CDK5RAP3-Mediated Mitochondrial RQC Alleviates Pathological Cardiac Hypertrophy

Area of Science:

• Molecular Biology
• Cardiovascular Biology
• Cell Biology

Background:

• Ribosome heterogeneity is increasingly recognized, yet its role in pathological cardiac hypertrophy remains unclear.
• Pathological cardiac hypertrophy involves significant alterations in cellular translation processes.

Purpose of the Study:

• To investigate the contribution of ribosome heterogeneity to pathological cardiac hypertrophy.
• To identify specific proteins involved in ribosome function during cardiac hypertrophy.

Main Methods:

• Utilized translating ribosome affinity purification coupled with mass spectrometry to profile ribosome-interacting proteins in cardiomyocytes.
• Induced pathological cardiac hypertrophy in vivo (transverse aortic constriction) and in vitro (phenylephrine stimulation).
• Performed cardiomyocyte-specific gene manipulation (knockout and overexpression) to assess protein function.

Main Results:

• Identified dynamic alterations in ribosome-interacting proteins during cardiac hypertrophy, including proteins associated with ribosome stalling.
• Discovered that CDK5RAP3 (CDK5 regulatory subunit-associated protein 3) is upregulated and binds to ribosomes in hypertrophic hearts.
• Demonstrated that CDK5RAP3 promotes UFMylation of RPL26, enhances ribosome-associated quality control on the mitochondrial surface, alleviates ribosome stalling, and improves mitochondrial function and protein import.

Conclusions:

• CDK5RAP3-mediated ribosome-associated quality control on the mitochondrial surface is a critical protective mechanism.
• This pathway preserves protein import and mitochondrial function during pathological cardiac hypertrophy.
• CDK5RAP3 acts as a key regulator mitigating cardiac hypertrophy by maintaining mitochondrial integrity.