TY - JOUR
T1 - Inactivation of Omi/HtrA2 protease leads to the deregulation of mitochondrial Mulan E3 ubiquitin ligase and increased mitophagy
AU - Cilenti, Lucia
AU - Ambivero, Camilla T.
AU - Ward, Nathan
AU - Alnemri, Emad S.
AU - Germain, Doris
AU - Zervos, Antonis S.
N1 - Funding Information:
We thank Julian Downward and L. Miguel Martins for the immortalized Omi/HtrA2-KO MEFs and Dr. Åsa Gustafsson for the GFP-LC3 Adenovirus. This work was supported by grant 2KB05 from James and Esther King Biomedical Research Program, Florida Department of Health to A.S.Z.
PY - 2014/7
Y1 - 2014/7
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Mitophagy
KW - Mnd2 mouse
KW - Mulan E3 ubiquitin ligase
KW - Omi/HtrA2
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=84905696703&partnerID=8YFLogxK
U2 - 10.1016/j.bbamcr.2014.03.027
DO - 10.1016/j.bbamcr.2014.03.027
M3 - Article
C2 - 24709290
AN - SCOPUS:84905696703
SN - 0167-4889
VL - 1843
SP - 1295
EP - 1307
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
IS - 7
ER -