AP39, a Modulator of Mitochondrial Bioenergetics, Reduces Antiangiogenic Response and Oxidative Stress in Hypoxia-Exposed Trophoblasts: Relevance for Preeclampsia Pathogenesis.

Although the cause of preeclampsia, a pregnancy complication with significant maternal and neonatal morbidity, has not been fully characterized, placental ischemia attributable to impaired spiral artery remodeling and abnormal secretion of antiangiogenic factors are thought to be important in the pathogenesis of the disease. Placental ischemia could impair trophoblast mitochondrial function and energy production, leading to the release of reactive oxygen species (ROS). ROS have been shown to stabilize hypoxia-inducible factor (HIF)-1α, which, in turn, may induce transcription of antiangiogenic factors, soluble fms-like tyrosine kinase 1 (sFLT1), and soluble endoglin in trophoblasts. Herein, we tested whether the angiogenic imbalance and oxidative stress in the preeclamptic placenta may be prevented by improving mitochondrial function. First, to evaluate the cause-effect relationship between mitochondrial function and sFLT1 production, a human trophoblast primary cell culture model was established in which hypoxia induced mitochondrial ROS production and concurrent sFLT1 increase. Second, treatment with AP39, a novel mitochondria-targeted hydrogen sulfide donor, prevented ROS production, reduced HIF-1α protein levels, and diminished sFLT1 production. Finally, AP39, a modulator of mitochondrial bioenergetics enhanced cytochrome c oxidase activity, reversed oxidative stress and antiangiogenic response in hypoxic trophoblasts. These results suggest that placental hypoxia induces ROS production, HIF-1α stabilization, and sFLT1 up-regulation; these pathophysiological alterations can be attenuated by mitochondrial-targeted antioxidants.

PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection.

The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischaemia. Acute kidney injury (AKI) affects 3% of all hospitalized patients. Here we show that the mitochondrial biogenesis regulator, PGC1α, is a pivotal determinant of renal recovery from injury by regulating nicotinamide adenine dinucleotide (NAD) biosynthesis. Following renal ischaemia, Pgc1α(-/-) (also known as Ppargc1a(-/-)) mice develop local deficiency of the NAD precursor niacinamide (NAM, also known as nicotinamide), marked fat accumulation, and failure to re-establish normal function. Notably, exogenous NAM improves local NAD levels, fat accumulation, and renal function in post-ischaemic Pgc1α(-/-) mice. Inducible tubular transgenic mice (iNephPGC1α) recapitulate the effects of NAM supplementation, including more local NAD and less fat accumulation with better renal function after ischaemia. PGC1α coordinately upregulates the enzymes that synthesize NAD de novo from amino acids whereas PGC1α deficiency or AKI attenuates the de novo pathway. NAM enhances NAD via the enzyme NAMPT and augments production of the fat breakdown product ß-hydroxybutyrate, leading to increased production of prostaglandin PGE2 (ref. 5), a secreted autacoid that maintains renal function. NAM treatment reverses established ischaemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of ß-hydroxybutyrate signalling or prostaglandin production similarly abolishes PGC1α-dependent renoprotection. Given the importance of mitochondrial health in ageing and the function of metabolically active organs, the results implicate NAM and NAD as key effectors for achieving PGC1α-dependent stress resistance.