The adenine nucleotide translocase family underlies cardiac ischemia-reperfusion injury through the mitochondrial permeability pore independently of cyclophilin D
Year: 2024
Type: article
Abstract: The mitochondrial permeability transition pore (mPTP) is implicated in cardiac ischemia-reperfusion (I/R) injury. During I/R, elevated mitochondrial Ca 2+ 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, Ca 2+ -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.
Source: Science Advances
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
OpenAlex ID: W4405280213