Cited by 70Autophagy in Disease and TherapyMitochondrial Function and PathologyUbiquitin and proteasome pathways

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

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Cilenti, Lucia, Ambivero, Camilla T., Ward, Nathan, Alnemri, Emad S., Germain, Doris, Zervos, Antonis S.·2014·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

Abstract

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 H(2)O(2), 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.

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Crossref · 10.1016/j.bbamcr.2014.03.027

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  • An aging-associated deficiency of Mfn2 may link impaired mitophagy to accumulation of dysfunctional mitochondria in muscle and neurons during sarcopenia.

    “Thus, an aging associated deficiency of Mfn2 may be the bridge between impaired mitophagy and an accumulation of dysfunctional mitochondria in muscle and neurons during sarcopenia.”

    From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [29]

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Authors
Cilenti, L., Ambivero, C. T., Ward, N., Alnemri, E. S., Germain, D., & Zervos, A. S.
Affiliations
  • University of Central Florida (US)
  • Thomas Jefferson University (US)
  • Mount Sinai Hospital (US)
Corresponding author
Zervos, Antonis S.
Venue
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Publisher
Elsevier BV
Published
2014-07
Volume
1843
Issue
7
Pages
1295-1307
ISSN
0167-4889 (ISSN-L)
OpenAlex
W2115282304
Cited by
70
References
79
Citations by year
2026: 2 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 7 · 2020: 7 · 2019: 5 · 2018: 9 · 2017: 9 · 2016: 7 · 2015: 7 · 2014: 4 · 2013: 1
FWCI
6.80
Type
journal article
Language
en
Open access
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
  • PubMed (publishedVersion)
  • Journal of International Crisis and Risk Communication Research (submittedVersion)
Funders
Florida Department of Health (2KB05)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
Omi/HtrA2, mitophagy, mitochondrial serine protease, mitofusin 2, motor neuron disease, premature aging, mitochondrial dysfunction, protein quality control, mitochondrial homeostasis
MeSH terms
High-Temperature Requirement A Serine Peptidase 2, Animals, Cell Line, Cell Nucleus, Cytoplasm, Fibroblasts, Gene Expression Regulation, Humans, Mitochondria, Serine Endopeptidases, Signal Transduction, Motor Neuron Disease, Apoptosis, Mice, Knockout, Oxidative Stress, Aging, Premature, GTP Phosphohydrolases, Protein Transport, Mitochondrial Proteins, Ubiquitin-Protein Ligases, Mice, HEK293 Cells, Mitophagy

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