ABAT Overexpression Protects Against Doxorubicin-Induced Cardiotoxicity by Preserving Mitochondrial Homeostasis

Doxorubicin is a widely used chemotherapeutic agent whose clinical application is limited by dose-dependent cardiotoxicity, with mitochondrial dysfunction being a central pathological mechanism. Gamma-aminobutyric acid transaminase (ABAT) is a mitochondrial matrix enzyme implicated in mitochondrial DNA (mtDNA) maintenance through its role in the salvage synthesis of deoxyribonucleotides (dNTPs). However, whether ABAT exerts a protective role against doxorubicin-induced cardiotoxicity remains unknown. Here, we investigated the effect of ABAT overexpression on doxorubicin-induced cardiac injury and explored the underlying mechanisms. We found that ABAT expression and enzymatic activity were significantly reduced in the myocardium of doxorubicin-treated mice. Using cardiomyocyte-specific ABAT transgenic mice, we demonstrated that ABAT overexpression ameliorated doxorubicin-induced cardiac dysfunction, as evidenced by improved ejection fraction and fractional shortening, reduced serum levels of cardiac injury markers, and alleviated myocardial fibrosis and cardiomyocyte atrophy. Mechanistically, ABAT overexpression reversed doxorubicin-induced mtDNA depletion, restored mitochondrial respiratory chain complex activity, and improved oxygen consumption rate and ATP production, accompanied by reduced cellular and mitochondrial reactive oxygen species levels. Furthermore, doxorubicin triggered the initiation of mitophagy, as reflected by the accumulation of phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) and Parkin, but did not sustain autophagic degradation, as reflected by a markedly blunted bafilomycin A1-induced accumulation of microtubule-associated protein 1 light chain 3 beta II (LC3B-II) so that autophagic structures containing mitochondria accumulated; ABAT overexpression attenuated these changes, partially restoring the responsiveness of LC3B-II to bafilomycin A1. Complementary in vitro experiments using ABAT-overexpressing H9c2 cells confirmed that ABAT attenuated doxorubicin-induced lactate dehydrogenase (LDH) release, caspase-3 activation, and apoptosis. Taken together, our findings demonstrate that ABAT overexpression protects against doxorubicin-induced cardiotoxicity and is associated with preservation of mtDNA and mitochondrial function, reduced oxidative stress, and a reduced burden of damaged mitochondria. Given the reported antitumor properties of ABAT, these findings provide a basis for further investigating ABAT as a potential therapeutic target for mitigating doxorubicin-induced cardiotoxicity.