Defining the mitochondrial sites of superoxide/H2O2 production to enable targeted therapy for metabolic disease
Speaker: Dr Renata Gonçalves, T.H. Chan Harvard School of Public Health, Harvard University.
Mitochondria are central organelles for processing nutrient-derived substrates, generating vital molecules and metabolites for cell function. Therefore, during ageing or in the setting of imbalanced nutrient intake and expenditure, as occur in obesity, mitochondria are dysfunctional, which contributes to the onset of insulin resistance, and diabetes. Increased levels of key signalling molecules, such as superoxide and H2O2, integrate mitochondrial dysfunction with metabolic deterioration. These species, collectively referred to as mitochondrial reactive oxygen species (mROS), are produced from at least 11 different sites in this organelle. How mROS production is altered at specific sites under metabolic stress remains unknown and introduces a critical roadblock for translational approaches. To identify the site(s) generating excess mROS in obesity, we isolated liver mitochondria from wild-type lean and obese mice to compare the maximum capacity of mROS from these 11 sites. We found that in the liver of obese mice, excess superoxide/H2O2 is produced mainly from one specific site, strongly supporting that this process is regulated in a site-specific manner. Therefore, we hypothesized that obesity-induced increased production of superoxide/H2O2 from a specific mitochondrial site causes metabolic deterioration in the liver, and that restoration of physiological mROS production from this site is necessary and sufficient to restore glucose homeostasis. In an attempt to selectively suppress mROS at specific sites without altering mitochondrial metabolism, we screened a library of >600,000 compounds and identified a new class of molecules capable of suppressing mROS at two distinct sites. We show here, that higher mROS production from one specific site is sufficient to cause metabolic stress and insulin resistance in vitro. Importantly, pharmacological interventions targeted to selectively decrease this site improves glucose homeostasis in vitro and in vivo. Our data provide a novel perspective on the mechanism, regulation and metabolic impact of site-specific mitochondrial superoxide/H2O2 production during obesity.
Renata Gonçalves did her PhD at the Federal University of Rio de Janeiro and then move to the Buck Institute for Research on Aging. She is currently a postdoctoral fellow in Prof Gokham Hotamisligil laboratory at the T.H. Chan Harvard School of Public Health (Harvard University). Her work is mainly focused on unravelling new crosstalk mechanisms between cellular organelles and their role in the regulation of cellular bioenergetics. These processes have been implicated in the pathophysiology of obesity and type 2 diabetes.
Renata is interested in studying how cytosolic signalling regulates mitochondria superoxide/hydrogen peroxide production under conditions where glucose homeostasis is impaired, especially on issues that are insulin responsive (liver, skeletal and adipose tissues). Her work provides new insights into organelle dysfunction and its impact on the metabolic deterioration in obesity and ageing.
Host: Dr Esperanza Perucha