Limits...
The Bioenergetic Health Index: a new concept in mitochondrial translational research.

Chacko BK, Kramer PA, Ravi S, Benavides GA, Mitchell T, Dranka BP, Ferrick D, Singal AK, Ballinger SW, Bailey SM, Hardy RW, Zhang J, Zhi D, Darley-Usmar VM - Clin. Sci. (2014)

Bottom Line: From these data we propose that a single value-the Bioenergetic Health Index (BHI)-can be calculated to represent the patient's composite mitochondrial profile for a selected cell type.In the present Hypothesis paper, we discuss how BHI could serve as a dynamic index of bioenergetic health and how it can be measured in platelets and leucocytes.We propose that, ultimately, BHI has the potential to be a new biomarker for assessing patient health with both prognostic and diagnostic value.

View Article: PubMed Central - PubMed

Affiliation: ‡Seahorse Bioscience, North Billerica, MA 01862, U.S.A.

ABSTRACT
Bioenergetics has become central to our understanding of pathological mechanisms, the development of new therapeutic strategies and as a biomarker for disease progression in neurodegeneration, diabetes, cancer and cardiovascular disease. A key concept is that the mitochondrion can act as the 'canary in the coal mine' by serving as an early warning of bioenergetic crisis in patient populations. We propose that new clinical tests to monitor changes in bioenergetics in patient populations are needed to take advantage of the early and sensitive ability of bioenergetics to determine severity and progression in complex and multifactorial diseases. With the recent development of high-throughput assays to measure cellular energetic function in the small number of cells that can be isolated from human blood these clinical tests are now feasible. We have shown that the sequential addition of well-characterized inhibitors of oxidative phosphorylation allows a bioenergetic profile to be measured in cells isolated from normal or pathological samples. From these data we propose that a single value-the Bioenergetic Health Index (BHI)-can be calculated to represent the patient's composite mitochondrial profile for a selected cell type. In the present Hypothesis paper, we discuss how BHI could serve as a dynamic index of bioenergetic health and how it can be measured in platelets and leucocytes. We propose that, ultimately, BHI has the potential to be a new biomarker for assessing patient health with both prognostic and diagnostic value.

Show MeSH

Related in: MedlinePlus

Change in the BHI of monocytes subjected to oxidative stress(A) The bioenergetic profiles of freshly isolated CD14+monocytes from healthy volunteers were exposed to 4-HNE (20 μM for1 h at 37°C) before the assay. AntiA, antimycin A; Oligo,oligomycin. (B) The BHI calculated using the mathematicalrelationship described in the text from the profile in (A) isdemonstrated. Mean data (n=3–5 replicates) were plottedwith ±S.E.M. (A) and +S.D. (B).#P ≤ 0.0001. All study protocols forcollection and handling of human samples were reviewed and approved by theInstitutional Review Board, University of Alabama at Birmingham.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4202728&req=5

Figure 3: Change in the BHI of monocytes subjected to oxidative stress(A) The bioenergetic profiles of freshly isolated CD14+monocytes from healthy volunteers were exposed to 4-HNE (20 μM for1 h at 37°C) before the assay. AntiA, antimycin A; Oligo,oligomycin. (B) The BHI calculated using the mathematicalrelationship described in the text from the profile in (A) isdemonstrated. Mean data (n=3–5 replicates) were plottedwith ±S.E.M. (A) and +S.D. (B).#P ≤ 0.0001. All study protocols forcollection and handling of human samples were reviewed and approved by theInstitutional Review Board, University of Alabama at Birmingham.

Mentions: In the present paper, we describe one of several possible variants for a BHI equation,which we designed using the standard statistical framework of LDA (linear discriminantanalysis), which is consistent with the basic principles of bioenergetics. To test itsresponsiveness to oxidative stress, monocytes were exposed to the lipid peroxidationproduct 4-HNE (hydroxynonenal) as described below. We have described previously theeffects of 4-HNE in cellular bioenergetics in a broad range of cell types [10,21,26,30]. Inthe 4-HNE example, a low BHI is associated with a lower reserve capacity, low ATP-linkedrespiration and increased proton leak (Figure 3).Eqn (1) shown below captures positiveaspects of bioenergetic function (reserve capacity and ATP-linked respiration) andcontrasts these with potentially deleterious aspects (non-mitochondrial oxygenconsumption and proton leak). The first term in the numerator is the reserve capacity.The larger the value for reserve capacity the more effectively mitochondria can meetboth the ATP needs of the cell and deal with increased energetic demand and ionic ormetabolic stress [12]. (1)BHI=log(reservecapacity)a×(ATP-linked)b(non-mitochondrial)c×(protonleak)d


The Bioenergetic Health Index: a new concept in mitochondrial translational research.

