Cookies help us deliver our services. By using our services, you agree to our use of cookies. More information

Talk:Donnelly 2022 MitoFit Hypoxia

From Bioblast

The ABC of hypoxia - special BEC issue

Questions raised by Dal on the strategy for the ABC of hypoxia triggered the concept of a special issue of BEC on the ABC of hypoxia. The special issue is introduced by the ‘definitions paper’ on ABC of hypoxia - what is the norm? Contributors of articles to the special issue will present their (peer-reviewed) manuscripts and may contribute to the introductory definitions paper.

Living Communication

For the Living Communication (future editions), we will invite additional contributors to ensure a broad perspective of hypoxia and hyperoxia, from comparative physiology, high altitude medicine, to clinical interventions and studies of isolated mitochondria, cultured cells, to living organisms in health and disease. We should clarify step-by-step who intends to join as a contributing 'author' or as a ‘signatory’. A good example is the following reference:
An example to learn from:
  • BEC_2020.1_doi10.26124bec2020-0001.v1 with 666 coauthors. Many coauthors (1) ignore the message in their current publications, or (2) do not cite the paper if they use the message. The history of this paper has contributed to initiating the MitoFit Preprints server, but only exceptional coauthors have submitted a manuscript to MitoFit Preprints since 2019 (Gnaiger 2019 MitoFit_Preprints).


Further reading

Respiratory cascade
  • Polymeropoulos ET, Milsom WK (2021) Editorial: Untangling the oxygen transport cascade: a tribute to Peter Frappell (Frapps). J Comp Physiol B 191:973-8. doi: 10.1007/s00360-021-01401-w. Epub 2021 Aug 31. PMID: 34463812. https://pubmed.ncbi.nlm.nih.gov/34463812/
  • Tung YC, Wang CK, Huang YK, Huang CK, Peng CC, Patra B, Chen HK, Tsao PN, Ling TY. Identifying distinct oxygen diffusivity through type I pneumocyte-like cell layers using microfluidic device (2022) Talanta 236:122882. doi: 10.1016/j.talanta.2021.122882. Epub 2021 Sep 11. PMID: 34635262.
  • Yoon S, Hong J, Park B, Choi Y, Khan MS, Hwang J, Tanaka M, Choi J (2021) Oxygen transport to mammalian cell and bacteria using nano-sized liposomes encapsulating oxygen molecules. J Biosci Bioeng 132:657-65. doi: 10.1016/j.jbiosc.2021.08.010. PMID: 34538590.
  • Motealleh A, Schäfer AH, Fromm O, Kehr NS (2021) 3D-printed oxygen-carrying nanocomposite hydrogels for enhanced cell viability under hypoxic and normoxic conditions. Biomacromolecules 22:4758-69. doi: 10.1021/acs.biomac.1c01067. Epub 2021 Oct 4. PMID: 34605650. https://pubmed.ncbi.nlm.nih.gov/34605650/
Tissue and intracellular hypoxia
  • Ubbink R, Prens EP, Mik EG (2021) Quantitative intracellular oxygen availability before and after 5-aminolevulinic acid skin photodynamic therapy. Photodiagnosis Photodyn Ther 36:102599. doi: 10.1016/j.pdpdt.2021.102599. Epub 2021 Oct 24. PMID: 34699980. https://pubmed.ncbi.nlm.nih.gov/34699980/
  • Horsman MR, Sørensen BS, Busk M, Siemann DW (2021) Therapeutic modification of hypoxia. Clin Oncol (R Coll Radiol) 33:e492-509. doi: 10.1016/j.clon.2021.08.014. PMID: 34535359. https://pubmed.ncbi.nlm.nih.gov/34535359/
  • Qin S, Xu Y, Li H, Chen H, Yuan Z (2021) Recent advances in in situ oxygen-generating and oxygen-replenishing strategies for hypoxic-enhanced photodynamic therapy. Biomater Sci 10:51-84. doi: 10.1039/d1bm00317h. PMID: 34882762.
Hyperoxia
  • Lilien TA, Groeneveld NS, van Etten-Jamaludin F, Peters MJ, Buysse CMP, Ralston SL, van Woensel JBM, Bos LDJ, Bem RA (2022) Association of arterial hyperoxia with outcomes in critically ill children: a systematic review and meta-analysis. JAMA Netw Open 5:e2142105. doi: 10.1001/jamanetworkopen.2021.42105. PMID: 34985516. https://pubmed.ncbi.nlm.nih.gov/34985516/
Geological


