Talk:Iyer 2022 Abstract Bioblast

Comments by the Editor

Gnaiger E 2022-05-26

mitoBHI

• mitoBHI was changed to mtBHI, according to abbreviation mt for mitochondria (see https://doi.org/10.26124/bec:2020-0001.v1, where you are coautor).

The mtBHI was based on four key aspects of mitochondrial respiration

• The 'four key aspects' are now listed in the abstract. In addition, it should be explained how the mtBHI was calculated from these four key aspects.

non-mitochondrial oxygen consumption

• non-mitochondrial oxygen consumption was changed to residual oxygen consumption Rox, since Rox may include mt-oxygen consumption that is not inhibited by rotenone and antimycin A (see https://doi.org/10.26124/bec:2020-0001.v1)

spare respiratory capacity

• Is it correct to assume that spare respiratory capacity was calculated as ET capacity minus ROUTINE respiration, E-R? How did you determine that E-R was a spare capacity, which implies that the cells did not make full use of their total capacity? The 'total capacity' of cell respiration may be compared to the OXPHOS capacity P of permeabilized cells (see https://doi.org/10.26124/bec:2020-0001.v1 for definition of P and E). A large E-P excess capacity is known for fibroblasts (Figure 6.12 in https://doi.org/10.26124/bec:2020-0002). Therefore, the actual spare capacity is P-R, and your estimation of spare capacity is overestimated by E-P. If it was not shown that E=P, then E-R is more appropriately termed "E-R reserve capacity". It is a reserve that cannot be fully activated by increasing ATP turnover but requires uncoupling or dyscoupling (https://doi.org/10.26124/bec:2020-0002).

ATP-linked respiration

• Is it correct to assume that ATP-linked respiration was calculated as R-L?

(After replacing spare respiratory capacity by E-R): .. E-R, which was an indicator of the cell’s capacity to adapt to the defect.

• This simple interpretation cannot be applied in general: If the defect in dyscoupling, then E-R is diminished by a compensatory increase of R. If the phosphorylation system is strongly inhibited without injury of the ETS, then E-R is increased.

The glycoBHI was based on four key aspects of glycolysis

• The 'four key aspects' are now listed in the abstract. In addition, it should be explained how the glycoBHI was calculated from these four key aspects.

proton leak

• How did you measure the proton leak? If proton leak was measured as LEAK respiration L (which includes proton slip and cycling of cations other than protons) then the correct term LEAK respiration should be applied (https://doi.org/10.26124/bec:2020-0001.v1).

basal proton efflux rate

• "Basal respiration or basal metabolic rate (BMR) is the minimal rate of metabolism required to support basic body functions, essential for maintenance only. BMR (in humans) is measured at rest 12 to 14 hours after eating in a physically and mentally relaxed state at thermally neutral room temperature" (see Basal respiration). Was 'basal proton efflux rate' measured in the LEAK state or ROUTINE state of the cells? If the latter was the case, the term should be replaced by "ROUTINE proton efflux rates". Which buffering capacity was measured or assumed to convert the measured acidification rate (change of pH over time) to the proton efflux rate (change of proton concentration over time)?

compensatory glycolysis

• Is it correct to assume that 'compensatory glycolysis' was calculated from the proton efflux rate after inhibition of respiration? Which corrections were applied to account for proton efflux not linked to glycolysis?

mitochondrial proton efflux rate

• How was the mitochondrial proton efflux rate measured or calculated?

basal (ROUTINE?) glycolysis, which was a measure of mitochondrial defect

• This simple interpretation cannot be applied in general: If the mitochondrial defect is mild dyscoupling, this can be compensated by a corresponding stimulation of R without impairment of the rate of aerobic ATP turnover, which then would not be reflected by a compensatory increase of ROUTINE glycolysis.

GENERAL COMMENT

• Even if some of the terms discussed above are used by several authors in the literature, this provides no scientific justification to uncritically apply those terms, if they are ambiguous or even misleading - in the spirit of Gentle Science.