Calcium Needed for Cell Energy Production
Metabolism provides energy in a useful form to maintain homeostasis and perform work in all cells. Adenosine-5-triphosphate (ATP) production from substrate oxidation and the release of free energy from its hydrolysis must be balanced and sufficient to support cell metabolic needs, including growth, proliferation, production of metabolites, and maintenance of homeostatic processes. Most eukaryotic cells rely on mitochondrial oxidative phosphorylation as the major source of ATP. However, the mechanisms by which mitochondrial respiration and ATP synthesis are controlled in intact cells are still not completely understood. Respiratory control models involving kinetic feedback from the products of ATP hydrolysis, allosteric effects of ATP and inorganic phosphate (Pi), rates of reducing equivalent delivery to mitochondria, O2 availability, and various controls over respiratory chain components are involved (Balaban, 1990,Brown, 1992,Huttemann et al., 2008). Nevertheless, neither the factors that exert primary control of oxidative phosphorylation and ATP production in the intact cell nor the signal transduction mechanisms that support the steady-state balance of ATP production and utilization are well understood (Balaban, 1990).
Normal respiration can be altered in several pathological situations (Smeitink et al., 2006,Wallace, 2005), including cancer (Vander Heiden et al., 2009), insufficient nutrient availability, ischemia, injury and exposure to metabolic inhibitors (Huttemann et al., 2008), neurodegenerative (Mattson et al., 2008) and cardiovascular (Gustafsson and Gottlieb, 2008) diseases, and aging (Balaban et al., 2005). In response to decreased cellular ATP, cells employ a variety of pathways to restore homeostasis, including activation of AMP-activated protein kinase (AMPK) (Hardie, 2007). AMPK phosphorylates substrates to limit anabolic pathways that consume ATP and to activate catabolic pathways to generate substrates to support oxidative phosphorylation (Hardie, 2007). Another mechanism involves activation of macroautophagy (autophagy), a degradation pathway involving delivery of cytoplasmic constituents by double-membrane autophagosomes (AV) that fuse with lysosomal membranes (Klionsky, 2007). Under metabolic stress, prosurvival autophagy is induced, promoting recycling of metabolites to meet metabolic demands, through synthesis of new macromolecules or by their oxidation in mitochondria to maintain ATP levels (Levine and Kroemer, 2008,Lum et al., 2005). Autophagy also functions in developmental cell death, tumor suppression, immunity, and aging, and it has been implicated in neurodegeneration, cardiovascular disease, and cancer (Levine and Kroemer, 2008).
Here, we have identified a fundamental cellular metabolic control mechanism involving activity of the endoplasmic reticulum-localized inositol trisphosphate receptor (InsP3R) Ca2+ release channel. In the absence of basal constitutive low-level Ca2+ signaling by the InsP3R, cells become metabolically compromised as a result of diminished Ca2+ uptake by mitochondria. Constitutive mitochondrial Ca2+ uptake of InsP3R-released Ca2+ is fundamentally required to maintain sufficient mitochondrial NADH production to support oxidative phosphorylation in resting cells. Absence of this Ca2+ transfer results in inhibition of pyruvate dehydrogenase and activation of AMPK, which activates prosurvival autophagy by an mTOR-independent mechanism. These results reveal a heretofore unexpected and fundamentally essential role for constitutive low-level InsP3R Ca2+ release to mitochondria to maintain viable levels of oxidative phosphorylation.
From press release:
University of Pennsylvania School of Medicine researchers have described a previously unknown biological mechanism in cells that prevents them from cannibalizing themselves for fuel. The mechanism involves the fuel used by cells under normal conditions and relies on an ongoing transfer of calcium between two cell components via an ion channel. Without this transfer, cells start consuming themselves as a way of to get enough energy.
"Altered metabolism is a feature of many diseases, as well as aging," says senior author J. Kevin Foskett, PhD, professor of Physiology. "The definition of this essential mechanism for regulating cell energy will have implications for a wide variety of physiological processes and diseases." The investigators describe their findings in the cover article in the most recent issue of Cell.
Most healthy cells in the body rely on a complicated process called oxidative phosphorylation to produce the fuel ATP. Knowledge about how ATP is produced by the cell's mitochondria, the energy storehouse, is important for understanding normal cell metabolism, which will provide insights into abnormal cell metabolism, as in the case of cancer.
Foskett and colleagues discovered that a fundamental control system regulating ATP is an ongoing shuttling of calcium to the mitochondria from another cell component called the endoplasmic reticulum.
The endoplasmic reticulum is the major reservoir of calcium in cells. The stored calcium is released to adjacent mitochondria through a calcium ion channel called the IP3 receptor. The researchers found that this calcium release occurs at a low level all the time.
When the researchers interfered with the calcium release using genetic or pharmacological methods, the mitochondria were unable to produce enough ATP to meet the needs of the cell. This indicates that mitochondria rely on the ongoing calcium transfer to make enough ATP to support normal cell metabolism. In the absence of this transfer, the mitochondria fail to make enough ATP, which triggers an extreme cell survival process called autophagy, or self eating.
"We discovered that this self consumption as a response to the lack of the calcium transfer appears to work in many types of cells, including hepatocytes from the liver, vascular smooth muscle cells, and various cultured cells lines," says Foskett.
Autophagy is important for clearing aggregated proteins from cells, for example in neurodegenerative diseases, and it plays a role in cancer and hypertension. The IP3 receptor plays important roles in the regulation of programmed cell death, a process that is subverted in many cancers, and in neurodegenerative diseases, including Alzheimer's and Huntington's diseases. Calcium release from the IP3 receptor may be at the nexus of neurodegeneration, cancer and the role of cell metabolism gone awry in these broad disease classes.
1.César Cárdenas, Russell A. Miller, Ian Smith, Thi Bui, Jordi Molgó, Marioly Müller, Horia Vais, King-Ho Cheung, Jun Yang, Ian Parker, Craig B. Thompson, Morris J. Birnbaum, Kenneth R. Hallows, J. Kevin Foskett.
Essential Regulation of Cell Bioenergetics by Constitutive InsP3 Receptor Ca2 Transfer to Mitochondria.
University of Pennsylvania School of Medicine