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A defect in mitochondrial protein translation influences mitonuclear communication in the heart

Feng Gao1,2, Tian Liang1,2, Yao Wei Lu3,4

  • 1Department of Cardiology, Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.

Nature Communications
|March 23, 2023
PubMed

Insights

Mitochondrial ribosomal protein S5 (MRPS5) is crucial for heart function, regulating communication between mitochondria and the nucleus. Its loss causes heart failure, but targeting MRPS5 may offer new heart disease therapies.

Area of Science:

  • Cardiovascular Biology
  • Mitochondrial Biology
  • Molecular Cardiology

Background:

  • Mitonuclear communication is vital for cardiac function but not fully understood.
  • Mitochondrial dysfunction contributes to heart failure pathogenesis.

Purpose of the Study:

  • To investigate the role of mitochondrial ribosomal protein S5 (MRPS5) in cardiac function and mitonuclear communication.
  • To identify downstream targets and mechanisms regulated by MRPS5 during cardiac stress.

Main Methods:

  • Genetic manipulation of Mrps5 in developing and adult mouse hearts.
  • Analysis of cardiac structure, function, and mitochondrial integrity.
  • Assessment of mitochondrial protein translation and oxidative phosphorylation (OXPHOS).
  • Identification and validation of downstream targets using molecular and metabolic analyses.

Main Results:

  • Loss of Mrps5 leads to cardiac defects, embryonic lethality, hypertrophy, and heart failure.
  • Mrps5 deficiency disrupts mitochondrial structure, protein translation, and OXPHOS.
  • Klf15 is identified as a downstream target, and its exogenous expression rescues cardiac defects.
  • Mrps5 represses Klf15 expression via c-myc and L-phenylalanine.

Conclusions:

  • MRPS5 plays a critical role in maintaining cardiac metabolism and mitonuclear communication.
  • Dysregulation of MRPS5 contributes to heart failure development.
  • MRPS5 represents a potential therapeutic target for heart failure treatment.

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