Abstract Body: Background: Mutations in AARS2 are associated with infantile mitochondrial cardiomyopathy, yet the molecular mechanisms underlying disease pathogenesis remain unclear.
Objective: We sought to determine how AARS2 alternative splicing is regulated in the heart and how its disruption contributes to cardiomyopathy.
Methods and Results: We identify PCBP1, a poly(rC)-binding RNA-binding protein, as a critical regulator of AARS2 alternative splicing. PCBP1 directly associates with the AARS2 transcript to ensure proper splicing fidelity. Cardiomyocyte-specific deletion of Pcbp1 in mice resulted in aberrant Aars2 splicing and premature transcript termination, leading to impaired cardiac development and early postnatal lethality. Mice engineered to harbor a disease-relevant Aars2 splicing lesion similarly developed structural and functional cardiac abnormalities reminiscent of infantile mitochondrial cardiomyopathy. Mechanistically, loss of Pcbp1 or Aars2 markedly reduced oxidative phosphorylation and disrupted the mitochondrial-encoded proteome. This mitochondrial dysfunction triggered mitonuclear signaling and activation of the unfolded protein response, inducing a compensatory nuclear-encoded mitochondrial gene program.
Conclusions: Our findings establish PCBP1 as a key safeguard of AARS2 alternative splicing required for mitochondrial integrity and cardiac development. Disruption of the PCBP1–AARS2 regulatory axis drives mitochondrial dysfunction and cardiomyopathy, providing mechanistic insight into AARS2-associated heart disease.