Mitochondrial interactome quantitation reveals structural changes in metabolic machinery in the failing murine heart
Open accessPublished version of a preprint
Abstract
Advancements in cross-linking mass spectrometry (XL-MS) bridge the gap between purified systems and native tissue environments, allowing the detection of protein structural interactions in their native state. Here we use isobaric quantitative protein interaction reporter technology (iqPIR) to compare the mitochondria protein interactomes in healthy and hypertrophic murine hearts, 4 weeks post-transaortic constriction. The failing heart interactome includes 588 statistically significant cross-linked peptide pairs altered in the disease condition. We observed an increase in the assembly of ketone oxidation oligomers corresponding to an increase in ketone metabolic utilization; remodeling of NDUA4 interaction in Complex IV, likely contributing to impaired mitochondria respiration; and conformational enrichment of ADP/ATP carrier ADT1, which is non-functional for ADP/ATP translocation but likely possesses non-selective conductivity. Our application of quantitative cross-linking technology in cardiac tissue provides molecular-level insights into the complex mitochondria remodeling in heart failure while bringing forth new hypotheses for pathological mechanisms.
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Cites
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- Authors
- Caudal, A., Tang, X., Chavez, J. D., Keller, A., Mohr, J. P., Bakhtina, A. A., Villet, O., Chen, H., Zhou, B., Walker, M. A., Tian, R., & Bruce, J. E.
- Affiliations
- University of Washington (US)
- Corresponding author
- Tian, Rong
- Bruce, James E.
- ORCID
- Venue
- Nature Cardiovascular Research
- Published
- 2022-09-09
- Volume
- 1
- Issue
- 9
- Pages
- 855-866
- ISSN
- 2731-0590 (ISSN-L)
- PMC
- PMC9667921
- OpenAlex
- W4295138518
- Cited by
- 33
- References
- 5
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 4 · 2023: 11
- FWCI
- 2.04
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Cardiovascular Research (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association (20PRE35120126, 18POST33990352, 930223)
- China Scholarship Council (202006320416)
- U.S. Department of Health & Human Services | National Institutes of Health (2T32DK007247, 5R01HL110349, 5R01HL129510, 5R01HL142628, 5R35GM136255, 5R01HL144778, 5R01GM086688)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Biotin and Related Studies
- Keywords
- heart failure, mitochondrial interactome, protein-protein interaction, cross-linking mass spectrometry, ketone oxidation, cytochrome c oxidase, adenine nucleotide translocase, mitochondrial respiration, transverse aortic constriction, cardiac metabolic remodeling
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