Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation and Heart Regeneration

Area of Science:

• Cardiology
• Mitochondrial Biology
• Molecular Biology

Background:

• Mitochondria are crucial for heart function, and metabolic changes are linked to heart disease.
• Mitochondrial ribosomal protein S5 (MRPS5) knockdown inhibits mitochondrial translation, causing mitonuclear protein imbalance.
• Investigating MRPS5 loss effects on cardiomyocyte proliferation is key to understanding heart disease mechanisms.

Purpose of the Study:

• To examine the effects of MRPS5 loss on cardiomyocyte proliferation and cardiac regeneration.
• To elucidate the role of mitochondrial stress response in heart repair.
• To identify potential therapeutic targets for myocardial injury.

Main Methods:

• Mice with a deleted MRPS5 allele underwent myocardial infarction induction.
• Cardiomyocyte proliferation, cardiac regeneration, and heart function were assessed in vivo and in vitro.
• Molecular analyses included gene expression, protein levels, and mitochondrial function assays.

Main Results:

• MRPS5 haploinsufficiency improved cardiac function and regeneration post-myocardial infarction.
• ATF4 was identified as a key regulator of the mitochondrial stress response, promoting cardiomyocyte proliferation via Knl1.
• MRPS5 inhibition or doxycycline treatment increased proliferation in human iPSC-derived cardiomyocytes.

Conclusions:

• MRPS5 and ATF4 play critical roles in cardiomyocyte function and cardiac repair.
• Targeting the MRPS5/ATF4 pathway presents a novel therapeutic strategy for myocardial injury.
• This study opens new avenues for developing treatments for heart disease.