TACO1 regulates mitochondrial adaptation in hypertension-induced cardiac remodeling and heart failure
- Res Sq. 2026 May 5:rs.3.rs-9589283. doi: 10.21203/rs.3.rs-9589283/v1.
- 1. Department of Foundational Science, East Carolina University, Greenville, NC, USA.
- 2. Department of Pharmacology and Toxicology, East Carolina University, Greenville, NC, USA.
- 3. Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, USA.
- 4. Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
- 5. Department of Medicine, Division of Genetic Medicine & Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
- 6. Department of Computer Science, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
- 7. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
- 8. Department of Social and Behavioral Sciences, Yale School of Public Health, New Haven, CT, 06520, USA.
- 9. Environmental Sciences Graduate Program, Oregon State University, Corvalis, OR 97331, USA.
- 10. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
- 11. Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
- 12. Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
- 13. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
- 14. Department of Chemistry, Vanderbilt University, Nashville, TN, USA.
- 15. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
- 16. Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, NC, USA.
- 17. Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN, USA.
- 18. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- 19. The Huck Institutes of the Life Sciences; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, USA.
Mitochondrial dysfunction drives hypertensive heart failure and reflects impaired Oxidative Phosphorylation and altered organelle structure. The mechanisms linking hypertensive signaling to mitochondrial translation and architecture remain unclear. TACO1 is a mitochondrial translational activator required for cytochrome c oxidase subunit I synthesis and may regulate respiratory chain assembly. We tested whether angiotensin II type 1 receptor activation disrupts TACO1-dependent translation and drives inner membrane remodeling. Using mRen also known as (mRen2)27 hypertensive rat hearts, we assessed mitochondrial function, ultrastructure, and metabolism. AT1R activation reduced TACO1-dependent COX I translation and produced a selective deficiency in complex IV activity. This impaired Oxidative Phosphorylation and increased the production of Reactive Oxygen Species. Mitochondria exhibited reduced volume, increased fragmentation, and disrupted cristae organization with lower integrity scores. Hypertensive hearts also showed reduced expression of OPA1 and MICOS components. Metabolomic profiling separated control and heart failure groups and revealed enrichment of amino acid, nucleotide, and mitochondrial energy pathways. Lipidomic analysis identified coordinated changes across lipid classes consistent with altered membrane composition. Pharmacological AT1R inhibition restored COX I translation, rescued complex IV activity, and improved cristae structure. These findings establish a mechanistic link between hypertensive signaling, mitochondrial translation, cristae organization, and metabolic remodeling in heart failure.