Points of discussion

To do

  • Bengt: My proposal would be that we write a short concise definition piece.
  • Erich: Priorities and aims:
  1. Contribute to an improved presentation of concepts on ‘oxia’ across disciplines, particularly considering hypoxia and hyperoxia in clinical settings, high-altitude medicine and sport physiology, comparative physiology, studies of cell models and mitochondrial preparations, and evolutionary biology. If we consider obligatory and facultative anaerobes among eucaryotic parasites and microbes, definitions must be much less rigorously ‘definite’.
  2. Critically consider previous efforts to communicate core concepts on hypoxia and hyperoxia with an attempt to harmonize the nomenclature within the framework of a theoretically founded and practical terminology.
  3. Avoid ad-hoc recommendations which – although justified in a specific context – may fail to receive recognition in a more general context. (This is why I favor an expanded list of coauthors.) - Bengt: I have just completed a so-called Delphi study, it was quite fun. We were able to recruit and have participate 50 % of the worlds most recognized experts in altitude medicine and physiology (defined as having more than 9 papers on AMS) to help define a list of statements of desirable minimal knowledge for lay persons traveling to and at altitude. Over a series of several rounds we could reach consensus. A student of mine is writing it up. Perhaps something to keep in mind. Once we have a solid document we could summarize it in a series of statements that we could then submit to a panel of experts in a Delphi study.
  4. If in doubt, give preference to terminology that is used already more widely – widely either in an interdisciplinary sense or in a practical sense of common use. This argument is not strictly scientific since science must progress beyond established paradigms. Scientific terminology and communication play key roles in the advancement of knowledge across disciplines and unfortunately also in resistance against new breakthroughs. To emphasize an openness for progress and innovation, any preference for established terminology should be taken into account only in cases of argumentative doubt.

Intracellular normoxia

The definitions summarized in the main text should guide the discussion towards controversies that have yet to be resolved.
  • Bengt: My idea is to label ‘anything’ that a healthy human can do while breathing sea level equivalent air, resting, sleeping, walking, running, one-legged kicking, maximal sprinting, can be labelled physiological, i.e. comprised in the range of what normal physiology can attain. The advantage of such is that it simplifies things so that any deviation from what is observed in all these activities when breathing low or high oxygen gas, or other ways of changing the amount of oxygen transported to the site at stake, can then be labelled as such.

One-legged kicking

  • Erich: One-legged kicking is the invention by Bengt Saltin as an experimental model to proof limitation by cardiovascular oxygen supply under physiological conditions of maximum aerobic work during running and cycling not restricted to one leg. One-legged kicking is not under evolutionary selection pressure (I do not include soccer players since their kicking is driven by the anaerobic mechanism of PCr splitting). Thus, one-legged kicking cannot provide an argument to define a norm for intracellular conditions nor can intracellular normoxia be a useful reference point, if it depends on training status, regulation by the brain in less motivated compared to professionally motivated maximum exercisers (several excellent papers by Bengt Kayser). With these arguments, it may well be that I must revise previous reference values of intracellular pO2 in view of “Thus mitochondrial respiration proceeds at 90 % of its hyperbolic maximum at the p50 of myoglobin, suggesting the possibility of a small but significant oxygen limitation even under normoxia in active muscle.“ Then intracellular tissue normoxia will not extend to the very low pO2 observed in non-steady state of maximum aerobic activity when intracellular pO2 drops towards the p50 of myoglobin – this is (C) functional hypoxia (defined by Critical functions and critical pc).
  • Bengt: The question then becomes, when making observations in our reference object (say, the usual suspect a 70 kg 170 cm healthy and active male ….. ;-) ), what do we consider in our observations in B and C as normoxic? Resting only would be too restricted I find, since physiology needs oscillation for homeostasis (in the originally intended definition of the latter term, see e.g. https://www.frontiersin.org/articles/10.3389/fphys.2020.00200/full). So we should include some increased levels of metabolism from physical activity, certainly an aspect of human behavior that should be considered physiological. But up what level? And by what type of that archetypical male? You are right that the leg-kicking of genius Bengt Saltin (on my PhD committee !) is perhaps too much, even though experimentally so well thought through to study physiology. The idea to set the limit at what is sustainable is good, but runs into the problem of what is sustainable … the so-called critical power concept (which I have my critical thoughts about …. but that is another story) is a decay towards ‘infinity’ at some quite sub-maximal power, lower than 80-90 VO2max, and dependent on training status. Hence my reasoning, instilled by a desire to look for an internally logical framework with no need for some arbitrary cut-off that cannot be defined precisely. This yearning for simple clarity led me to wish taking the observations in environmental normoxia as the baseline of systems normoxia, i.e. any oxygen concentration anywhere in the organism, at rest up to that observed in maximal large and small muscle mass exercise paradigms.
  • Erich: I share your concerns against having to set an arbitrary activity level to define (B) compartmental hypoxia. Therefore, I proposed neither VO2max nor basal nor standard metabolism as a reference for normoxia, but routine metabolism. This is not an arbitrarily defined state but can be considered as the activity level averaged over the awake period of an organism. An attempt to define routine metabolism is lacking to my knowledge in the mammalian literature, hence my reference to the literature on fishes, and a reference to steady-state (averaged, allowing for oscillations). An alternative could be to combine from our ABC the arguments on (B) and (C): If normoxic critical functions (e.g. respiration, protein synthesis) are defined as those not limited by oxygen availability in a healthy organism, then (B) normoxia in the compartmental microenvironments (e.g. intracellular) might be defined as those oxygen levels supporting (C) normoxic function. Perhaps we would find that the two alternatives of normoxia (B) ― compartmental oxygen pressure at routine metabolism versus compartmental oxygen pressure above a critical oxygen pressure inducing oxygen limitation ― lead to closely corresponding results.

