As most important part of every cell, energy production and thus mitochondrial respiration control is intertwined with alost or all cellular pathways. I would say disruption of any intercellular pathway can lead to downstream disregulation of energy production and vice versa. I guess in 10/10 diseases energy production will be changed in some way. It is very fascinating and important topic and I hope it will open scientifically very valuable discussion. I don't have all the literature with me at the moment but I will try to link it here when I will be able. In the meantime these are some of the articles I came across lately that might be of interest for the topic. 

http://www.sciencedirect.com/science/article/pii/S0167488909001670

http://www.sciencedirect.com/science/article/pii/S0005272811001605

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1386111/

http://www.tandfonline.com/doi/abs/10.4161/cbt.9.2.10379#/doi/abs/10.4161/cbt.9.2.10379

Kind regards,

Jan Homolak

Hi,

     I totally agree with Jan. I, however need a clarification before I answer your question. So when you say switching of aerobic to anaerobic respiration do you actually mean the shift from oxydative phosphorylation to glycolysis for energy production? or do you mean using a different electron acceptor other than oxygen?

I studied respiratory metabolism in stress conditions and I show that a stimulation of secondary pathway (fermentation, you can check this pathway by mesuring alcohol dehydrogenase activity), and alternative pathway (pentose phosphate by mesuring glucose 6 phosphate dehydrogenase) and also by mesuring glycolysis flux for exemple pyruvate kinase. I show that all activity are stimulated in anearobic conditions. For mitochondrial respiration i check Krebs enzymes and respiratory chaine. these enzyme are inhibited by anearobic condition.

for more detail, you can see articles of smiri et al. 2009-2012

Glucose >5mM will drive most cells in vitro to use high levels of glycolysis as measured by media acidification. Working below this will stimulate respiration as long as glutamine is present as a carbon source. In our hands glucose is a key driver of glycolysis and will rapidly supress respiration ( Oxygen consumption). The environment is a key regulator as to whether cells use aerobic glycolysis or use mitochondrial respiration. Perhaps more powerful than genetic differences.

Dear Jeff Pristupa, Dr. Datta asked a right question, which is important for the answer. Can you clarify your question?

As regards Dr. Morten's answer, I think that the issue with cells is mostly irrelevant because most researchers working with cultured cells use antibiotics, which inhibit mitochondrial respiration. Normally, cells without exception must consume oxygen for utilization of any substrate. As far as I understood, Jeff' asked about a switch from anaerobic to aerobic metabolism. This can occur in cells like yeast and even in this case the metabolic pathway is determined by the availability of oxygen. The organisms in general are divided on aerobic and anaerobic. For aerobic cells there is no such a switch to become anaerobic.

We are aware of the literature on antibiotics in culture media affecting mitochondrial respiration. In our experience the concs of antibiotics used in our culture media do not appear to affect mitochondrial respiration. An easy thing to test if you are able to measure oxygen consumption.

The measurements of oxygen consumption by whole cells is not the proof of the mitochondrial functionality, unless, of course you also used addition of inhibitors and uncouplers. I have isolated mitochondria from cells grown in the presence of streptomycin, and there was no respiration. In addition, normal whole cells in NaCl media respire very slowly with external substrates. I have also to add that most cell lines taken from a cell bank already have been treated with antibiotics. I am very critical to the mitochondrial cell research.

Really interesting I  have read some of your papers and they sent alarm bells ringing!!We have only looked at one line in detail HepG2. Cells were grown without antibiotics for 2 weeks and then we compare rates of oxygen consumption in treated and untreated whole cells with the luxcel O2 probes. There was a slight decrease in respiration but not significant. The oxygen consumption rate in most cell lines is primarily mitochondrial we have a 2-5% left after inhibition with mito inhibitors. Which cell line did you  use for your mitochondrial isolation work? It would be interesting to look at them in a whole cell respiration system. We are very interested in mitochondrial drug toxicity and likely drug side effects which vary in different individuals. Do you think cell lines could show different levels of mitochondrial inhibition by antibiotics? We looked at pen and strep but aminoglycoside antibiotics have nasty effects in patients carrying mitochondrial mutations so maybe the level of mitochondrial activity is important.HEPG2 have very high levels of mito respiration other lines can be much lower. There are clear thresholds for mtDNA mutations with high levels required to affect mito function. This is also the case for inhibitors. We have some interesting cybrid lines with different mtDNA mutant loads it would be interesting to run some titration expts with standard cell culture antibiotics.

Thank you, Karl for your response. I have isolated mitochondria +/- PenStrep from several prostate cancer cells, three cell lines from human lymphoblsatoid cells and cultured hepatocytes (primary cultures). In all cases respiration was undetected in mitos from PenStrep cells. Prostate cancer cells have very active respiration when incubated in the KCl-based medium for mitochondria (I have attached my book I have posted on my RG account). In comparison with the NaCl based media, cells respired practically with all external substrates much faster in the KCl medium (I named it "Full medium"). Even more, to my observations all cancer cell lines (three prostate cancer lines: PC-3, DU145 & LNCaP,, human fibrosrcoma HT1080 cells respired much faster in KCl medium than the non-cancer cells: Normal prostate cells and human lumphoblastoid cells. Therefore, the differences between the NaCl and KCl media were much larger in cancer cells. Normal cells respired very slowly with external substrates in the NaCl medium (succinate, glutamate + malate, pyruvate + malate). However, you cannot compare cells between each other even with isolated mitochondria. This is because mitochondria have different intrinsic activities, which I have mentioned in my paper in Mol. Cell Biol. (I have attached as well).

I tried to publish these results, but 15 years ago this was regarded as unimportant and the paper was rejected. Because I stored my data on ZIP discs, all information was lost. ZIP discts died in two years.

It was nice to communicate with you. I will read your papers.

Sincerely,

Alexander

I also agree with what was said previously, that the presence of glucose in cell culture medium is a key driver of glycolysis.  Here is a paper showing that when glucose is no longer available the cells will switch from glycolysis to lactate consumption via mitochondrial OXPHOS.

Article Circumventing the Crabtree Effect: A method to induce lactat...

Thank you for that excellent reference, Alexandra. That is a very helpful read. Points directly to mitochondrial control being 'environmental' in nature.

Please find blog https://blogs.scientificamerican.com/guest-blog/the-hallmarks-of-cancer-9-reprogramming-energy-metabolism/

The control of the respiration is done at the glycolysis level. If not it is the number of the mitochondria that influence the aerobic respiration if there is not anomaly or blockage of the mitochondria