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Tag: mTOR (Page 1 of 2)

MCJ: A mitochondrial target for cardiac intervention in pulmonary hypertension

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

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.

MCJ stainimg in lungs of patients with chronic obstructive pulmonary disease.

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

MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation

Rafael Romero-Becerra, Alfonso Mora, Elisa Manieri, Ivana Nikolic, Ayelén Melina Santamans, Valle Montalvo-Romeral, Francisco Miguel Cruz, Elena Rodríguez, Marta León, Luis Leiva-Vega, Laura Sanz, Víctor Bondía, David Filgueiras-Rama, Luis Jesús Jiménez-Borreguero, José Jalife, Barbara Gonzalez-Teran & Guadalupe Sabio.

Stress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38β, p38γ, and p38δ) that are activated by MKK3 and MKK6.

Cardiac hypertrophy under the microscope.
Cardiac hypertrophy in a heart lacking MKK6 (Image: Bárbara González-Terán).

Here, we demonstrate that lack of MKK6 reduces the lifespan in mice. Longitudinal study of cardiac function in MKK6 KO mice showed that young mice develop cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mammalian target of rapamycin (mTOR) signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in MKK6 KO mice is reverted by knocking out either p38γ or p38δ or by inhibiting the mTOR pathway with rapamycin.

In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity.

Protocol for the assessment of mTOR activity in mouse primary hepatocytes

Ana Belén Plata-Gómez, María Crespo, Celia de la Calle Arregui, Lucía de Prado-Rivas, Guadalupe Sabio, Alejo Efeyan.

We present a protocol for measuring the activity of the mechanistic target of rapamycin (mTOR) pathway in ex vivo isolated mouse primary hepatocytes. It can be used as a tool for genetic, pharmacological, metabolomic, and signal transduction procedures.

We discuss critical aspects for improving yield, viability, and modulation of the mTOR pathway. This protocol can be adapted to other signaling cascades and is compatible with multiple readouts.

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