Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response

Moisoi, Nicoleta; Klupsch, Kristina; Fedele, Valentina; East, Philip; Sharma, Sushant; Renton, Alan E.; Plun‐Favreau, Hélène; Edwards, Richard E.; Teismann, Peter; Esposti, Mauro Degli; Morrison, Alastair; Wood, Nicholas W.; Downward, Julian; Martins, L. Miguel

doi:10.1038/cdd.2008.166

Cited by 157 publications

(159 citation statements)

References 37 publications

(57 reference statements)

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“…In lymphocytes, the presence of HtrA2 prevents accumulation of activated Bax in the mitochondrial outermembrane, which would initiate cytochrome c release and cell death. 12 Moisoi et al 30 showed that HtrA2 is necessary for preventing accumulation of unfolded protein and oxidative stress in mitochondria. A recent study by Li et al 31 reported that HtrA2 is responsible for the maintenance of constitutive autophagy, which can eliminate damaged mitochondria.…”

Section: Discussionmentioning

confidence: 99%

The Role of Parl and HtrA2 in Striatal Neuronal Injury After Transient Global Cerebral Ischemia

Yoshioka

Katsu

Sakata

et al. 2013

J Cereb Blood Flow Metab

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The presenilin-associated rhomboid-like (PARL) protein and high temperature requirement factor A2 (HtrA2) are key regulators of mitochondrial integrity and play pivotal roles in apoptosis. However, their roles after cerebral ischemia have not been thoroughly elucidated. To clarify these roles, mice were subjected to transient global cerebral ischemia, and striatal neuronal injury was assessed. Western blot and coimmunoprecipitation analyses revealed that PARL and processed HtrA2 localized to mitochondria, and that PARL was bound to HtrA2 in sham animals. Expression of PARL and processed HtrA2 in mitochondria significantly decreased 6 to 72 hours after ischemia, and the binding of PARL to HtrA2 disappeared after ischemia. In contrast, expression of processed HtrA2 increased 24 hours after ischemia in the cytosol, where HtrA2 was bound to X chromosome-linked inhibitor-ofapoptosis protein (XIAP). Administration of PARL small interfering RNA inhibited HtrA2 processing and worsened ischemic neuronal injury. Our results show that downregulation of PARL after ischemia is a key step in ischemic neuronal injury, and that it decreases HtrA2 processing and increases neuronal vulnerability. In addition, processed HtrA2 released into the cytosol after ischemia contributes to neuronal injury via inhibition of XIAP.

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Section: Discussionmentioning

confidence: 99%

The Role of Parl and HtrA2 in Striatal Neuronal Injury After Transient Global Cerebral Ischemia

Yoshioka

Katsu

Sakata

et al. 2013

J Cereb Blood Flow Metab

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“…30 Omi is a key component needed to maintain mitochondrial integrity and the function of the respiratory chain, and loss of Omi produces a large number of damaged mitochondria. 10,29 We report here that Omi is responsible for the maintenance of constitutive autophagy (Figure 2). The autophagy system is a conserved pathway that eliminates damaged mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…28 Recently, an important finding revealed that the loss of Omi activates the PERK branch of the UPR, with transcriptional upregulation of CHOP and modulation of a number of other genes leading to neuronal cell death. 29 It is therefore possible that the upregulation of Omi and resulting activation of autophagy in response to stress are protective reactions, and the loss of this protective effect could result in sustained activation of the UPR. The upregulation of Omi by ER stress is similar to that observed for other prosurvival stress response proteins such as Grp78, which is also upregulated in response to ER stress; its knockdown also spontaneously activates UPR and upregulates CHOP.…”

Section: Discussionmentioning

confidence: 99%

Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases

Wang

et al. 2010

Cell Death Differ

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Omi, also known as high temperature requirement factor A2 (HtrA2), is a serine protease that was originally identified as a proapoptotic protein. Like Smac/Diablo, it antagonizes inhibitor of apoptosis proteins when released into the cytosol on apoptotic stimulation. Loss of its protease activity in mnd2 (motor neuron degeneration 2) mice is associated with neurodegeneration. However, the detailed mechanisms by which Omi regulates the pathogenesis of neurodegenerative disease remain largely unknown. We report here that Omi participates in the pivotal cellular degradation process known as autophagy. It activates autophagy through digestion of Hax-1, a Bcl-2 family-related protein that represses autophagy in a Beclin-1 (mammalian homologue of yeast ATG6)-dependent pathway. Moreover, Omi-induced autophagy facilitates the degradation of neurodegenerative proteins such as pathogenic A53T a-synuclein and truncated polyglutamine-expanded huntingtin, as well as the endogenous autophagy substrate p62. Knockdown of Omi decreases the basal level of autophagy and increases the level of the above target proteins. Furthermore, S276C Omi, the protease-defective mutant found in mnd2 mice, fails to regulate autophagy. Increased autophagy substrates and the formation of aggregate structures are observed in the brains of mnd2 mice. These results identify Omi as a novel regulator of autophagy and suggest that Omi might be important in the cellular quality control of proteins involved in neurodegenerative diseases.

