TY - JOUR
T1 - HtrA2/Omi influences the stability of LON protease 1 and prohibitin, proteins involved in mitochondrial homeostasis
AU - Goo, Hui Gwan
AU - Rhim, Hyangshuk
AU - Kang, Seongman
N1 - Funding Information:
We are grateful to Dr. Julian Downward at Cancer Research UK London Research Institute for offering HtrA2 +/+ and HtrA2 −/− MEF cells. This study was supported by a Grant from the National R&D Program for Cancer Control, the Ministry of Health & Welfare, Republic of Korea ( 1320010 ) and by a Korea University Grant.
PY - 2014/11/1
Y1 - 2014/11/1
N2 - High temperature requirement A2 (HtrA2)/Omi is a serine protease localized in mitochondria. In response to apoptotic stimuli, HtrA2 is released to the cytoplasm and cleaves many proteins, including XIAP, Apollon/BRUCE, WT1, and Ped/Pea-15, to promote apoptosis. However, the function of HtrA2 in mitochondria under normal conditions remains unclear. Here, we show that the mitochondrial proteins, LON protease 1 (LONP1) and prohibitin (PHB), are overexpressed in HtrA2-/- mouse embryonic fibroblast (MEF) cells and HtrA2 knock-down HEK293T cells. We also confirm the effect of the HtrA2 protease on the stability of the above mitochondrial quality control proteins in motor neuron degeneration 2 (mnd2) mice, which have a greatly reduced protease activity as a result of a Ser276Cys missense mutation of the HtrA2 gene. In addition, PHB interacts with and is directly cleaved by HtrA2. Luminescence assays demonstrate that the intracellular ATP level is decreased in HtrA2-/- cells compared to HtrA2+/+ cells. HtrA2 deficiency causes a decrease in the mitochondrial membrane potential, and reactive oxygen species (ROS) generation is greater in HtrA2-/- cells than in HtrA2+/+ cells. Our results implicate that HtrA2 might be an upstream regulator of mitochondrial homeostasis.
AB - High temperature requirement A2 (HtrA2)/Omi is a serine protease localized in mitochondria. In response to apoptotic stimuli, HtrA2 is released to the cytoplasm and cleaves many proteins, including XIAP, Apollon/BRUCE, WT1, and Ped/Pea-15, to promote apoptosis. However, the function of HtrA2 in mitochondria under normal conditions remains unclear. Here, we show that the mitochondrial proteins, LON protease 1 (LONP1) and prohibitin (PHB), are overexpressed in HtrA2-/- mouse embryonic fibroblast (MEF) cells and HtrA2 knock-down HEK293T cells. We also confirm the effect of the HtrA2 protease on the stability of the above mitochondrial quality control proteins in motor neuron degeneration 2 (mnd2) mice, which have a greatly reduced protease activity as a result of a Ser276Cys missense mutation of the HtrA2 gene. In addition, PHB interacts with and is directly cleaved by HtrA2. Luminescence assays demonstrate that the intracellular ATP level is decreased in HtrA2-/- cells compared to HtrA2+/+ cells. HtrA2 deficiency causes a decrease in the mitochondrial membrane potential, and reactive oxygen species (ROS) generation is greater in HtrA2-/- cells than in HtrA2+/+ cells. Our results implicate that HtrA2 might be an upstream regulator of mitochondrial homeostasis.
KW - HtrA2
KW - Mitochondria
KW - Mitochondrial homeostasis
KW - Mnd2
KW - PHB
KW - Protein quality control
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U2 - 10.1016/j.yexcr.2014.07.032
DO - 10.1016/j.yexcr.2014.07.032
M3 - Article
C2 - 25094062
AN - SCOPUS:84908237888
VL - 328
SP - 456
EP - 465
JO - Experimental Cell Research
JF - Experimental Cell Research
SN - 0014-4827
IS - 2
ER -