New Target Emerges for AARS2-Related Cardiomyopathy With Early-Life Mortality

A study in murine and human cardiomyocyte models found PCBP1 loss disrupts AARS2 function and mitochondrial activity, identifying a potential target in infant cardiomyopathy.

New Target Emerges for AARS2-Related Cardiomyopathy With Early-Life Mortality

AARS2-related cardiomyopathy, a rare inherited disorder driven by mutations in the alanyl–transfer RNA synthetase 2 (AARS2) gene, is associated with onset at birth and high mortality within the first year of life, with no approved disease-modifying therapies. Prior investigational approaches have focused on correcting the underlying mutation, but progress has been limited by incomplete understanding of upstream regulatory mechanisms.

PCBP1 Identified as Upstream Regulator of AARS2 Function

New findings published in Nature Cardiovascular Research identify poly(rC)-binding protein 1 (PCBP1) as a potential therapeutic target, functioning as a regulator of AARS2 activity independent of direct gene correction.

Preclinical Models Recapitulate Disease Phenotype

In murine models, cardiomyocyte-specific deletion of PCBP1 reproduced key features of AARS2-related cardiomyopathy, including mitochondrial dysfunction and activation of maladaptive stress signaling. Parallel studies in human induced pluripotent stem cell–derived cardiomyocytes demonstrated similar mitochondrial impairment following PCBP1 suppression, supporting cross-species relevance.

Mechanistic Link to Mitochondrial Dysfunction

Mechanistically, loss of PCBP1 disrupted post-transcriptional processing of AARS2, resulting in reduced functional protein output. This was associated with impaired mitochondrial energy production and compensatory stress pathway activation, consistent with the metabolic phenotype observed in affected infants.

Translational Implications and Broader Relevance

Investigators also developed a novel mouse model of AARS2-related cardiomyopathy, enabling further therapeutic exploration. These findings suggest that targeting upstream regulators of gene function may offer a viable strategy in monogenic cardiomyopathies. Given the central role of mitochondrial dysfunction across cardiac and systemic diseases, the PCBP1–AARS2 axis may have broader therapeutic relevance beyond this ultra-rare condition.

HCPLive spoke with Yao Wei Lu, PhD, assistant professor of medicine and member of the Hastings Center for Pulmonary Research at the Keck School of Medicine of USC, who explained that this represents the first evidence linking PCBP1 to the pathogenesis of AARS2-related cardiomyopathy.

HCPLive: Can you walk us through the background of why past efforts to treat AARS2-related cardiomyopathy focused on repairing mutations in the AARS2 gene, and what prompted investigators to look beyond it?

Lu: AARS2 has long been established as the causal gene in infantile mitochondrial cardiomyopathy, so most efforts logically focused on correcting coding mutations, through gene replacement or editing. More broadly, mitochondrial disease research has been gene-centric. What shifted our thinking was growing evidence from the field of RNA biology that certain genetic mutations can affect alternative splicing, implicating RNA-binding proteins as crucial upstream players. This prompted us to look for upstream regulators rather than the gene alone.

HCPLive: How did PCBP1 first emerge as a gene of interest in your investigation?

Lu: We took an unbiased approach to identify RNA-binding proteins that regulate AARS2 transcripts in cardiomyocytes. PCBP1 stood out because of its known role in poly(C)-rich RNA binding and splicing regulation, and its strong interaction with AARS2 pre-mRNA. While PCBP1 has been studied in RNA metabolism and stress responses, it hadn’t been definitively linked to cardiac mitochondrial biology, making it an unexpected but compelling candidate.

HCPLive: Can you walk us through how PCBP1 influences AARS2 at the molecular level, particularly in terms of RNA processing and mitochondrial function?

Lu: PCBP1 ensures proper inclusion of a critical exon in AARS2 during pre-mRNA splicing. Loss of PCBP1 leads to aberrant splicing and premature transcript termination, effectively reducing functional AARS2. Because AARS2 is essential for mitochondrial protein translation, this disrupts oxidative phosphorylation and mitochondrial proteostasis, triggering downstream stress pathways. This connects RNA processing directly to mitochondrial function.

HCPLive: When you deleted or inhibited PCBP1 in your mouse and iPSC models, how closely did the resulting phenotype mirror AARS2-related cardiomyopathy?

Lu: Strikingly well. In both our mouse models and human iPSC-derived cardiomyocytes, PCBP1 loss reproduced the key hallmarks of AARS2-related disease: impaired mitochondrial respiration, activation of integrated stress response, and severe defects in cardiac development and survival. Importantly, the phenotypes we observed in both our mouse models and human iPSC-derived cardiomyocytes were highly concordant with those in human COXPD8 patients with mitochondrial cardiomyopathy, supporting a shared disease mechanism.

HCPLive: Given that mitochondrial dysfunction underlies many rare diseases, how do you see this PCBP1–AARS2 pathway informing therapeutic strategies beyond this specific cardiomyopathy?

Lu: Our work supports a shift from a purely gene-centric view to an RNA-regulatory framework for mitochondrial disease. Many mitochondrial disorders lack effective treatments despite known genetic causes. Targeting RNA processing—such as splicing regulators or specific transcript isoforms—could offer a more flexible therapeutic strategy, not only for AARS2-related cardiomyopathy but also for other disorders in which mitochondrial dysfunction is driven by defective gene expression rather than irreversible DNA mutations. Additionally, there are similarities in the downstream pathways affected by mitochondrial dysfunction that underlie many rare diseases; our findings will therefore inform therapeutic strategies beyond this specific cardiomyopathy.

References

1. Lu YW, Liang Z, Dorr K, et al. PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy. Nature Cardiovascular Research. 2026;5(4):328-350. doi:https://doi.org/10.1038/s44161-026-00798-3

2. Study points to new treatment target for fatal infant heart disease. EurekAlert! Published April 20, 2026. Accessed April 28, 2026. https://www.eurekalert.org/news-releases/1124804