Mitophagy Facilitates Cytosolic Proteostasis to Preserve Cardiac Function

Area of Science:

• Cardiovascular Biology
• Cellular Biology
• Molecular Medicine

Background:

• Protein quality control (PQC) is vital for cardiac myocyte function.
• Mutations in PQC proteins like CRYAB and BAG3 cause protein aggregate pathology and cardiomyopathy.
• Mitochondrial uptake of cytosolic protein aggregates suggests a role in PQC.

Purpose of the Study:

• To investigate if mitochondrial uptake and mitophagy of cytosolic protein aggregates facilitate PQC in cardiac myocytes.
• To determine the role of TRAF2-mediated mitophagy in clearing protein aggregates and its therapeutic potential in cardiomyopathy.

Main Methods:

• Assessed protein aggregates and DESMIN mis-localization in mice with TRAF2-deficient cardiac myocytes.
• Studied mitochondrial uptake of aggregate-prone CRYAB and BAG3 mutants in cardiomyocytes.
• Utilized transgenic mice (R120G-CRYAB) with modulated TRAF2 levels (gain- and loss-of-function) to assess cardiac function and pathology.

Main Results:

• TRAF2 ablation in cardiac myocytes led to protein aggregate accumulation and DESMIN mis-localization.
• Isolated mitochondria took up cardiomyopathy-associated CRYAB and BAG3 mutants.
• TRAF2 modulation in R120G-CRYAB mice affected mortality, cardiac function, and protein aggregate load, with TRAF2 gain-of-function ameliorating pathology.

Conclusions:

• TRAF2-mediated mitophagy in cardiac myocytes is crucial for removing cytosolic protein aggregates.
• Stimulating TRAF2-mediated mitophagy can be a therapeutic strategy for proteotoxic cardiomyopathy.