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

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.

Imaging genetics approach to Parkinson’s disease and its correlation with clinical score

“…The interaction term between rs9346876 (PARK2) and rs363611 (HtrA2) led to 15.28% and 9.11% of explained variance for models B and C , respectively, in the linear regression analysis. This finding is consistent with previous studies reporting that HtrA2 specifically binds to and directly cleaves the E3 ubiquitin ligase PARK23839.…”

New roles for mitochondrial proteases in health, ageing and disease

“…Notably, several other mitoproteases, including the mAAA protease, CLPXP and LONP, are involved in PINK1 turnover in the mitochondrial matrix, in a poorly understood manner 85 . HTRA2 also seems to inhibit mitophagy by binding and degrading parkin when released into the cytosol under some stress conditions or by processing an intramitochondrial domain of Mulan E3 ubiquitin-protein ligases 88,89 . The pseudoprotease protein DJ-1 (also known as PARK7) also regulates mitophagy by assembling with PINK1 and parkin to form E3 ubiquitin-protein ligase complex PPD, which promotes ubiquitylation and proteasomal degradation of unfolded or misfolded parkin substrates 90 .…”

Structural insights into the activation mechanisms of human HtrA serine proteases

“…Furthermore, HtrA2 deficiency leads to damage and mutations of mitochondrial DNA [51], and increases mitophagy. The protease was found to influence function of the Optic atrophy 1 (OPA1) protein [50] and regulation of the mitochondrial Mulan E3 ligase and mitofusin 2 (Mfn2), proteins involved in mitochondrial dynamics [52].…”