Mitochondrial calcium homeostasis and aging

The process of cellular aging is related to a decline in various physiological functions. As cellular power plants and executors of programmed cell death, mitochondria are in a unique position to affect these cellular processes. Notably, the second messenger calcium plays a critical role in mitochondrial function. By activating mitochondrial enzymes, calcium ions regulate the metabolic activity of mitochondria. However, an overload of mitochondria with calcium initiates devastating processes leading to cell death. Consequently, a machinery of proteins tightly controls mitochondrial calcium homeostasis as well as the exchange of calcium between the different cellular compartments, including calcium flux between mitochondria and the endoplasmic reticulum (ER). This project is based on my previous work under the guidance of Prof. Dr. Wolfgang F. Graier, which revealed a control mechanism of mitochondrial calcium uptake in cancer cells by post-translational modification of a protein regulating mitochondrial calcium uptake, recently also demonstrated to impact the survival rates of lung carcinoma patients. In addition, we found that a tight linkage between mitochondria and ER strongly affects the susceptibility of cancer cells to the cytotoxic effects of polyphenols due to an increased risk for mitochondrial Ca2+ overload. Strikingly, we found similar regulation mechanisms of mitochondrial calcium homeostasis also in senescent porcine aortic endothelial cells. Consistent with these preliminary findings, we hypothesize that mitochondrial calcium uptake and its regulatory mechanisms crucially change during the process of aging and, thereby, contribute to the development of age-related cellular dysfunction. During my Schrödinger Fellowship I will investigate in detail alterations in mitochondrial and cellular calcium homeostasis during aging and their impact on cellular (dys)function in vitro as well as in the Caenorhabditis elegans (C. elegans) aging model, which is well established in the laboratory of Prof. Dr. Michael Ristow (ETH Zurich), by various methods, including microscopy, proteomic approaches and assays for measuring viability and lifespan. In addition to in vitro studies in the PAEC aging model and in vivo experiments in the C. elegans aging model, critical determinants will be tested in a mouse aging model in order to gain deeper knowledge about in vivo effects occurring in mammals. In a rapidly aging society, gaining an understanding of the molecular processes during aging is increasingly important and I hope that my research will contribute to revealing potential targets for novel treatment strategies of age-associated cellular damage and dysfunction.

As cellular power plants and main cellular production sites of reactive oxygen species (ROS), mitochondria are in a unique position to affect the process of aging. Notably, the second messenger calcium plays a critical role in mitochondrial function. By activating mitochondrial enzymes, calcium ions regulate the metabolic activity of mitochondria. However, an overload of mitochondria with calcium initiates devastating processes leading to ce ll death. Within this Schrödinger project, the function of mitochondria during aging and their regulation by mitochondrial calcium homeostasis has been investigated in cellular aging models, nematodes (Caenorhabditis elegans), and mice in cooperation with the research groups of Michael Ristow, ETH Zurich, and Wolfgang Graier, Medical University of Graz. Establishing two different cellular aging models and using fluorescence microscopy enabled us to show an enhanced interaction between mitochondria and the biggest internal calcium store, the endoplasmic reticulum, during aging. While increased mitochondrial calcium uptake ensures proper mitochondrial metabolic function during aging, it also carries the risk of mitochondrial calcium overload. Consequently, applying the polyphenol resveratrol that further enhances mitochondrial calcium uptake results in a senolytic effect, specifically killing aged cells. Another possibility to prolong lifespan by modulation of mitochondrial activity was revealed by studying the aging process in nematodes. Green tea catechins provoke a transient rise in ROS by inhibiting the mitochondrial respiration chain, inducing so-called mitohormesis. Thereby, low levels of ROS initiate enhanced ROS defense mechanisms during aging, resulting in prolonged lifespan and improved fitness of nematodes. Moreover, experiments in mice revealed significant differences in metabolic activity during aging between the sexes, emphasizing the importance of considering sex-specific differences in the development of new prevention and treatment strategies against age-related diseases. As an assistant professor, Corina Madreiter-Sokolowski is now further investigating these new strategies unveiled during her Schrödinger project to counteract the cellular aging process and the development of age- related diseases at the Medical University of Graz.