Preprint
Gamma-interferon-inducible lysosomal thiol reductase maintains cardiac immuno-metabolic homeostasis in heart failure
bioRxiv
Cold Spring Harbor Laboratory Press
02/22/2023
DOI: 10.1101/2022.07.03.498477
Abstract
Background: The lysosome is a central player in maintaining immuno-metabolic homeostasis. However, mechanistic insights into the regulation of lysosome-dependent immuno-metabolism in the heart are lacking. Lysosomal reductase Gamma Interferon-Inducible Thiol Reductase (GILT) is the only identified lysosomal reductase that controls diverse sets of lysosomal enzymes and cargoes. Methods: The role of cardiac GILT was assessed by generating a novel genetic mouse model and employing a multidisciplinary approach including surgical interventions, live in situ high resolution microscopy, whole-tissue respirometry analysis, unbiased transcriptomic and metabolomic analyses, and various cell biology and biochemical assays. Results: We found that expression and activity of GILT are reduced in hearts from humans and mice with heart failure (HF). Mice with cardiac specific loss of GILT develop late onset systolic HF at baseline. In the setting of nutrient-overload and experimental left ventricular pressure overload conditions, loss of GILT in cardiomyocytes accelerates the development of heart dysfunction. Transcriptomic and metabolic analyses further revealed that cardiac GILT deficiency alters adaptive immuno-metabolic signatures in the heart. Finally, at the cellular level, cardiac GILT deletion impaired mitochondrial respiration, which was in part due to NLR Family Pyrin Domain Containing 3 (NLRP3)-mediated elevation of mitochondrial oxidative stress. Conclusions: Together, these findings identify a causal link between a lysosome-inflammation axis, mitochondrial function and heart failure. Elucidation of these mechanisms will identify novel therapeutic strategies for treating HF. Competing Interest Statement The authors have declared no competing interest. Footnotes * This version of the manuscript has been revised to update our new data.
Details
- Title: Subtitle
- Gamma-interferon-inducible lysosomal thiol reductase maintains cardiac immuno-metabolic homeostasis in heart failure
- Creators
- Mark Li - University of IowaJinxi Wang - University of IowaQingwen Qian - University of IowaBiyi Chen - University of IowaZeyuan Zhang - University of IowaElizabeth BarrosoYuan Zhang - University of IowaDuan Hall - University of IowaEvan AbelLong-Sheng SongLing Yang - University of Iowa
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- DOI
- 10.1101/2022.07.03.498477
- Publisher
- Cold Spring Harbor Laboratory Press; Cold Spring Harbor
- Language
- English
- Date posted
- 02/22/2023
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984447838302771
Metrics
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