José Carlos Santos Teixeira

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30 % of the global population. Its progression is commonly linked to excessive hepatic fat accumulation, elevated oxidative stress, and impaired mitochondrial function. Given the central role of mitochondria in cellular energy metabolism and redox balance, mitochondria-targeted bioactive molecules have emerged as a promising strategy for the prevention and treatment of MASLD. To this end, we develop AntiOxBEN<inf>2</inf>, a mitochondria-targeted compound generated by conjugating the antioxidant moiety of gallic acid with the lipophilic triphenylphosphonium cation . This design enables selective accumulation of AntiOxBEN<inf>2</inf> in the mitochondrial matrix, taking advantage of the organelle’s negative membrane potential. In multiple in vitro disease model s , AntiOxBEN<inf>2</inf> has demonstrated remarkable antioxidant properties, effectively mitigating oxidative stress and preserving mitochondrial function. However, effects on cellular and mitochondrial energy metabolism in vivo remain unexplored. In the present study, we tested whether chronic peripheral administration of AntiOxBEN<inf>2</inf> (0.5 or 2.5 mg/kg, 3x/week) could prevent MASLD development in male and female C57BL/6 J mice fed with a 30 % high-fat, 30 % high-sucrose (Western Diet, WD) diet for 16 weeks. Our results demonstrate that AntiOxBEN<inf>2</inf> treatment significantly reduced hepatic lipid accumulation in both sexes without affecting body weight. This reduction was accompanied by improvements in mitochondrial function, including enhanced fatty acid oxidation (FAO) and increased activities of mitochondrial electron transport chain (ETC) complexes. Moreover, AntiOxBEN<inf>2</inf> administration lowered circulating levels of hepatic damage markers (ALT and AST), as well as insulin and leptin. Notably, a clear sexual dimorphism was observed, with female mice displaying a more pronounced improvement in mitochondrial parameters. Collectively, these findings highlight the therapeutic potential of AntiOxBEN<inf>2</inf> for the prevention and/or treatment of MASLD. © © 2026. Published by Elsevier Masson SAS.

Abstract Metabolic syndrome (MetS) has been associated with disruptions in tissue mechanical homeostasis and inflammatory and metabolic derangements. However, the direct correlation between metabolic alterations and changes in tissue stiffness, and whether they could play a role as upstream initiators of disease pathology remains to be investigated. This emerging concept has yet to be put into clinical practice as many questions concerning the interplay between extracellular matrix mechanical properties and regulation of metabolic pathways remain unsolved. This review will highlight key foundational studies examining mutual regulation of cell metabolism and mechanotransduction, and opening questions lying ahead for better understanding MetS pathophysiology.

Abstract [No abstract available]

Abstract S-1 MitoPlates™ from Biolog enable the characterization of mitochondria’s function in live cells by measuring the rates of electron flow into and through the electron transport chain from different NADH or FADH2 producing metabolic substrates. This technology uses 96-well microplates pre-coated with triplicate repeats of a set of 31 substrates. Those 31 metabolic substrates have different routes of entry into the mitochondria, use different transporters, and are also oxidated by different dehydrogenases, producing reducing equivalents in the form of NADH or FADH2. The electrons produced upon oxidation of NADH or FADH2 at complex I or II, respectively, then travel to cytochrome c, where a tetrazolium redox dye (MC) can act as terminal acceptor, turning purple and absorbing at 590 nm. This mechanism allows the evaluation of cellular substrate preference by following the kinetics of MC reduction in the presence of selected substrates. In this chapter, we describe the step-by-step protocol to prepare an experiment using MitoPlate S-1 array and the OmniLog instrument to assess the metabolism of human dermal fibroblasts. We also give detailed information on how to analyze the raw data generated by the Biolog Data Analysis software to extract meaningful information and produce useful data visualizations, using reproducible methods based on a single structured dataset. © The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature 2025.

Abstract Mitochondrial dysfunction and increased reactive oxygen species (ROS) generation play an import role in different human pathologies. In this context, mitochondrial targeting of potentially protective antioxidants by their coupling to the lipophilic triphenylphosphonium cation (TPP) is widely applied. Employing a six-carbon (C6) linker, we recently demonstrated that mitochondria-targeted phenolic antioxidants derived from gallic acid (AntiOxBEN2) and caffeic acid (AntiOxCIN4) counterbalance oxidative stress in primary human skin fibroblasts by activating ROS-protective mechanisms. Here we demonstrate that C6-TPP (but not AntiOxBEN2 and AntiOxCIN4) induce cell death in human skin fibroblasts. This indicates that C6-TPP cytoxocity is counterbalanced by the antioxidant moieties of AntiOxBEN2 and AntiOxCIN4. Remarkably, C6-TPP and AntiOxBEN2 (but not AntiOxCIN4) induced a glycolytic switch, as exemplified by a reduced cellular oxygen consumption rate (OCR), increased extracellular acidification rate (ECAR), elevated extracellular lactate levels, and higher protein levels of glucose transporter 1 (GLUT-1). This switch involved activation of AMP-activated protein kinase (AMPK) and fully compensated for the loss in mitochondrial ATP production by sustaining cellular ATP content. When glycolytic switch induction was prevented ( i.e. by using a glucose-free, galactose-containing medium), AntiOxBEN2 induced cell death whereas AntiOxCIN4 did not. We conclude that, despite their similar chemical structure and antioxidant capacity, AntiOxBEN2 and AntiOxCIN4 display both common (redox-adaptive) and specific (bioenergetic-adaptive) effects.