Resources > MitoNews > Archives > Volume 04, Issue 02 - March, 2008

Volume 04, Issue 02 - March, 2008




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MitoNews
Mitochondrial Research Bulletin

Published by:
MitoSciences Inc.
Advancing Vital Discoveries in Mitochondrial Research
http://www.mitosciences.com

Edited by:
Roderick Capaldi, D.Phil.
rcapaldi@mitosciences.com

Written by:
Roderick Capaldi, D.Phil.
Volume 04, Issue 02 - March 2008
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Past Issues of MitoNews can be found at:
http://www.mitosciences.com/mitonews_archives.html

SYSTEMS OF MITOCHONDRIAL FUNCTION CONTROL

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I’ve been trying to get my head around the control of various mitochondrial functions. It is abundantly clear that for apoptosis, oxidative phosphorylation, biogenesis and the several other key functions of the organelle, their control can be expressed simply, as follows; For event A to occur, events B and C must be turned off, which induces D as long as E and F are each below 50%, except when H and I are turned on so that J can enhance the rate of A. My son calls this systems biology, of which he is a practitioner, and recommends mathematical modeling. However if I could do this I would have been a physicist or even a chemist!

Fortunately there are some aspects I can understand. Short term regulation of functioning is through changes in post- translational modification of the proteins involved e.g. phophorylation/dephosphorylation, acetylation/ deacetylation, sumoylation etc. which affect functioning by competitive or allosteric effects, altered protein associations and/or altered location such as movements in and out of or onto the mitochondrion. Long-term regulation occurs via transcriptional/translational changes involving post-translational modifications of transcription factor (TF) co-activators and their interaction with the TFs, which, in turn, up or down regulate the levels of enzymes involved in the function. Some recent studies below demonstrate the extent of, and intricacy in, control brought about by reaction of NAD+ with mitochondrial proteins. The reader can ponder the significance that these reactions have for responding to energy levels in a cell.

Getting Started…. NAD+ and NADP+ are more than redox enzyme co-factors. For those like me who have not kept up, there are 2 good reviews to help in putting the regulatory role of NAD+ into perspective, especially in explaining the chemistry by which this small molecule controls deacetylation of proteins as well as its role in poly-ADP ribosylation of cellular proteins. These reviews also provide a useful introduction to the enzymes involved in these NAD+ (and NADP+) dependent signaling processes.

LIN. H Org.Biomol.chem. 5. 2541-54 (2007) Nicotinamide adenine dinucleotide; beyond a redox coenzyme. POLLAK. N.,DOLLE C & ZEIGLER. M. Biochem J. 402. 205-218 (2007). The power to reduce: pyridine nucleotides-small molecules with a multitude of functions.

The article by Pollak et al provides a particularly useful review of the roles of NAD+ and NADP+ based signaling in cell physiology.

One interesting role of poly (ADP) ribosylation is in signaling of apoptosis as a result of DNA damage. Two recent reviews illuminate this aspect and describe the role of poly (ADP-ribose)polymerase (PARP) at the mitochondrion to induce release of cytochrome c and AIF.

HONG S.J. DAWSON TM &DAWSON VL. Trends in Pharmacological Sci. 25.259-64 (2004) Nuclear and Mitochondrial concersions in cell death; PARP-1 and AIF signaling.
HEERES. JT & HERGENROTHER. PJ Current Opinion in Chem Biol. 11. 1-10 (2007) Poly(ADP-ribose) makes a date with death.

The acetylation of cellular, and particularly mitochondrial, proteins is much wider than had been imagined. New substrates of acetytransferase enzymes are continuously being identified. A recent proteomic analysis of cellular proteins indicates just how widespread. Kim et al have identified nearly 400 sites on 195 proteins in HELA cells and mouse liver mitochondria, a preponderance of which are mitochondrial.
KING SC et al. Mol. Cell 23. 607-18 (2006) Substrate and functional diversity of lysine acetylation revealed by a proteomics survey.

For effective signaling, “what gets acetylated must be deacetylated” …welcome to the world of sirtuins of which 7 different forms have been identified in mammals so far. Two of these, sirtuin 3 and sirtuin 4, have a mitochondrial location. Present data indicate that Sirt 3 broadly regulates mitochondrial functioning. LOMBARD et al. Mol. Cell. Biol. 27. 8807-14 (2007) Mammalian sir2 homolog sirt3 regulates global mitochondrial lysine regulation.

The other mitochondrial sirtuin, sirt 4 appears to be a different beast! It acts as an ADP-ribosyltransferase and has recently been linked to insulin secretion.
AHUJA et. al J. Biol. Chem. 282. 33583-92 (2007). Regulation of insulin secretion by Sirt4, a mitochondrial ADP-ribosyltransferase.

A summary of studies of sirt 4 and just one of its targets serves to emphasize the overall complexity and (oh dear) the importance of a systems biology approach.

Sirt 4 has been shown to use NAD+ to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH). HAIGIS et al. Cell. 126. 941-54 (2006) Sirt 4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells.
And…..GDH promotes the metabolism of glutamate and glutamine, generating ATP and promoting insulin secretion in the pancreas. (as above)
And…..GDH uses and reduces NAD+ (or NADP+).
And…...GDH is also an mRNA binding protein which post –transcriptionally regulates cytochrome c oxidase.

PREISS et al FEBS Lett 367. 291-6 (1995) The mRNA binding protein COLBP is glutamate dehydrogenase. And…..Levels of cytochrome c oxidase affect the redox poise of NADH/NAD+.

AND SO IT GOES. For event A to occur, events B and C etc. etc.

GDH is not the only enzyme whose properties are subject to multiple post-translational regulatory modifications. Sir2 is involved in the regulation of acetyl-coA synthetase.
HALLOWS. WC, LEE.S & DENU. JM Proc Natl Acad Sci USA 103. 10230-35 (2006) Situins deacetylate and activate mammalian acetyl-coA synthetases. SCHWER. B et al Proc. Natl. Acad.Sci USA 103. 10224-9 (2006). Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl coA synthase 2.

Clearly, overall metabolism is controlled by substrate and product levels but in ways we are only now beginning to understand. ATP/ADP ratios, NADH/NAD+ ratios, NADPH/NADP+ ratios all regulate the coordination of the multiple metabolic pathways. Now, where is my algebra book!


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