Chacko BK, Kramer PA, Ravi S, Benavides GA, Mitchell T, Dranka BP, Ferrick D, Singal AK, Ballinger SW, Bailey SM, Hardy RW, Zhang J, Zhi D, Darley-Usmar VM - Clin. Sci. (2014)

Change in the BHI of monocytes subjected to oxidative stress(A) The bioenergetic profiles of freshly isolated CD14+monocytes from healthy volunteers were exposed to 4-HNE (20 μM for1 h at 37°C) before the assay. AntiA, antimycin A; Oligo,oligomycin. (B) The BHI calculated using the mathematicalrelationship described in the text from the profile in (A) isdemonstrated. Mean data (n=3–5 replicates) were plottedwith ±S.E.M. (A) and +S.D. (B).#P ≤ 0.0001. All study protocols forcollection and handling of human samples were reviewed and approved by theInstitutional Review Board, University of Alabama at Birmingham.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4202728&req=5

Figure 3: Change in the BHI of monocytes subjected to oxidative stress(A) The bioenergetic profiles of freshly isolated CD14+monocytes from healthy volunteers were exposed to 4-HNE (20 μM for1 h at 37°C) before the assay. AntiA, antimycin A; Oligo,oligomycin. (B) The BHI calculated using the mathematicalrelationship described in the text from the profile in (A) isdemonstrated. Mean data (n=3–5 replicates) were plottedwith ±S.E.M. (A) and +S.D. (B).#P ≤ 0.0001. All study protocols forcollection and handling of human samples were reviewed and approved by theInstitutional Review Board, University of Alabama at Birmingham.
Mentions: In the present paper, we describe one of several possible variants for a BHI equation,which we designed using the standard statistical framework of LDA (linear discriminantanalysis), which is consistent with the basic principles of bioenergetics. To test itsresponsiveness to oxidative stress, monocytes were exposed to the lipid peroxidationproduct 4-HNE (hydroxynonenal) as described below. We have described previously theeffects of 4-HNE in cellular bioenergetics in a broad range of cell types [10,21,26,30]. Inthe 4-HNE example, a low BHI is associated with a lower reserve capacity, low ATP-linkedrespiration and increased proton leak (Figure 3).Eqn (1) shown below captures positiveaspects of bioenergetic function (reserve capacity and ATP-linked respiration) andcontrasts these with potentially deleterious aspects (non-mitochondrial oxygenconsumption and proton leak). The first term in the numerator is the reserve capacity.The larger the value for reserve capacity the more effectively mitochondria can meetboth the ATP needs of the cell and deal with increased energetic demand and ionic ormetabolic stress [12]. (1)BHI=log(reservecapacity)a×(ATP-linked)b(non-mitochondrial)c×(protonleak)d

Bottom Line: From these data we propose that a single value-the Bioenergetic Health Index (BHI)-can be calculated to represent the patient's composite mitochondrial profile for a selected cell type.In the present Hypothesis paper, we discuss how BHI could serve as a dynamic index of bioenergetic health and how it can be measured in platelets and leucocytes.We propose that, ultimately, BHI has the potential to be a new biomarker for assessing patient health with both prognostic and diagnostic value.

View Article: PubMed Central - PubMed

Affiliation: ‡Seahorse Bioscience, North Billerica, MA 01862, U.S.A.

ABSTRACT
Bioenergetics has become central to our understanding of pathological mechanisms, the development of new therapeutic strategies and as a biomarker for disease progression in neurodegeneration, diabetes, cancer and cardiovascular disease. A key concept is that the mitochondrion can act as the 'canary in the coal mine' by serving as an early warning of bioenergetic crisis in patient populations. We propose that new clinical tests to monitor changes in bioenergetics in patient populations are needed to take advantage of the early and sensitive ability of bioenergetics to determine severity and progression in complex and multifactorial diseases. With the recent development of high-throughput assays to measure cellular energetic function in the small number of cells that can be isolated from human blood these clinical tests are now feasible. We have shown that the sequential addition of well-characterized inhibitors of oxidative phosphorylation allows a bioenergetic profile to be measured in cells isolated from normal or pathological samples. From these data we propose that a single value-the Bioenergetic Health Index (BHI)-can be calculated to represent the patient's composite mitochondrial profile for a selected cell type. In the present Hypothesis paper, we discuss how BHI could serve as a dynamic index of bioenergetic health and how it can be measured in platelets and leucocytes. We propose that, ultimately, BHI has the potential to be a new biomarker for assessing patient health with both prognostic and diagnostic value.

Show MeSH
Related in: MedlinePlus