Advances in research on cell mechanisms that interact with mitochondrial activity to regulate ageing

Understanding the complex interaction between different cell signaling pathways and mitochondrial function means advancing to counteract ageing. This is the basis of a study carried out by a research group from Universidad Pablo de Olavide, led by researcher Marta Artal Sanz from the Department of Molecular Biology and Biochemistry Engineering. The study has been published in the scientific journal Aging Cell and it has been funded by the program H2020 ERC-Starting Grant ‘Mitochondrial signaling crosstalk in the regulation of ageing (MitoSigAge)’.

This research group has focused its efforts on learning the interaction of signaling pathway TORC2/SGK-1 and prohibitins (PHB) in ageing process by using C. elegans worm as a model organism, thus advancing in knowledge of cell mechanisms that interact with mitochondrial activity to regulate this process.

Prohibitins, with a very peculiar effect on longevity, are highly conserved proteins in evolution that are found in the mitochondrion and affect energy production (ATP) and lipid metabolism, depending on the individual’s genetics and environmental conditions. While PHB deficiency shortens lifespan of wild‐type animals, it enhances longevity of several metabolically compromised mutants. Among them, mutants of Serum- and Glucocorticoid-inducible Kinase protein (SGK-1). SGK-1 participates in cell signaling pathways that regulate the development, lipid metabolism and longevity.

“In our study we show that SGK-1 mutants have mitochondrial homeostasis, lipogenesis and lipoprotein production altered. Surprisingly, PHB deficiency suppresses those defects by enhancing these mutants’ lifespan”, researcher Marta Artal explains.

There are several cell mechanisms necessary to enhance longevity that activate in response to PHB deficiency. Among them, the transcription factor Sterol Regulatory Binding Protein 1 (SRBP1/ SBP-1) that regulates lipid metabolism and cholesterol synthesis.

Another necessary cell mechanism to enhance longevity is autophagy. Autophagy (from Greek «autos» (αυτος), oneself, and «phagein» (φαγηιν), eat or feed; that is to say, eating oneself) is a process whereby cells break down old and useless matter (proteins and lipids) preventing their accumulation, which can lead to pathologies such as cancer or Alzheimer’s and accelerate ageing.

In addition, the research team shows in their study that PHB deficiency induces a response to the stress that is caused by misfolded proteins, known as Unfolded Protein Response Mitochondrial (UPRmt), which is also essential for the enhance of longevity.

“Understanding cell mechanisms that regulate mitochondrial activity is crucial as it is a necessary step to counteract ageing and age-related diseases”, claims Marta Artal, who adds that “given the involvement of SGK-1, PHB and autophagy in the process of ageing and cancer, our findings can contribute to improving pathogenesis of conditions related to this process”.

Reference:Patricia de la Cruz‐Ruiz; Blanca Hernando‐Rodríguez; Mercedes M. Pérez‐Jiménez; María Jesús Rodríguez‐Palero; Manuel D. Martínez‐Bueno; Antoni Pla Roxani Gatsi; Marta Artal‐Sanz. Prohibitin depletion extends lifespan of a TORC2/SGK‐1 mutant through autophagy and the mitochondrial UPR. Aging Cell 2021; https://doi.org/10.1111/acel.13359