HADHA Regulates Respiratory Complex Assembly and Couples FAO and OXPHOS
Oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) are key bioenergetics pathways. The machineries for both processes are localized in mitochondria. Secondary OXPHOS defects have been documented in patients with primary FAO deficiencies, and vice versa. However, the underlying mechanisms remain unclear. Intrigued by the observations that regulation of supercomplexes (SCs) assembly in a mouse OXPHOS deficient cell line and its derivatives is associated with the changes in lipid metabolism, a proteomics analysis is carried out and identified mitochondrial trifunctional protein (MTP) subunit alpha (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha, HADHA) as a potential regulatory factor for SCs assembly. HADHA-Knockdown cells and mouse embryonic fibroblasts (MEFs) derived from HADHA-Knockout mice displayed both reduced SCs assembly and defective OXPHOS. Stimulation of OXPHOS induced in cell culture by replacing glucose with galactose and of lipid metabolism in mice with a high-fat diet (HFD) both exhibited increased HADHA expression. HADHA Heterozygous mice fed with HFD showed enhanced steatosis associated with a reduction of SCs assembly and OXPHOS function. The results indicate that HADHA participates in SCs assembly and couples FAO and OXPHOS.
Authors
- Ting Liang (ORCID: https://orcid.org/0000-0002-7924-5195)
- Susan T. Weintraub (ORCID: https://orcid.org/0000-0002-8328-7814)
- Shasha Gong (ORCID: https://orcid.org/0000-0003-0236-2323)
- James D. Lechleiter (ORCID: https://orcid.org/0000-0001-9000-0722)
- Shujie Song (ORCID: https://orcid.org/0009-0009-3350-9747)
- M. Lazcano Ortíz (ORCID: https://orcid.org/0000-0002-9653-9291)
- Peiqing Hu
- Janice Deng (ORCID: https://orcid.org/0009-0006-6827-048X)
- Chaoying Qin (ORCID: https://orcid.org/0000-0002-4476-0533)
- Thomas Jue (ORCID: https://orcid.org/0000-0003-1549-8414)
- Yidong Bai (ORCID: https://orcid.org/0000-0002-0954-7980)
- Exing Wang
- Yuji Ikeno (ORCID: https://orcid.org/0000-0002-9234-8738)
- Zhaofu Zhang (ORCID: https://orcid.org/0000-0002-1406-1256)
- Bi Zhu
- Yaguang Liu (ORCID: https://orcid.org/0000-0002-7900-8528)
Institutions
- Central South University (CN)
- The University of Texas at San Antonio Health Science Center (US)
- Murphy Oil Corporation (United States) (US)
- Geriatric Research Education and Clinical Center (US)
- Taizhou Central Hospital (CN)
- South Texas Veterans Health Care System (US)
- Xiangya Hospital Central South University (CN)
- Mays Cancer Center at UT Health San Antonio (US)
- The University of Texas at San Antonio (US)
- Taizhou University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2024-11-03
- DOI
- https://doi.org/10.1002/advs.202405147
- Citations
- 5
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 1.17
Funders
- National Institutes of Health
- University of Texas Health Science Center at San Antonio