Inactivation of Omi/HtrA2 protease leads to the deregulation of mitochondrial Mulan E3 ubiquitin ligase and increased mitophagy

Lucia Cilenti, Camilla T. Ambivero, Nathan Ward, Emad S. Alnemri, Doris Germain, Antonis S. Zervos

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Omi/HtrA2 is a nuclear encoded mitochondrial serine protease with dual and opposite functions that depend entirely on its subcellular localization. During apoptosis, Omi/HtrA2 is released into the cytoplasm where it participates in cell death. While confined in the inter-membrane space of the mitochondria, Omi/HtrA2 has a pro-survival function that may involve the regulation of protein quality control (PQC) and mitochondrial homeostasis. Loss of Omi/HtrA2's protease activity causes the neuromuscular disorder of the mnd2 (motor neuron degeneration 2) mutant mice. These mice develop multiple defects including neurodegeneration with parkinsonian features. Loss of Omi/HtrA2 in non-neuronal tissues has also been shown to cause premature aging. The normal function of Omi/HtrA2 in the mitochondria and how its deregulation causes neurodegeneration or premature aging are unknown. Here we report that the mitochondrial Mulan E3 ubiquitin ligase is a specific substrate of Omi/HtrA2. During exposure to H2O2, Omi/HtrA2 degrades Mulan, and this regulation is lost in cells that carry the inactive protease. Furthermore, we show accumulation of Mulan protein in various tissues of mnd2 mice as well as in Omi/HtrA2(-/-) mouse embryonic fibroblasts (MEFs). This causes a significant decrease of mitofusin 2 (Mfn2) protein, and increased mitophagy. Our work describes a new stress-signaling pathway that is initiated in the mitochondria and involves the regulation of Mulan by Omi/HtrA2 protease. Deregulation of this pathway, as it occurs in mnd2 mutant mice, causes mitochondrial dysfunction and mitophagy, and could be responsible for the motor neuron disease and the premature aging phenotype observed in these animals. Mitochondrial Mulan E3 ubiquitin ligase is a substrate of Omi/HtrA2 protease.Omi/HtrA2 regulates mitophagy through Mulan. Deregulation of Omi-Mulan pathway leads to neurodegeneration in mice.

Original languageEnglish
Pages (from-to)1295-1307
Number of pages13
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Issue number7
StatePublished - Jul 2014


  • Apoptosis
  • Mitophagy
  • Mnd2 mouse
  • Mulan E3 ubiquitin ligase
  • Omi/HtrA2
  • Oxidative stress


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