Alterations in Mitochondrial Function in Pulmonary Vascular Diseases

Figures

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  FIG. 1.. Effect of sex and race on mitochondrial assays. (A) Mitochondrial mass was significantly higher in Black participants. Mitochondrial transmembrane potential and superoxide production were not affected by race. (B) Male participants tended to have higher mitochondrial transmembrane potential. Mass and superoxide production were not affected by sex. Individual data points shown. Black line represents the mean. Gray circles represent controls, and black circles pulmonary hypertension (PH). Wilcoxon p value used.

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  FIG. 2.. Mitochondrial transmembrane potential is inversely related to superoxide production. In our overall cohort, there is an inverse correlation between mitochondrial transmembrane potential and superoxide production. Pearson’s correlation used with line of best fit shown for visualization.

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  FIG. 3.. Group1 (G1) pulmonary arterial hypertension (PAH) has lower mitochondrial transmembrane potential and higher superoxide production. Mitochondrial transmembrane potential and superoxide production varied across PH groups. G1 PAH had significantly lower transmembrane potential compared with G2 and 3 PH and a tendency for lower transmembrane potential compared with healthy controls. G3 PH had lower superoxide production compared with G1, 2, and 4 PH. Gray circles represent controls and black circles PH. Box plots show median and 25%−75% quartiles. Whiskers mark the maximum and minimum values excluding outliers. The gray thick line represents the mean for healthy controls. Black thick lines represent the mean of each corresponding group. Wilcoxon p values for overall comparison and pairwise comparisons are shown. Bonferroni-adjusted significance level required p < 0.005.

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  FIG. 4.. Mitochondrial electron transport chain (ETC) and the tricarboxylic acid (TCA) cycle. (A) ETC, a series of protein complexes in the inner mitochondrial membrane, picks electrons from reduced electron carriers (NADH/FADH2) produced by the TCA cycle and fatty acid β-oxidation creating an electrochemical gradient that leads to the production of ATP. Superoxide is produced during the process. Fatty acid β-oxidation transfers electrons to the ETC directly through complex III or by generating acetyl-coA that goes into the TCA cycle. (B) TCA cycle metabolites are different among PH groups and controls with an elevated lactate-to-pyruvate ratio noted in G1 PAH. Data shown as mean with Standard Error of the Mean (SEM). p Value adjusted for age, race, sex, and estimated glomerular filtration rate (eGFR).

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  FIG. 5.. Mitochondrial transmembrane potential is a predictor of survival in G1 PAH. We performed Cox proportional hazard survival analysis to predict clinical outcomes using predictors age, sex, REVEAL LITE 2, and transmembrane potential. Only in G1 PAH, transmembrane potential was a predictor of survival (hazard ratio = 0.45 [0.25–0.79], p = 0.009). Forty-eight months of survival plots are shown for transmembrane potential and REVEAL LITE 2 score. In contrast to REVEAL LITE 2, which demonstrates a robust predictive value for survival across its entire range, transmembrane potential exhibits a nonlinear association. Specifically, at lower values, the survival curve remains relatively flat, while at higher transmembrane potential values (>3000–3500 × 104), there is a significant association with improved survival.

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