Maturation of Mitochondrially Targeted Prx V Involves a Second Cleavage by Mitochondrial Intermediate Peptidase That

Juhyun Sim1,2, Jiyoung Park2, Hyun Ae Woo2,3

  • 1National Forensic Service, 10 Ipchun-ro, Wonju 26460, Gangwon-do, Korea.

Insights

Mitochondrial intermediate peptidase (MIP) is inhibited by hydrogen peroxide (H₂O₂), affecting peroxiredoxin V (Prx V) maturation. This redox regulation impacts Prx V levels and stability within mitochondria.

Area of Science:

  • Mitochondrial biology
  • Redox signaling
  • Protein processing

Background:

  • Peroxiredoxin V (Prx V) exists in long (L-Prx V) and short (S-Prx V) forms, with L-Prx V acting as a precursor.
  • L-Prx V contains a mitochondrial targeting sequence, indicating its localization within mitochondria.

Purpose of the Study:

  • To elucidate the proteolytic maturation pathway of L-Prx V in mitochondria.
  • To investigate the role of hydrogen peroxide (H₂O₂) in regulating Prx V processing and expression.

Main Methods:

  • Investigated the cleavage of L-Prx V by mitochondrial processing peptidase (MPP) and mitochondrial intermediate peptidase (MIP).
  • Utilized rotenone treatment in HeLa cells and genetic modifications (Prx III deletion, Srx deletion) in mice to induce mitochondrial oxidative stress.
  • Monitored the accumulation of intermediate Prx V (I-Prx V) and levels of mature S-Prx V under varying H₂O₂ conditions.

Main Results:

  • L-Prx V is processed by MPP to I-Prx V, and subsequently by MIP to mature S-Prx V.
  • Increased mitochondrial H₂O₂ levels lead to transient accumulation of I-Prx V and decreased mature S-Prx V.
  • MIP appears to be inhibited by H₂O₂, disrupting the conversion of I-Prx V to S-Prx V.

Conclusions:

  • Mitochondrial intermediate peptidase (MIP) activity is redox-sensitive and inhibited by H₂O₂.
  • This inhibition leads to altered Prx V maturation, impacting its levels and stability.
  • Identified a novel mechanism of redox-mediated regulation of Prx V proteolytic maturation and expression in mitochondria.

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