Tissue work-induced physiological hypoxia

  • Erich: Would we then drop the concept of tissue work-induced physiological hypoxia? We would run against a strong literature.
  • Bengt: That is indeed the central question that I am grappling with. I tend to wish to see the combination of ‘physiological’ and ‘hypoxia’ to be interpreted as an oxymoron (😉). As an archetypical example, lactate release from muscle fibers during exercise up to max, accompanied by conditions of lowering oxygen concentrations in working muscle which are indeed labeled hypoxic by others, but which are not the reason for the increased lactate release which has more to do with mass effects upstream from the Krebs cycle, and also being perfectly physiological with the lactate released serving important physiological mechanisms. This is something that starts to occur already at quite submaximal power outputs, that we can consider as being within the scope of usual metabolic fluctuations over the day in people engaging into the recommended physical activity levels by the WHO. As a second example we can look at the low oxygen concentrations in some specific tissus such is the renal papillae, pretty low but again perfectly physiological. I would consider both examples to be physiological, but not necessarily hypoxic, even though low in oxygen tensions as compared to arterial blood. If we would decide to go with the status quo we must define some frontier between physiological and pathological hypoxia. One way is indeed to look at what the effect functionally is of some drop in oxygen beyond what is observed in physiological conditions, but where to draw the line, and how to define some way that is applicable in various tissus? The idea of routine metabolism would not take away the problem of labeling for the two examples? So, my take remains, but I am of course OK to let go (!), is that we do need some additional terminology to distinguish between physiological and not physiological, hence my initial proposal to also use euoxia and dysoxia. In the renal papillae there are low oxygen concentrations but they are euoxic; a patient with angina pectoris has periods of low oxygen concentrations in myocardial tissu and they are dysoxic.
  • Erich: On your “arechetypical example, lactate release from muscle fibers during exercise up to max, accompanied by conditions of lowering oxygen concentrations in working muscle which are indeed labeled hypoxic by others, but which are not the reason for the increased lactate release which has more to do with mass effects upstream from the Krebs cycle, and also being perfectly physiological with the lactate released serving important physiological mechanisms". - Correlative and causative relations must be distinguished. The best method to do this is measurement of oxygen kinetics which reveals responses related to (1) hypoxia and hyperoxia directly and (2) mechanisms other than control by O2.
  • Erich: In hyperbolic oxygen kinetics a critical function (e.g. mitochondrial respiration) is measured at kinetic oxygen saturation and pO2 lowered towards anoxia. Below a critical pO2 (pc) the function is oxygen limited and conditions below the pc are hypoxic. The problem of defining the pc has been addressed in Gnaiger (2003). The function is reduced to 50 % of maximum at the oxygen pressure p50; to 75 % at p75; 90 % at p90; 95 % at p95; 99 % at p99. Where is the pc?

Terms


Current conferences

» https://www.rsc.org/events/detail/3610/keystone-symposia-hypoxia-molecular-mechanisms-of-oxygen-sensing-and-response-pathways
» https://www.hypoxia.net/
» https://www.dwscientific.com/2nd-whitley-hypoxia-symposium
» https://waset.org/hypoxia-exercise-and-hypoxic-exposure-conference-in-january-2022-in-bali
» https://conferenceindex.org/event/international-conference-on-hypoxia-inducible-factors-and-oxygen-biology-ichifob-2022-may-dubai-ae