Mitochondrial Respiratory Complexes as Targets of Drugs: The PPAR Agonist Example

Abstract

Mitochondrial bioenergetics are progressively acquiring significant pathophysiological roles. Specifically, mitochondria in general and Electron Respiratory Chain in particular are gaining importance as unintentional targets of different drugs. The so-called PPAR ligands are a class of drugs which not only link and activate Peroxisome Proliferator-Activated Receptors but also show a myriad of extrareceptorial activities as well. In particular, they were shown to inhibit NADH coenzyme Q reductase. However, the molecular picture of this intriguing bioenergetic derangement has not yet been well defined. Using high resolution respirometry, both in permeabilized and intact HepG2 cells, and a proteomic approach, the mitochondrial bioenergetic damage induced by various PPAR ligands was evaluated. Results show a derangement of mitochondrial oxidative metabolism more complex than one related to a simple perturbation of complex I. In fact, a partial inhibition of mitochondrial NADH oxidation seems to be associated not only with hampered ATP synthesis but also with a significant reduction in respiratory control ratio, spare respiratory capacity, coupling efficiency and, last but not least, serious oxidative stress and structural damage to mitochondria.

Rutin Protects Fibroblasts from UVA Radiation through Stimulation of Nrf2 Pathway

“…In confirmation of this, experimental evidence shows that cells of Nrf2-KO animals are highly sensitive to chemical-induced mitochondrial damage, whereas chemo-preventive agents protect against mitochondrial damage [ 54 , 55 ]. The results of our study confirm this axiom; in fact, HRR measurements obtained on intact fibroblasts under physiological feeding conditions with a mating control protocol [ 56 , 57 ] revealed that the antioxidant activity exerted by rutin and its ability to activate Nrf2 is also significantly displayed at the mitochondrial level. Indeed, cellular respiration was found to be strongly inhibited in UVA-exposed fibroblasts and maintained at levels comparable to those of the control in rutin-treated cells.…”

The polyphenolic compound punicalagin protects skin fibroblasts from UVA radiation oxidative damage

“…Measurement of OCR is very useful in assessing the functional properties of mitochondria. In particular, this method, which allows the assessment of respiratory function without the addition of exogenous substrates and ADP, has been shown to be particularly suitable for preserving all mitochondrial perturbations affecting cellular respiration ( Brand and Nicholls, 2011 ; Bottoni et al, 2022 ). Interestingly, these results are consistent with measurements of complex I activity.…”