Biology subjects

Rustin, P.

Publications and source records attributed to Rustin, P..

4 recordsLinked to original sources

bioRxiv2024

One-to-one Benefit provided by Antioxidants to cultured skin Fibroblasts from Friedreich Ataxia patients

With the hope of better understanding and characterizing the dramatic differences in antioxidant response of human cells carrying mutations in the frataxin gene responsible for Friedreich ataxia (FRDA), we studied primary cultures of skin fibroblasts derived from five FRDA patients harboring different large expansion sizes in the frataxin gene. Because oxidative stress was previously established to be instrumental in FRDA, among the many enzymes likely to modulate sensitivity to oxidative stress, we selected some previously shown to play a critical role in this stress. However, we failed to identify a consistent clue to order individual cultures based on these measurements. We therefore focused our study on cell death of FRDA fibroblasts and its modulation by different antioxidants under culture conditions exacerbating sensitivity to oxidative stress. Under conditions that force the cells to rely on mitochondrial activity, we observed significant yet variable FRDA cell proliferation. These conditions were thereafter used to screen the effectiveness of a set of antioxidant molecules targeting different steps of the pro-oxidant cascade previously documented in FRDA, i.e. Uridine, Pyruvate, and Pioglitazone, to prevent or slow down cell mortality. We observed a surprising variability of response to antioxidant molecules even under the similar, controlled conditions used to culture patients fibroblasts. We conclude that the specific response of each individual already discernable at cellular level may well play an important role in the frequent difficulties encounter to reach firm conclusions when testing the capacity of antioxidants to counteract the consequences of frataxin depletion, including in clinical trials.

cell biology↗

bioRxiv2023

Mitochondrial temperature homeostasis resists external metabolic stresses

Based on studies with a fluorescent reporter dye, Mito Thermo Yellow, and the genetically encoded gTEMP ratiometric fluorescent temperature indicator targeted to mitochondria, the temperature of active mitochondria in four mammalian and one insect cell-line was estimated to be up to 15 {degrees}C above that of the external environment to which the cells were exposed. High mitochondrial temperature was maintained in the face of a variety of metabolic stresses, including substrate starvation or modification, decreased ATP demand due to inhibition of cytosolic protein synthesis, inhibition of the mitochondrial adenine nucleotide transporter and, if an auxiliary pathway for electron transfer was available via the alternative oxidase, even respiratory poisons acting downstream of OXPHOS complex I. We propose that the high temperature of active mitochondria is an inescapable consequence of the biochemistry of oxidative phosphorylation and is homeostatically maintained as a primary feature of mitochondrial metabolism. IMPACT STATEMENTMitochondria are up to 15 {degrees}C hotter than their external environment in living cells. In response to diverse metabolic stresses, mitochondrial temperature re-adjusts to this value whenever possible.

biochemistry↗

bioRxiv2018

A new threat identified in the use of SDHIs pesticides targeting the mitochondrial succinate dehydrogenase enzyme

Succinate dehydrogenase inhibitors (SDHIs) are now widely used worldwide as fungicides to limit the proliferation of molds in cereal crops, or to better preserve fruits, vegetables, and seeds from these molds, as well as to facilitate the lawn care for public spaces and golf courses. According to the companies that produce them, the SDHIs quite specifically inhibit the activity of the succinate dehydrogenase in the molds. We here establish that these inhibitors readily inhibit the earthworm and the human enzyme, raising a new concern on the danger of their large scale utilization in agriculture. This is all the more worrying as we know that the loss of function, partial or total, of the SDH activity caused by genetic variants causes severe human neurological diseases, or leads to the development of tumors and/or cancers.

ecology↗

bioRxiv2017

Mitochondria Are Physiologically Maintained At Close To 50 C

In endothermic species, heat released as a product of metabolism ensures stable internal temperature throughout the organism, despite varying environmental conditions. Mitochondria are major actors in this thermogenic process. Part of the energy released by the oxidation of respiratory substrates drives ATP synthesis and metabolite transport, while a noticeable proportion is released as heat. Using a temperature-sensitive fluorescent probe targeted to mitochondria, we measured mitochondrial temperature in situ under different physiological conditions. At a constant external temperature of 38 {degrees}C, mitochondria were more than 10 {degrees}C warmer when the respiratory chain was fully functional, both in HEK293cells and primary skin fibroblasts. This differential was abolished in cells lacking mitochondrial DNA or by respiratory inhibitors, but preserved or enhanced by expressing thermogenic enzymes such as the alternative oxidase or the uncoupling protein 1. The activity of various RC enzymes was maximal at, or slightly above, 50 {degrees}C. Our study prompts a re-examination of the literature on mitochondria, taking account of the inferred high temperature.

cell biology↗