Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Jan;12(1):77-85.
doi: 10.1016/j.mito.2011.07.004. Epub 2011 Jul 21.

Mitochondrial calcium homeostasis as potential target for mitochondrial medicine

Carlotta Giorgi  1 , Chiara Agnoletto, Angela Bononi, Massimo Bonora, Elena De Marchi, Saverio Marchi, Sonia Missiroli, Simone Patergnani, Federica Poletti, Alessandro Rimessi, Jan M Suski, Mariusz R Wieckowski, Paolo Pinton
Affiliations
Review

Mitochondrial calcium homeostasis as potential target for mitochondrial medicine

Carlotta Giorgi et al. Mitochondrion. 2012 Jan.

Abstract

Mitochondria are crucial in different intracellular pathways of signal transduction. Mitochondria are capable of decoding a variety of extracellular stimuli into markedly different intracellular actions, ranging from energy production to cell death. The fine modulation of mitochondrial calcium (Ca(2+)) homeostasis plays a fundamental role in many of the processes involving this organelle. When mitochondrial Ca(2+) homeostasis is compromised, different pathological conditions can occur, depending on the cell type involved. Recent data have shed light on the molecular identity of the main proteins involved in the handling of mitochondrial Ca(2+) traffic, opening fascinating and ambitious new avenues for mitochondria-based pharmacological strategies.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Mitochondrial physiology and mitochondrial Ca2+ handling. Ca2+ enters in the mitochondrial matrix via a low affinity uniporter (MCU) and through a high electronegative potential (− 180 mV). Extrusion of Ca2+ takes two major routes, one driven by the Na+/Ca2+ exchanger, and another pathway which involves H+–Ca2+ exchanger. In the matrix, Ca2+ stimulates the activity of three Ca2+-sensitive dehydrogenases of the Krebs cycle. The gradient across the inner membrane is important for the mitochondrial state and is established by the activity of the mitochondrial respiratory chain. VDAC: voltage-dependent anion channel, ANT: adenosine nucleoside transporter, HK: hexokinase, CD: cyclophilin D, CK: creatine kinase, BR: benzodiazepine receptor, PTP: permeability transition pore.
Fig. 2
Fig. 2
Schematic representation of mitochondrial dysfunctions in some common disease. A. In pancreatic β cells, generalized reduction of mitochondrial Ca2+ uptake (due to reduced extracellular Ca2+ influx or Ca2+ release from stores) impairs Krebs cycle and electron transport chain (ETC) activity. Anomalous ROS production can generate mitochondrial DNA mutations, leading to further malfunctioning of ETC. The resulting impairment in ATP production brings to reduced β cell activity and reduced insulin release. B. Excessive mitochondrial Ca2+ uptake induces opening of PTP leading to well known toxic effects. Further excessive ion concentration impairs ETC efficiency promoting ROS generation with consequent lipid perodxation and enhancement the probability of PTP opening. C. Ca2+ overload induce cell death in neurons. In Alzheimer's disease the presence of β-amyloid leads to ROS generation in neurons, causing cytosolic Ca2+ accumulation by different mechanisms. This homeostasis deregulation brings to mitochondrial Ca2+ overload and PTP opening. Mitochondrial Ca2+ overload is also responsible for dopaminergic neurons death in Parkinson's disease. D. Neuronal severe dysfunctions can be generated by reduced mitochondrial Ca2+ uptake in mitochondrial primary diseases (MIDs). Mutations in mtDNA are able to affect ETC and mitochondrial membrane potential and ROS generation, leading to impaired ATP synthesis and reduced Ca2+ accumulation. Because of the Ca2+ dependency of some enzymes of Krebs cycle a positive feedback progressively reduced the ability of mitochondria to synthetize ATP affecting cell physiology and survival.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Adlam V.J., Harrison J.C., Porteous C.M., James A.M., Smith R.A., Murphy M.P., Sammut I.A. Targeting an antioxidant to mitochondria decreases cardiac ischemia–reperfusion injury. FASEB J. 2005;19:1088–1095. - PubMed
    1. Akao M., O'Rourke B., Kusuoka H., Teshima Y., Jones S.P., Marban E. Differential actions of cardioprotective agents on the mitochondrial death pathway. Circ. Res. 2003;92:195–202. - PubMed
    1. Anandatheerthavarada H.K., Devi L. Amyloid precursor protein and mitochondrial dysfunction in Alzheimer's disease. Neuroscientist. 2007;13:626–638. - PubMed
    1. Andrienko T., Kuznetsov A.V., Kaambre T., Usson Y., Orosco A., Appaix F., Tiivel T., Sikk P., Vendelin M., Margreiter R., Saks V.A. Metabolic consequences of functional complexes of mitochondria, myofibrils and sarcoplasmic reticulum in muscle cells. J. Exp. Biol. 2003;206:2059–2072. - PubMed
    1. Balaban R.S., Nemoto S., Finkel T. Mitochondria, oxidants, and aging. Cell. 2005;120:483–495. - PubMed

Publication types