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“…Indeed, increased ROS production was previously reported in thymocytes and MEFs from HtrA2-deficient mice. 24 ROS could damage the respiratory complexes and other mitochondrial proteins including PolgA, resulting in decreased respiratory chain activity, and increased mutation and deletions of mtDNA. Eventually, these deleterious effects can cause mitochondrial dysfunction, which triggers mitophagy to clear the defective mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…22 HtrA2 (also known as Omi) is an ATP-independent serine protease structurally and functionally related to the bacterial quality control proteases DegP and DegS. 23 HtrA2 resides in the intermembrane space of the mitochondrion, and its loss leads to accumulation of unfolded proteins in the mitochondria, oxidative stress, and defective mitochondrial respiration, 24 suggesting that, like its bacterial counterparts, HtrA2 functions as a quality control protease. Mice lacking HtrA2 protease activity as a result of missense mutation (mnd2 mice) or targeted deletion (HtrA2 knockout mice) of the HtrA2 (Prss25) gene exhibit early onset neurodegeneration and motor abnormalities similar to Parkinson's disease, and die between postnatal day (dP) 30 and dP40.…”

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confidence: 99%

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

et al. 2012

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mnd2 mice die prematurely as a result of neurodegeneration 30-40 days after birth due to loss of the enzymatic activity of the mitochondrial quality control protease HtrA2/Omi. Here, we show that transgenic expression of human HtrA2/Omi in the central nervous system of mnd2 mice rescues them from neurodegeneration and prevents their premature death. Interestingly, adult transgenic mnd2 mice develop accelerated aging phenotypes, such as premature weight loss, hair loss, reduced fertility, curvature of the spine, heart enlargement, increased autophagy, and death by 12-17 months of age. These mice also have elevated levels of clonally expanded mitochondrial DNA (mtDNA) deletions in their tissues. Our results provide direct genetic evidence linking mitochondrial protein quality control to mtDNA deletions and aging in mammals. Cell Death and Differentiation (2013) 20, 259-269; doi:10.1038/cdd.2012 published online 14 September 2012 Mitochondria are dynamic organelles primarily involved in the production of adenosine triphosphate (ATP) through oxidative phosphorylation. They also play important roles in diverse cellular processes such as cell death, autophagy and innate immunity. 1 As a consequence of oxidative phosphorylation, mitochondria produce reactive oxygen species (ROS), which damages mitochondrial proteins, lipids and nucleic acids, because of their proximity to the source of ROS production. Accumulation over time of mutations and deletions in mitochondrial DNA (mtDNA) together with increased protein misfolding, as a result of ROS damage, leads to ageassociated decline in mitochondrial function, which is believed to be responsible for organismal aging and age-associated diseases. [2][3][4] To maintain optimal mitochondrial function over time, a number of quality control mechanisms exist that monitor and regulate all aspects of mitochondrial physiology. Damaged and unfolded mitochondrial proteins are removed by mitochondrial quality control proteases, which recognize these proteins and degrade them. 5,6 The ATP-dependent AAA (ATPase-Associated with diverse cellular Activities) proteases, are among the best-characterized proteases implicated in mitochondrial protein quality control. 7 The AAA proteases, ClpXP and Lon, located in the matrix are involved in quality control of matrix proteins. Although no specific mitochondrial substrate has been identified for the ClpXP protease, in vitro studies showed that Lon protease preferentially targets oxidatively damaged matrix aconitase. 8 Two additional AAA proteases, Paraplegin (encoded by the SPG7 gene) and YME1L, are associated with the inner membrane with their catalytic sites facing the matrix and intermembrane space, respectively. 7 These proteases are believed to be primarily involved in the degradation of damaged and unfolded membrane proteins of the electron transport chain. In addition, Paraplegin has been shown to process the mitochondrial ribosomal protein MrpL32, 9 suggesting that it might also function in mitochondrial ribosome assembly. Loss-of-functi...

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Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response

Cited by 157 publications

References 37 publications

The Role of Parl and HtrA2 in Striatal Neuronal Injury After Transient Global Cerebral Ischemia

The Role of Parl and HtrA2 in Striatal Neuronal Injury After Transient Global Cerebral Ischemia

Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

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