Increased levels of mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol

EMBO J. 2021 Aug 16;40(16):e107913. doi: 10.15252/embj.2021107913. Epub 2021 Jun 30.

Abstract

The formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient samples and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but causalities remain unclear. We used Saccharomyces cerevisiae to analyze how mitochondrial processes regulate the behavior of aggregation-prone polyQ protein derived from human huntingtin. Expression of Q97-GFP rapidly led to insoluble cytosolic aggregates and cell death. Although aggregation impaired mitochondrial respiration only slightly, it considerably interfered with the import of mitochondrial precursor proteins. Mutants in the import component Mia40 were hypersensitive to Q97-GFP, whereas Mia40 overexpression strongly suppressed the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the post-translational import of mitochondrial precursor proteins into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Mia40 regulates this competition as it has a rate-limiting role in mitochondrial protein import. Therefore, Mia40 is a dynamic regulator in mitochondrial biogenesis that can be exploited to stabilize cytosolic proteostasis.

Keywords: Mia40; huntingtin; mitochondria; protein aggregation; protein translocation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cytosol / metabolism
  • Humans
  • Mitochondria / metabolism
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Peptides / metabolism*
  • Protein Aggregation, Pathological / metabolism*
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • CHCHD4 protein, human
  • MIA40 protein, S cerevisiae
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Peptides
  • Saccharomyces cerevisiae Proteins
  • polyglutamine