Endogenous complement 1q binding protein (C1qbp) regulates mitochondrial permeability transition and post-myocardial infarction remodeling and dysfunction.

Autor: Gutiérrez-Aguilar M; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA; Departamento de Bioquímica, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico., Klutho PJ; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA., Aguayo-Ortiz R; Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico., Song L; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA., Baines CP; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA; Department of Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA; Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65211, USA. Electronic address: bainesc@missouri.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2024 Nov; Vol. 196, pp. 1-11. Date of Electronic Publication: 2024 Aug 30.
DOI: 10.1016/j.yjmcc.2024.08.005
Abstrakt: The mitochondrial permeability transition (MPT) pore regulates necrotic cell death following diverse cardiac insults. While the componentry of the pore itself remains controversial, Cyclophilin D (CypD) has been well-established as a positive regulator of pore opening. We have previously identified Complement 1q-binding protein (C1qbp) as a novel CypD-interacting molecule and a negative regulator of MPT-dependent cell death in vitro. However, its effects on the MPT pore and sensitivity to cell death in the heart remain untested. We therefore hypothesized that C1qbp would inhibit MPT in cardiac mitochondria and protect cardiac myocytes against cell death in vivo. To investigate the effects of C1qbp in the myocardium we generated gain- and loss-of-function mice. Transgenic C1qbp overexpression resulted in decreased complex protein expression and reduced mitochondrial respiration and ATP production but MPT was unaffected. In contrast, while C1qbp +/- mice did not exhibit any changes in mitochondrial protein expression, respiration, or ATP, the MPT pore was markedly sensitized to Ca 2+ in these animals. Neither overexpression nor depletion of C1qbp significantly affected baseline heart morphology or function at 3 months of age. When subjected to myocardial infarction, C1qbp transgenic mice exhibited similar infarct sizes and cardiac remodeling to non-transgenic mice, consistent with the lack of an effect on MPT. In contrast, cardiac scar formation and dysfunction were significantly increased in the C1qbp +/- mice compared to C1qbp +/+ controls. Our results suggest that C1qbp is required for normal regulation of the MPT pore and mitochondrial function, and influences cardiac remodeling following MI, the latter more likely being independent of C1qbp effects on the MPT pore.
Competing Interests: Declaration of competing interest None.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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