ABSTRACT
Cancer cells have increased energy requirements due to their enhanced proliferation activity. This energy demand is, among others, met by mitochondrial ATP production. Since the second messenger Ca2+ maintains the activity of Krebs cycle dehydrogenases that fuel mitochondrial respiration, proper mitochondrial Ca2+ uptake is crucial for a cancer cell survival. However, a mitochondrial Ca2+ overload induces mitochondrial dysfunction and, ultimately, apoptotic cell death. Because of the vital importance of balancing mitochondrial Ca2+ levels, a highly sophisticated machinery of multiple proteins manages mitochondrial Ca2+ homeostasis. Notably, mitochondria sequester Ca2+ preferentially at the interaction sites between mitochondria and the endoplasmic reticulum (ER), the largest internal Ca2+ store, thus, pointing to mitochondrial-associated membranes (MAMs) as crucial hubs between cancer prosperity and cell death. To investigate potential regulatory mechanisms of the mitochondrial Ca2+ uptake routes in cancer cells, we modulated mitochondria-ER tethering and the expression of UCP2 and analyzed mitochondrial Ca2+ homeostasis under the various conditions. Hence, the expression of contributors to mitochondrial Ca2+ regulation machinery was quantified by qRT-PCR. We further used data from The Cancer Genome Atlas (TCGA) to correlate these in vitro findings with expression patterns in human breast invasive cancer and human prostate adenocarcinoma. ER-mitochondrial linkage was found to support a mitochondrial Ca2+ uptake route dependent on uncoupling protein 2 (UCP2) in cancer cells. Notably, combined overexpression of Rab32, a protein kinase A-anchoring protein fostering the ER-mitochondrial tethering, and UCP2 caused a significant drop in cancer cells' viability. Artificially enhanced ER-mitochondrial tethering further initiated a sudden decline in the expression of UCP2, probably as an adaptive response to avoid mitochondrial Ca2+ overload. Besides, TCGA analysis revealed an inverse expression correlation between proteins stabilizing mitochondrial-ER linkage and UCP2 in tissues of human breast invasive cancer and prostate adenocarcinoma. Based on these results, we assume that cancer cells successfully manage mitochondrial Ca2+ uptake to stimulate Ca2+-dependent mitochondrial metabolism while avoiding Ca2+-triggered cell death by fine-tuning ER-mitochondrial tethering and the expression of UCP2 in an inversed manner. Disruption of this equilibrium yields cancer cell death and may serve as a treatment strategy to specifically kill cancer cells.
ABSTRACT
Senescence is related to the loss of cellular homeostasis and functions, which leads to a progressive decline in physiological ability and to aging-associated diseases. Since mitochondria are essential to energy supply, cell differentiation, cell cycle control, intracellular signaling and Ca2+ sequestration, fine-tuning mitochondrial activity appropriately, is a tightrope walk during aging. For instance, the mitochondrial oxidative phosphorylation (OXPHOS) ensures a supply of adenosine triphosphate (ATP), but is also the main source of potentially harmful levels of reactive oxygen species (ROS). Moreover, mitochondrial function is strongly linked to mitochondrial Ca2+ homeostasis and mitochondrial shape, which undergo various alterations during aging. Since mitochondria play such a critical role in an organism's process of aging, they also offer promising targets for manipulation of senescent cellular functions. Accordingly, interventions delaying the onset of age-associated disorders involve the manipulation of mitochondrial function, including caloric restriction (CR) or exercise, as well as drugs, such as metformin, aspirin, and polyphenols. In this review, we discuss mitochondria's role in and impact on cellular aging and their potential to serve as a target for therapeutic interventions against age-related cellular dysfunction.
ABSTRACT
Cancer cells have developed unique strategies to meet their high energy demand. Therefore, they have established a setting of Ca2+-triggered high mitochondrial activity. But mitochondrial Ca2+ uptake has to be strictly controlled to avoid mitochondrial Ca2+ overload that would cause apoptotic cell death. Methylation by protein arginine methyl transferase 1 (PRMT1) desensitizes the mitochondrial Ca2+ uptake machinery and reduces mitochondrial Ca2+ accumulation in cancer cells. In case of PRMT1-driven methylation, proper mitochondrial Ca2+ uptake is reestablished by increased activity of uncoupling protein 2 (UCP2), pointing to an importance of these proteins for cancer cell survival and activity. Accordingly, in this study we investigated the impact of UCP2 and PRMT1 on the fate of human lung cancer cells (A549, Calu-3 and H1299) as well as on patients suffering from lung carcinoma. We show that combined overexpression of UCP2 and PRMT1 significantly enhances viability, proliferation as well as mitochondrial respiration. In line with these findings, the overall survival probability of lung carcinoma patients with high mRNA expression levels of UCP2 and PRMT1 is strongly reduced. Furthermore, analysis via The Cancer Genome Atlas (TCGA) reveals upregulation of both proteins, UCP2 and PRMT1, as common feature of various cancer types. These findings suggest that proper mitochondrial Ca2+ uptake is essential for devastating tumor growth, and highlight the importance of a tightly controlled mitochondrial Ca2+ uptake to ensure proper ATP biosynthesis while avoiding dangerous mitochondrial Ca2+ overload. By that, the study unveils proteins of the mitochondrial Ca2+ uptake as potential targets for cancer treatment.
ABSTRACT
The naturally occurring polyphenol, resveratrol (RSV), is known for a broad range of actions. These include a positive impact on lifespan and health, but also pro-apoptotic anti-cancer properties. Interestingly, cell culture experiments have revealed a strong impact of RSV on mitochondrial function. The compound was demonstrated to affect mitochondrial respiration, structure and mass of mitochondria as well as mitochondrial membrane potential and, ultimately, mitochondria-associated cell death pathways. Notably, the mitochondrial effects of RSV show a very strict and remarkable concentration dependency: At low concentrations, RSV (<50 µM) fosters cellular antioxidant defense mechanisms, activates AMP-activated protein kinase (AMPK)- and sirtuin 1 (SIRT1)-linked pathways and enhances mitochondrial network formation. These mechanisms crucially contribute to the cytoprotective effects of RSV against toxins and disease-related damage, in vitro and in vivo. However, at higher concentrations, RSV (>50 µM) triggers changes in (sub-)cellular Ca2+ homeostasis, disruption of mitochondrial membrane potential and activation of caspases selectively yielding apoptotic cancer cell death, in vitro and in vivo. In this review, we discuss the promising therapeutic potential of RSV, which is most probably related to the compound's concentration-dependent manipulation of mitochondrial function and structure.
