Blood-based bioenergetics: An emerging translational and clinical tool

Abstract

Accumulating studies demonstrate that mitochondrial genetics and function are central to determining the susceptibility to, and prognosis of numerous diseases across all organ systems. Despite this recognition, mitochondrial function remains poorly characterized in humans primarily due to the invasiveness of obtaining viable tissue for mitochondrial studies. Recent studies have begun to test the hypothesis that circulating blood cells, which can be obtained by minimally invasive methodology, can be utilized as a biomarker of systemic bioenergetic function in human populations. Here we present the available methodologies for assessing blood cell bioenergetics and review studies that have applied these techniques to healthy and disease populations. We focus on the validation of this methodology in healthy subjects, as well as studies testing whether blood cell bioenergetics are altered in disease, correlate with clinical parameters, and compare with other methodology for assessing human mitochondrial function. Finally, we present the challenges and goals for the development of this emerging approach into a tool for translational research and personalized medicine.

Keywords: Bioenergetics; Biomarker; Blood cell; Mitochondria; Platelets; Precision medicine.

Figure 1.. Mitochondrial bioenergetic profile generated by Seahorse XF.

Bioenergetic profile generated by measuring oxygen consumption rate in the basal state as well as after the sequential addition of mitochondrial modulators (Oligomycin A, FCCP, Rotenone and Antimycin A). Electron transport chain diagram in which electron transport and oxygen consumption by complexes I-IV are linked to ATP production at complex V by the protonmotiv force is shown to depict the action of each modulator that used to produce the bioenergetic profile (basal respiration, proton leak, maximal respiration and non-mitochondrial respiration). See text for more details.

Figure 2.. Variability in the platelet bioenergetic profile between individuals and in the same individual over time.

(A) Variability between platelet basal OCR (pmol/min/5×10⁷ platelets) and maximal OCR (pmol/min/5×10⁷ platelets) in 75 individuals with no diagnosed disease. (B) Platelet basal OCR (pmol/min/5×10⁷ platelets) and maximal OCR (pmol/min/5×10⁷ platelets) in 12 individuals over time. Platelets were isolated from independent blood draws in each individual made at baseline then 1 week, 1 month and 3 months later. (C) Coefficient of variation for platelet basal OCR and maximal OCR describing the variability between individuals – calculated from the data in Panel A. Second two bars are the coefficient of variability of the measurements made over time from the same individual (raw data shown in Panel B). The second two bars show the mean and standard deviation of the coefficient of variability of the 12 individuals measured.

Figure 3.. Blood cell bioenergetics are altered in disease.

Summary of human studies that show altered mitochondrial bioenergetics in platelets (left side) and peripheral blood mononuclear cells (PBMCs – right side) in individuals with Asthma (¹Winnica et al., 2019, and ²Xu et al., 2015), Pulmonary Hypertension with Heart Failure with Preserved Ejection Fraction (PH-HFpEF) (³Nguyen et al., 2019), Pulmonary Arterial Hypertension (PH) (⁴Nguyen et al., 2017), Type 2 Diabetes (T2D) (⁵Avila et al., 2012, and ⁶Mahapatra et al., 2018), Sickle cell disease (SCD) (⁷Cardenes et al. 2017), Sepsis (⁸Sjovall et al., 2010), Aging (⁹Braganza et al., 2019), Parkinson’s disease (¹⁰Michalak et al., 2017), post-operative cardiac surgery changes in Bioenergetic Health Index (BHI) (¹¹Kramer et al., 2015), Porphyria (¹²Chacko et al., 2019) and HIV (¹³Willig et al., 2017).

Figure 4.. Blood cell bioenergetics correlate with tissue energetics.

Platelet ATP-linked respiration (measured by Seahorse XF Analysis) correlates with muscle state 3 respiration (respiration in the presence of pyruvate and ADP; measured by Oxygraph 2K, r = 0.568, P = 0.005) as well as with muscle ATP synthesis (measured by ³¹P-MRS, r = 0.643, P = 0.0004) in older humans (ages>75).