Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle

We previously demonstrated that the deletion of the poly(ADP-ribose) polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the therapeutic use of PARP inhibitors to enhance mitochondrial function remains to be explored. Here, we show tight negative correlation between Parp-1 expression and energy expenditure in heterogeneous mouse populations, indicating that variations in PARP-1 activity have an impact on metabolic homeostasis. Notably, these genetic correlations can be translated into pharmacological applications. Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity. Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans. Overall, our work validates in worm, mouse, and human models that PARP inhibition may be used to treat both genetic and acquired muscle dysfunction linked to defective mitochondrial function.

Genetic, metabolic, and molecular insights into the diverse outcomes of diet-induced obesity in mouse

Alexis Maximilien Bachmann

Overweight and obesity are increasingly common public health issues worldwide, leading to a wide range of diseases from metabolic syndrome to steatohepatitis and cardiovascular diseases. While the increase in the prevalence of obesity is partly attributable to changes in lifestyle (i.e. increased sedentarity and changes in eating behaviour), the metabolic and clinical impacts of these obesogenic conditions varies between sexes and genetic backgrounds. The conception of personalised treatments of obesity and its complications require a thorough understanding of the diversity of responses to environmental stimuli such as high-fat diet intake. In this thesis, by analysing nine genetically diverse mouse strains, we show that much like humans, mice respond to high-fat diet in a genetic- and sex-dependent manner. Physiological and molecular responses to high-fat diet are associated with the expression of genes involved in immunity and mitochondrial function. Finally, we find that mitochondrial function and mitochondrial supercomplex assembly may explain part of the diversity of physiological responses. By exploring the complex interactions between genetics and metabolic phenotypes via gene expression and molecular traits, we shed light on the importance of genetic background and sex in determining metabolic outcomes. In addition to providing the community with an extensive resource for optimizing future experiments, this work serves as an exemplary design for more generalizable translational studies.

EPFL2021

Identification of genetic determinants and pharmacological modulators of mitochondrial function

Pénélope Andreux

Increased life expectancy goes hand in hand with a higher incidence of age-related diseases that affect the nervous and metabolic systems, such as type 2 diabetes, cancer, Parkinson’s and Alzheimer’s disease. These complex diseases are a product of the combined actions of large networks of genes, and environmental factors, such as diet, exercise, drug use, and levels of acute and chronic stress. One of the main challenges in biomedical research is determining how these factors interact to influence human healthspan, in order to develop effective strategies for the diagnosis, prevention, and treatment of these chronic multifactorial diseases. A strategy that has emerged in the last decade is the modulation of mitochondrial function. Accumulating evidence support the involvement of mitochondrial dysfunction in the pathogenesis of type 2 diabetes, Parkinson’s disease, cancer, and to a lesser extent, Alzheimer’s disease. Mitochondrial processes are regulated by a highly dynamic and complex network of enzymes and transcription factors. One of the best characterized branches of this network is the AMPK/SIRT1 pathway and its downstream effectors. Recently, additional pathways important for the regulation of mitochondrial function have been described such as mitochondrial fusion and fission, specific autophagy of mitochondria, termed mitophagy, and mitochondrial unfolded protein response (UPRmt). These recent discoveries have extended the scope of potential therapeutic targets. This thesis describes the development of two complementary approaches to identify novel genetic and pharmacological determinants of mitochondrial function. 1. The first approach aims to identify novel genetic determinants of the regulatory networks that control metabolism in general, and mitochondrial function in particular, by using the mouse BXD genetic reference population (GRP). Chapter II summarizes the analysis of 140 metabolic traits in 42 BXD strains, and demonstrates the suitability and usefulness of the BXD GRP for the identification of genetic regulators of metabolism. 2. The second approach is focused on the development of pharmacological tests for the identification and characterization of novel drugs that modulate mitochondrial phenotypes. Chapter III presents the establishment and validation of a platform of mitochondrial assays in two species, i.e. mammalian cells and the worm C.elegans. A successful example of its use is shown in chapter IV, where the role of copper in tumorigenesis is elucidated by applying these mitochondrial assays Altogether, these two synergistic approaches pave the way that will lead to the identification of novel key factors and treatments for mitochondrial diseases and pathologies associated with mitochondrial dysfunction.

EPFL2013

Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population

Ruedi Aebersold, Johan Auwerx, Sébastien Dubuis, Virginija Jovaisaite, Adrienne Joëlle Laurence Mottis, Evan Graehl Williams

The manner by which genotype and environment affect complex phenotypes is one of the fundamental questions in biology. In this study, we quantified the transcriptome--a subset of the metabolome--and, using targeted proteomics, quantified a subset of the liver proteome from 40 strains of the BXD mouse genetic reference population on two diverse diets. We discovered dozens of transcript, protein, and metabolite QTLs, several of which linked to metabolic phenotypes. Most prominently, Dhtkd1 was identified as a primary regulator of 2-aminoadipate, explaining variance in fasted glucose and diabetes status in both mice and humans. These integrated molecular profiles also allowed further characterization of complex pathways, particularly the mitochondrial unfolded protein response (UPR(mt)). UPR(mt) shows strikingly variant responses at the transcript and protein level that are remarkably conserved among C. elegans, mice, and humans. Overall, these examples demonstrate the value of an integrated multilayered omics approach to characterize complex metabolic phenotypes.

Cell Press2014

Identification of genetic determinants and pharmacological modulators of mitochondrial function

Pénélope Andreux

EPFL2013