Mitochondrial calcium as a key regulator of mitochondrial ATP production in mammalian cells

Abstract

Mitochondrial Ca(2+) transport was initially considered important only in buffering of cytosolic Ca(2+) by acting as a "sink" under conditions of Ca(2+) overload. The main regulator of ATP production was considered to be the relative concentrations of high energy phosphates. However, work by Denton and McCormack in the 1970s and 1980s showed that free intramitochondrial Ca(2+) ([Ca(2+)](m)) activated dehydrogenase enzymes in mitochondria, leading to increased NADH and hence ATP production. This leads them to propose a scheme, subsequently termed a "parallel activation model" whereby increases in energy demand, such as hormonal stimulation or increased workload in muscle, produced an increase in cytosolic [Ca(2+)] that was relayed by the mitochondrial Ca(2+) transporters into the matrix to give an increase in [Ca(2+)](m). This then stimulated energy production to meet the increased energy demand. With the development of methods for measuring [Ca(2+)](m) in living cells that proved [Ca(2+)](m) changed over a dynamic physiological range rather than simply soaking up excess cytosolic [Ca(2+)], this model has now gained widespread acceptance. However, work by ourselves and others using targeted probes to measure changes in both [Ca(2+)] and [ATP] in different cell compartments has revealed variations in the interrelationships between these two in different tissues, suggesting that metabolic regulation by Ca(2+) is finely tuned to the demands and function of the individual organ.

Age-Related Changes in Axonal and Mitochondrial Ultrastructure and Function in White Matter

“…On the MAM, calnexin and calreticulin regulate Ca 2ϩ flux via IP3 receptors and SERCA (sarcoplasmic/endoplasmic reticulum Ca 2ϩ ATPase;Camacho et al, 2003). As a result of Ca 2ϩ signaling between these two organelles, mitochondria take up these local high amounts of Ca 2ϩ in a quasi-synaptic manner (Kirichok et al, 2004;Graier et al, 2007), and increased intramitochondrial Ca 2ϩ levels promote activity of ATP synthase (Jouaville et al, 1999;Griffiths and Rutter, 2009). Consistent with this, the reduction in calreticulin and calnexin levels in aging axons is associated with lower ATP production, suggesting an impaired Ca 2ϩ signaling between SER and mitochondria in axons.…”

“…Our results have direct implications for the pathophysiology of age-related WM diseases, including glaucoma and stroke. Age is an established major risk factor for glaucoma, and recent studies suggest that age-related changes inherent to optic nerve significantly contribute to the onset and prognosis of this leading cause of blindness (Baltan et al, 2010;Guedes et al, 2011). Similarly, stroke occurs in the elderly and WM is injured in most strokes, contributing to the disability associated with clinical deficits.…”

Actin-based confinement of calcium responses during Shigella invasion

“…The confinement of RATPs at invasion sites may also allow to limit the spreading of apoptotic signals linked to prolonged elevated mitochondrial Ca 2 þ during the early stages of infection. Mitochondrial activation through InsP 3 -mediated Ca 2 þ increase allows ATP production through oxidative phosphorylation 34 . Interestingly, local ATP supply was shown critical for cytoskeletal remodelling processes requiring high energy during phagocytosis, a process sharing similarities with Shigella invasion 44 .…”

“…Because Ca 2 þ is a key regulator of mitochondrial functions, we next wanted to test the consequences of RATPs on mitochondrial activation during Shigella invasion 34,35 . Although Ca 2 þ transients activate mitochondrial ATP synthesis, sustained mitochondrial Ca 2 þ increases lead to the loss of mitochondrial membranes integrity and the release of pro-apoptotic factors and cell death 35 .…”

Development of Signaling Echo Method for Cell-based Quantitative Efficacy Evaluation of Anti-cancer Drugs in Apoptosis without Drug Presence Using High-precision Surface Plasmon Resonance Sensing

“…35 Furthermore, a mitochondrial electrochemical network exists through Ca 2+ flux or oscillation, creating the strong magnetic field. 36 The magneto-optic activity of magnetic materials enhances the SPR sensitivity. 37 Based on those results of earlier studies, we infer that the evanescent field can reach all mitochondria in a cell.…”