The Mitochondrial Protease, LonP1, is a Potential Mediator of Doxorubicin (DOX) Induced Cardiotoxicity

ABSTRACT: Doxorubicin (DOX), a first line chemotherapeutic agent, causes severe off-target cardiotoxicity. Previous works implicate mitochondria, energy producing organelles of cardiomyocytes, as key mediators of this cardiotoxicity. While DOX treatment has been shown to cause multiple forms of cell death within the heart, the precise mechanisms governing this cell death remain poorly understood. Using an in-vitro human cardiac cell model (AC-16) of DOX cardiotoxicity, we show that apoptotic signaling, a cell death mechanism activated following mitochondrial damage, is a top differentially expressed pathway as determined by Hallmark Gene Set Enrichment Analysis (GSEA). We further show that LonP1, a key regulator of mitochondrial homeostasis, is upregulated by DOX in both AC-16 cells and primary (1°) human cardiomyocytes. Using LonP1 knockdown (KD) AC-16 cells, we show that reduction of LonP1 exacerbates DOX mediated apoptotic signaling. Conversely, overexpression (OE) of LonP1 in AC-16 cells attenuates apoptosis under DOX. Given that release of mitochondrial DNA (mtDNA) is also a known contributor to adverse inflammatory signaling after DOX administration, we subsequently examined trends in mtDNA release in LonP1 KD and OE cell models. Results from these experiments indicated LonP1 levels are inversely correlated with mtDNA release under DOX, highlighting a potential novel role for LonP1 in regulating mtDNA release during times of mitochondrial stress. Together, these findings elucidate a cytoprotective role for LonP1 in the heart following DOX treatment, supporting LonP1 as a novel therapeutic target for prevention of DOX cardiotoxicity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE318106 | GEO | 2026/09/30

REPOSITORIES: GEO