Inter-organ communication and mitochondrial stress drive altered metabolism in Drosophila

Abstract

In animals, inter-organ communication maintains overall homeostasis under physiological conditions and exposure to stress. Exogenous stress from drugs or toxins affects multiple organs, triggering different responses. Mitochondria respond to toxic insults by transducing adaptive responses or activating cell death. Although organ-specific side-effects caused by mitochondrial toxicity are well-studied, less is known about how organs communicate in response to mitochondrial stress. As mitochondrial function is tightly linked to energy metabolism, local stressors can have a profound impact on the metabolism of a whole organism. The digestive tract is particularly vulnerable to the side-effects of drugs and toxins, as all xenobiotics ingested orally come into contact with the gut epithelium. The overarching aim of this Thesis is to use Drosophila to model the impact of mitochondrial toxins on the gastrointestinal tract and to understand the whole-body metabolic reprogramming that occurs in response to mitochondrial dysfunction. Aripiprazole, a commonly prescribed third generation antipsychotic drug, was recently found to have an off-target effect on mitochondrial respiratory complex I (CI). To understand the effect on the gastrointestinal tract of a medication with an off-target effect on mitochondria, I supplemented flies with aripiprazole. I show that in Drosophila, aripiprazole impairs intestinal function, and causes a shift in microbiome composition. It also decreases mitochondrial membrane potential and increases the generation of reactive oxygen species (ROS) in enterocytes. These ROS activate the c-Jun N-terminal kinase pathway, inducing cellular stress and cell death, while gastrointestinal function could be restored by the administration of an antioxidant. Mitochondrial function can be perturbed using exogenous toxins, or by endogenous genetic manipulation. An organism is a dynamic system, and disrupting mitochondrial function in one organ system can have a profound impact on the whole organism. To investigate this, I expressed an RNAi against ND-75, a subunit of CI, specifically in the gut enterocytes. This impaired mitochondrial function, and altered gut physiology. Flies expressing the RNAi had alterations in whole-body metabolism, with reduced lipid storage, and behaviour. I used a bulk RNA-seq approach on dissected guts and heads to identify differentially-expressed genes in response to knockdown of CI in the gut. I identified alterations in the transcriptome of both the gut and the brain. My results suggest a shift in whole-body metabolism and behaviour resulting from tissue-specific mitochondrial inhibition. Inter-organ communication can occur in various ways, including alterations in neuronal signalling, levels of circulating metabolites, or modulation of hormone levels. In Drosophila, two well-characterised hormones, the insulin-like peptide and the adipokinetic hormone (Akh) pathways are involved in the control of metabolism. Obesity is a multifactorial condition which may result in part from dysregulated metabolism, resulting from impaired communication between different organs. Many genes have been linked to obesity and changes in metabolism in humans and Drosophila. I found that eyes absent (eya) loss-of-function mutant Drosophila have an obese phenotype. I show that this increased body mass results from alterations in Akh-mediated regulation of adult body weight and metabolism. In this Thesis, I use Drosophila as a model system to investigate the effect of mitochondrial dysfunction caused by both pharmacological agents and genetic perturbation. Through this, I provide novel insights into how mitochondrial stress impacts tissues, organs, and the organism as a whole.