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 poorly understood.
• Pathological cardiac hypertrophy involves significant alterations in protein translation, highlighting a potential link to ribosome function.

Purpose of the Study:

• To investigate the role of ribosome heterogeneity in pathological cardiac hypertrophy.
• To identify specific proteins and mechanisms linking ribosome function to cardiac hypertrophy.

Main Methods:

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

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, promoting UFMylation of RPL26 and ribosome-associated quality control on mitochondria.
• Demonstrated that CDK5RAP3 protects against cardiac hypertrophy by alleviating ribosome stalling, restoring mitochondrial protein import, and improving mitochondrial function, notably maintaining PDP1 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, offering a novel therapeutic target for pathological cardiac hypertrophy.