Endotoxemia impairs heart mitochondrial function by decreasing electron transfer, ATP synthesis and ATP content without affecting membrane potential

Abstract

Acute endotoxemia (LPS, 10 mg/kg ip, Sprague Dawley rats, 45 days old, 180 g) decreased the O₂ consumption of rat heart (1 mm³ tissue cubes) by 33% (from 4.69 to 3.11 μmol O₂/min. g tissue). Mitochondrial O₂ consumption and complex I activity were also decreased by 27% and 29%, respectively. Impaired respiration was associated to decreased ATP synthesis (from 417 to 168 nmol/min. mg protein) and ATP content (from 5.40 to 4.18 nmol ATP/mg protein), without affecting mitochondrial membrane potential. This scenario is accompanied by an increased production of O₂·⁻ and H₂O₂ due to complex I inhibition. The increased NO production, as shown by 38% increased mtNOS biochemical activity and 31% increased mtNOS functional activity, is expected to fuel an increased ONOO⁻ generation that is considered relevant in terms of the biochemical mechanism. Heart mitochondrial bioenergetic dysfunction with decreased O₂ uptake, ATP production and contents may indicate that preservation of mitochondrial function will prevent heart failure in endotoxemia.

Mitochondrial Function in Sepsis

“…Acute endotoxemia decreased cardiac muscle mitochondrial O 2 consumption and complex I activity, a change that was associated with decreased ATP synthesis and ATP content (5), whereas cecal ligation and puncture (CLP) models show decreased complex IV activity, a change associated with decreased contractility. During sepsis, there is a significant increase in nitric oxide (NO), mediated in part by increased inducible nitric oxide synthase (iNOS) activity.…”

Pathophysiology of Sepsis-Related Cardiac Dysfunction: Driven by Inflammation, Energy Mismanagement, or Both?

“…Mitochondrial dysfunction is triggered by increased production of ROS that occurs in septic hearts, as has been shown in LPS-treated mice [134] and rats [135]. This is associated with reduced levels of complex II and IV of the oxidative phosphorylation machinery and reduced enzymatic activity of several mitochondrial enzymes, such as NADH cytochrome c reductase, succinate cytochrome c reductase, and cytochrome c oxidase [136].…”

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

“…Targeting mitochondrial dysfunction may more broadly improve cardiac outcomes: repression of Complex I components (Fig. S21) is consistent with Complex I specific dysfunction and ROS generation in mitochondria from endotoxemic hearts [75,79].…”

“…This has been linked to abnormalities in myofibrillar Ca 2+ sensitivity [70,71], adrenergic control [71][72][73][74] and mitochondrial function [75], together with cell death [23,76,77]. Transient changes in preload may also mediate early reversible depression in vivo [78].…”