Last update 19 Sep 2024

DNAJC15

Last update 19 Sep 2024

Basic Info

Synonyms

Cell growth-inhibiting gene 22 protein, DnaJ heat shock protein family (Hsp40) member C15, DnaJ homolog subfamily C member 15

+ [4]

Introduction

Negative regulator of the mitochondrial respiratory chain. Prevents mitochondrial hyperpolarization state and restricts mitochondrial generation of ATP (By similarity). Acts as an import component of the TIM23 translocase complex. Stimulates the ATPase activity of HSPA9.

Drugs associated with DNAJC15

MT-003

Target

DNAJC15

Mechanism

DNAJC15 inhibitors

Active Org.

Mitotherapeutix LLCStartup

Originator Org.

Mitotherapeutix LLCStartup

Active Indication

Acute Kidney Injury [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with DNAJC15

100 Translational Medicine associated with DNAJC15

0 Patents (Medical) associated with DNAJC15

Literatures (Medical) associated with DNAJC15

19 Jan 2024·Science Advances

MCJ: A mitochondrial target for cardiac intervention in pulmonary hypertension

Article

Author: Rocha, Susana F ; Spinelli, Jessica B ; García Lunar, Inés ; Cicuéndez, Beatriz ; Hernansanz-Agustín, Pablo ; Vo, Paula ; Rajlic, Sanela ; Villalba-Orero, María ; Leiva, Magdalena ; García-Álvarez, Ana ; Macías, Álvaro ; Mora, Alfonso ; Crespo, María ; León, Marta ; Vázquez, Jesús ; Rodríguez, Elena ; Peinado, Víctor I ; Ibañez, Borja ; Sabio, Guadalupe ; Leiva, Luis ; Barberá, Joan Albert ; Oliver, Eduardo ; Jerome, Madison ; López, Juan Antonio ; Pintor Chocano, Aránzazu ; Santamans, Ayelén M ; Daiber, Andreas

Pulmonary hypertension (PH) can affect both pulmonary arterial tree and cardiac function, often leading to right heart failure and death. Despite the urgency, the lack of understanding has limited the development of effective cardiac therapeutic strategies. Our research reveals that MCJ modulates mitochondrial response to chronic hypoxia. MCJ levels elevate under hypoxic conditions, as in lungs of patients affected by COPD, mice exposed to hypoxia, and myocardium from pigs subjected to right ventricular (RV) overload. The absence of MCJ preserves RV function, safeguarding against both cardiac and lung remodeling induced by chronic hypoxia. Cardiac-specific silencing is enough to protect against cardiac dysfunction despite the adverse pulmonary remodeling. Mechanistically, the absence of MCJ triggers a protective preconditioning state mediated by the ROS/mTOR/HIF-1α axis. As a result, it preserves RV systolic function following hypoxia exposure. These discoveries provide a potential avenue to alleviate chronic hypoxia-induced PH, highlighting MCJ as a promising target against this condition.

01 Jan 2024·International Journal of Biological Sciences

S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver

Article

Author: Robinson, Aaron ; Van Eyk, Jenny ; Chhimwal, Jyoti ; Kim, So Yeon ; Yang, Heping ; Lu, Shelly C ; Barbier-Torres, Lucía ; Mato, José M ; Liangpunsakul, Suthat ; Seki, Ekihiro ; Ramani, Komal

MCJ (Methylation-Controlled J protein), an endogenous repressor of the mitochondrial respiratory chain, is upregulated in multiple liver diseases but little is known about how it is regulated. S-adenosylmethionine (SAMe), the biological methyl donor, is frequently depleted in chronic liver diseases. Here, we show that SAMe negatively regulates MCJ in the liver. While deficiency in methionine adenosyltransferase alpha 1 (MATα1), enzyme that catalyzes SAMe biosynthesis, leads to hepatic MCJ upregulation, MAT1A overexpression and SAMe treatment reduced MCJ expression. We found that MCJ is methylated at lysine residues and that it interacts with MATα1 in liver mitochondria, likely to facilitate its methylation. Lastly, we observed that MCJ is upregulated in alcohol-associated liver disease, a condition characterized by reduced MAT1A expression and SAMe levels along with mitochondrial injury. MCJ silencing protected against alcohol-induced mitochondrial dysfunction and lipid accumulation. Our study demonstrates a new role of MATα1 and SAMe in reducing hepatic MCJ expression.

18 Dec 2023·Gut Microbes

Mitochondrial dysfunction-associated microbiota establishes a transmissible refractory response to anti-TNF therapy during ulcerative colitis

Article

Author: Abecia, Leticia ; Palacios, Ainhoa ; Martín-Ruiz, Itziar ; Pellón, Aize ; Gonzalez-Lopez, Monika ; Barriales, Diego ; Pascual-Itoiz, Miguel Angel ; Rodríguez-Lago, Iago ; Rodriguez, Hector ; Aransay, Ana Mª ; Martinez-Chantar, María L ; Seoane, Iratxe ; Fuertes, Miguel ; Gutiérrez de Juan, Virginia ; Peña-Cearra, Ainize ; Bárcena, Laura ; Castelo, Janire ; Fullaondo, Asier ; Lavín, Jose Luis ; Anguita, Juan

Anti-TNF therapy can induce and maintain a remission status during intestinal bowel disease. However, up to 30% of patients do not respond to this therapy by mechanisms that are unknown. Here, we show that the absence of MCJ, a natural inhibitor of the respiratory chain Complex I, induces gut microbiota changes that are critical determinants of the lack of response in a murine model of DSS-induced inflammation. First, we found that MCJ expression is restricted to macrophages in human colonic tissue. Therefore, we demonstrate by transcriptomic analysis of colon macrophages from DSS-induced mice that MCJ-deficiency is linked to the expression of genes belonging to the FcγR signaling pathway and contains an anti-TNF refractory gene signature identified in ulcerative colitis patients. The gut microbial composition changes observed upon DSS treatment in the MCJ-deficient mice revealed the increased presence of specific colitogenic members, including Ruminococcus gnavus and Oscillospira, which could be associated with the non-response to TNF inhibitors. Further, we show that the presence of a microbiota associated resistance to treatment is dominant and transmissible to responsive individuals. Collectively, our findings underscore the critical role played by macrophage mitochondrial function in the gut ecological niche that can substantially affect not only the severity of inflammation but also the ability to successfully respond to current therapies.

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DNAJC15

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