., Tippetts TS; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA., Nikolova LS; Electron Microscopy Core Facility; University of Utah; Salt Lake City, UT; USA., Choi 崔蘭煕 RH; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA.; Molecular Medicine Program; University of Utah; Salt Lake City, UT; USA., Decker ST; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA.; Molecular Medicine Program; University of Utah; Salt Lake City, UT; USA., Patil M; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA.; Molecular Medicine Program; University of Utah; Salt Lake City, UT; USA., Catrow JL; Metabolomics Core Research Facility; University of Utah; Salt Lake City, UT; USA., Holland WL; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA.; Department of Biochemistry; University of Utah; Salt Lake City, UT; USA.; Molecular Medicine Program; University of Utah; Salt Lake City, UT; USA., Nowinski SM; Department of Metabolism and Nutritional Programming; Van Andel Institute; Grand Rapids, MI; USA., Lark DS; College of Health and Human Sciences; Colorado State University; Fort Collins, CO; USA.; Columbine Health Systems Center for Healthy Aging; Colorado State University; Fort Collins, CO; USA., Fisher-Wellman KH; Department of Cancer Biology, Wake Forest University School of Medicine; Atrium Health Wake Forest Baptist Comprehensive Cancer Center; Winston-Salem, NC; USA., Mimche PN; Departments of Dermatology and Medicine; Division of Gastroenterology and Hepatology, Indiana University School of Medicine; Indianapolis, IN; USA., Evason KJ; Huntsman Cancer Institute; University of Utah, Salt Lake City, UT; USA.; Department of Pathology; University of Utah; Salt Lake City, UT; USA., Cox JE; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Biochemistry; University of Utah; Salt Lake City, UT; USA.; Metabolomics Core Research Facility; University of Utah; Salt Lake City, UT; USA., Summers SA; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA.; Department of Biochemistry; University of Utah; Salt Lake City, UT; USA.; Huntsman Cancer Institute; University of Utah, Salt Lake City, UT; USA.; Molecular Medicine Program; University of Utah; Salt Lake City, UT; USA., Gerhart-Hines Z; Novo Nordisk Foundation Center for Basic Metabolic Research; University of Copenhagen; Copenhagen; DK.; Center for Adipocyte Signaling (ADIPOSIGN); University of Southern Denmark; Odense; DK., Funai 船井勝彦 K; Diabetes & Metabolism Research Center; University of Utah; Salt Lake City, UT; USA.; Department of Nutrition and Integrative Physiology; University of Utah; Salt Lake City, UT; USA.; Department of Biochemistry; University of Utah; Salt Lake City, UT; USA.; Huntsman Cancer Institute; University of Utah, Salt Lake City, UT; USA.; Department of Physical Therapy and Athletic Training; University of Utah; Salt Lake City, UT; USA.; Molecular Medicine Program; University of Utah; Salt Lake City, UT; USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 10. Date of Electronic Publication: 2024 Oct 10.
DOI: 10.1101/2024.10.10.617517
Abstrakt: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, cardiolipin (CL) was downregulated across four mouse models of MASLD. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous MASH with elevated mitochondrial electron leak. Loss of CL interfered with the ability of coenzyme Q (CoQ) to transfer electrons, promoting leak primarily at sites II F and III Q0 . Data from human liver biopsies revealed a highly robust correlation between mitochondrial CL and CoQ, co-downregulated with MASH. Thus, reduction in mitochondrial CL promotes oxidative stress and contributes to pathogenesis of MASH.
Databáze: MEDLINE