Language
English
Publication Date
12-13-2024
Journal
Science Advances
DOI
10.1126/sciadv.adp7444
PMID
39661674
PMCID
PMC11633734
PubMedCentral® Posted Date
12-11-2024
PubMedCentral® Full Text Version
Post-print
Abstract
The mitochondrial permeability transition pore (mPTP) is implicated in cardiac ischemia-reperfusion (I/R) injury. During I/R, elevated mitochondrial Ca2+ triggers mPTP opening, leading to necrotic cell death. Although nonessential regulators of this pore are characterized, the molecular identity of the pore-forming component remains elusive. Two of these genetically verified regulators are cyclophilin D (CypD) and the adenine nucleotide translocase (ANT) family. We investigated the ANT/CypD relationship in mPTP dynamics and I/R injury. Despite lacking all ANT isoforms, Ca2+-dependent mPTP opening persisted in cardiac mitochondria but was desensitized. This desensitization conferred resistance to I/R injury in ANT-deficient mice. CypD is hypothesized to trigger mPTP opening through isomerization of ANTs at proline-62. To test this, we generated mice that expressed a P62A mutated version of ANT1. These mice showed similar mPTP dynamics and I/R sensitivity as the wild type, indicating that P62 is dispensable for CypD regulation. Together, these data indicate that the ANT family contributes to mPTP opening independently of CypD.
Keywords
Animals, Mitochondrial Permeability Transition Pore, Peptidyl-Prolyl Isomerase F, Mice, Myocardial Reperfusion Injury, Mitochondrial ADP, ATP Translocases, Calcium, Mitochondrial Membrane Transport Proteins, Mitochondria, Heart, Mice, Knockout, Cyclophilins
Published Open-Access
yes
Recommended Citation
Patel, Pooja; Mendoza, Arielys; Ramirez, Daniel; et al., "The Adenine Nucleotide Translocase Family Underlies Cardiac Ischemia-Reperfusion Injury Through the Mitochondrial Permeability Pore Independently of Cyclophilin D" (2024). Faculty, Staff and Students Publications. 8109.
https://digitalcommons.library.tmc.edu/baylor_docs/8109