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NEMF-mediated Listerin-independent mitochondrial translational surveillance by E3 ligase Pirh2 and mitochondrial

Liang Lv1, Jinyou Mo2, Yumin Qing3

  • 1Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.

Cell Reports
|February 27, 2024
PubMed

Insights

Scientists discovered a new mitochondrial quality control pathway that clears stalled proteins. This pathway, independent of Listerin, uses Pirh2 and ClpXP to prevent mitochondrial damage and disease.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Mitochondrial Biology

Background:

  • The ribosome-associated protein quality control (RQC) pathway maintains cellular proteostasis by degrading stalled translation products.
  • In mammalian cells, cytoplasmic RQC utilizes Listerin E3 ligase for ubiquitination and degradation of stalled nascent polypeptides.
  • Quality control for nuclear-encoded mitochondrial nascent polypeptides is poorly understood due to partial mitochondrial import.

Purpose of the Study:

  • To elucidate the quality control mechanisms for nuclear-encoded mitochondrial nascent polypeptides.
  • To identify the factors and pathways involved in clearing ribosome-stalled mitochondrial proteins.
  • To investigate the role of this pathway in mitochondrial integrity and associated diseases.

Main Methods:

  • Investigated the role of nuclear export mediator factor (NEMF) in mitochondrial protein quality control.
  • Identified novel E3 ligases and proteases involved in the degradation of stalled mitochondrial polypeptides.
  • Utilized cell-based assays to assess mitochondrial integrity and protein aggregation upon pathway disruption.

Main Results:

  • Discovered a Listerin-independent, organelle-specific mitochondrial RQC pathway.
  • This pathway involves NEMF-mediated carboxy-terminal poly-alanine modification.
  • The cytosolic E3 ligase Pirh2 and mitochondrial ClpXP protease coordinate the clearance of stalled mitochondrial nascent polypeptides.
  • Defects in this pathway lead to NEMF-mediated aggregates and mitochondrial integrity failure.

Conclusions:

  • A novel mitochondrial RQC pathway involving Pirh2 and ClpXP clears stalled mitochondrial nascent polypeptides.
  • This pathway is crucial for maintaining mitochondrial integrity and preventing the accumulation of aberrant proteins.
  • Dysfunction of this pathway may contribute to mitochondrial-associated human diseases.
Keywords:
CP: MicrobiologyCP: Molecular biologyClpXPListerinNEMFPirh2mitochondrion

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