Regulation of Oxidative Stress by Methylation-Controlled J Protein Controls Macrophage Responses to Inflammatory Insults

Abstract

Mitochondria contribute to macrophage immune function through the generation of reactive oxygen species, a byproduct of the mitochondrial respiratory chain. MCJ (also known as DnaJC15) is a mitochondrial inner membrane protein identified as an endogenous inhibitor of respiratory chain complex I. Here we show that MCJ is essential for the production of tumor necrosis factor by macrophages in response to a variety of Toll-like receptor ligands and bacteria, without affecting their phagocytic activity. Loss of MCJ in macrophages results in increased mitochondrial respiration and elevated basal levels of reactive oxygen species that cause activation of the JNK/c-Jun pathway, lead to the upregulation of the TACE (also known as ADAM17) inhibitor TIMP-3, and lead to the inhibition of tumor necrosis factor shedding from the plasma membrane. Consequently, MCJ-deficient mice are resistant to the development of fulminant liver injury upon lipopolysaccharide administration. Thus, attenuation of the mitochondrial respiratory chain by MCJ in macrophages exquisitely regulates the response of macrophages to infectious insults.

The mitochondrial negative regulator MCJ modulates the interplay between microbiota and the host during ulcerative colitis

“…Therefore, we investigated the expression of both Adam17 and Timp3. As reported in bone marrow-derived macrophages 21 , the absence of MCJ resulted in significantly increased expression levels of Timp3, while the levels of Adam17 remained invariable www.nature.com/scientificreports www.nature.com/scientificreports/ (Fig. 3E).…”

“…MCJ absence during colitis results in the upregulation of the Tace inhibitor Timp3, which inhibits TACE activity probably affecting Tnf and Tnfr1 shedding from the cell membrane. Indeed, we have reported that the loss of MCJ in macrophages inhibits Tnf shedding from the plasma membrane 21 . Similarly, both TNF receptors are TACE substrates 38 .…”

Deficiency of mitochondrial modulator MCJ promotes chemoresistance in breast cancer

“…Lack of MCJ does not seem to affect mammary tumor development or growth, but it decreases the response to chemotherapy in vivo. MCJ is an endogenous inhibitor of complex I of the mitochondrial respiratory chain (20), and loss of MCJ in macrophages (22), CD8 T cells (36), and both breast cancer cell lines and primary mammary tumor cells (data not shown) results in marked increase in mitochondrial respiration. While research has focused on the need to inhibit glycolysis as a means of preventing cancer growth, emerging evidence indicates that mitochondria are important targets in cancer (37–39).…”

“…Moreover, we have shown that MCJ is one of the first endogenous inhibitors of complex I of the respiratory chain (20). Using MCJ-deficient mice, we have shown that loss of MCJ leads to increased complex I activity, mitochondrial membrane potential, and mitochondrial ATP production (20, 22). MCJ was initially identified as a gene negatively regulated by methylation at CpG islands in ovarian cancer (23, 24).…”

Fine-Tuning of CD8 + T Cell Mitochondrial Metabolism by the Respiratory Chain Repressor MCJ Dictates Protection to Influenza Virus

“…We have recently shown that MCJ is abundantly expressed primarily in tissues with a highly active mitochondrial metabolism, including heart and liver (Hatle et al, 2013). Within the immune system, MCJ is highly expressed in CD8 cells, but not in CD4 and B cells (Hatle et al, 2013), and it is also expressed in macrophages although at lower levels (Navasa et al, 2015a). Importantly, MCJ localizes to the inner membrane of mitochondria (Hatle et al., 2013; Schusdziarra et al, 2013).…”