Mitochondrial Gene Signatures Linked to Heart Damage in Childhood Cancer Survivors

10/07/2025
A new study published in Cardio-Oncology offers compelling evidence that anthracycline-induced cardiomyopathy—a serious and often delayed complication of chemotherapy—may be driven by widespread mitochondrial dysfunction detectable at the genetic level.
Researchers from the University of Alabama at Birmingham and the Children’s Oncology Group analyzed gene expression in 104 childhood cancer survivors treated with anthracyclines, a class of chemotherapeutic agents essential to many pediatric cancer protocols but known for their cardiotoxicity. 40 of these individuals had developed cardiomyopathy, while 64 matched peers had not.
Using RNA sequencing of peripheral blood samples, investigators identified 900 genes that were expressed differently between the two groups. Strikingly, genes encoding proteins that localize to mitochondria were more than twice as likely to be altered, and nearly all were upregulated in those with cardiomyopathy.
Among the 12 mitochondrial processes most affected were the electron transport chain complexes (I, III, IV, and V), reactive oxygen species (ROS) metabolism, mitophagy and autophagy, apoptosis regulation, and heme synthesis. The study also revealed a dose-response pattern in apoptotic signaling: the ratio of BAX to BCL-2 gene expression—a marker of pro-apoptotic activity—was highest in survivors with severe cardiomyopathy, intermediate in mild cases, and lowest in controls.
Anthracyclines such as doxorubicin are known to promote oxidative injury by accumulating iron in mitochondria and generating excess ROS. The new data suggest that even years after treatment, survivors who develop cardiomyopathy may exhibit a maladaptive genetic response characterized by elevated ROS defense mechanisms, dysregulated heme biosynthesis, and persistent activation of intrinsic apoptotic pathways.
Upregulation of ferredoxin reductase, for example, may reflect a compensatory response to mitochondrial iron overload, while increased expression of ALAS2 and ferrochelatase—key enzymes in heme production—could further amplify oxidative stress. The authors note that this combination may create a feedback loop of mitochondrial injury, ROS generation, and cardiomyocyte apoptosis.
This work reinforces the idea that cardioprotection in oncology is not only about limiting drug exposure but also about understanding—and potentially intervening in—the molecular aftermath of therapy.