Age- and Genotype-Specific Effects of the Angiotensin-Converting Enzyme Inhibitor Lisinopril on Mitochondrial and Metabolic Parameters in Drosophila melanogaster.

Karis Ederer,Daniel Raftery,Maria De Luca,Patricia Jumbo-Lucioni,Douglas Moellering,Gregory Gorman,Kelly Jin,Glenn Rowe,Sarah Bouslog,Lu Wang,Peter Abadir,Daniel Promislow

doi:10.3390/ijms19113351

Abstract

The angiotensin-converting enzyme (ACE) is a peptidase that is involved in the synthesis of Angiotensin II, the bioactive component of the renin-angiotensin system. A growing body of literature argues for a beneficial impact of ACE inhibitors (ACEi) on age-associated metabolic disorders, mediated by cellular changes in reactive oxygen species (ROS) that improve mitochondrial function. Yet, our understanding of the relationship between ACEi therapy and metabolic parameters is limited. Here, we used three genetically diverse strains of Drosophila melanogaster to show that Lisinopril treatment reduces thoracic ROS levels and mitochondrial respiration in young flies, and increases mitochondrial content in middle-aged flies. Using untargeted metabolomics analysis, we also showed that Lisinopril perturbs the thoracic metabolic network structure by affecting metabolic pathways involved in glycogen degradation, glycolysis, and mevalonate metabolism. The Lisinopril-induced effects on mitochondrial and metabolic parameters, however, are genotype-specific and likely reflect the drug’s impact on nutrient-dependent fitness traits. Accordingly, we found that Lisinopril negatively affects survival under nutrient starvation, an effect that can be blunted by genotype and age in a manner that partially mirrors the drug-induced changes in mitochondrial respiration. In conclusion, our results provide novel and important insights into the role of ACEi in cellular metabolism.

Highlights

The circulating renin-angiotensin system (RAS) is a hormonal system whose primary function is to regulate arterial pressure as well as water and sodium homeostasis [1]
We report that Lisinopril administration affects thoracic mitochondrial function, mitochondrial content, and H2O2 levels as well as starvation survival in D. melanogaster, strongly suggesting the existence of evolutionarily conserved physiological mechanisms linking ACE inhibitors (ACEi) and cellular energy metabolism
We found that Lisinopril significantly reduces mitochondrial state 3 respiration but it does so in a genotype- and age-dependent manner (Figure 1A and Supplementary Table S1)

Summary

Introduction

The circulating renin-angiotensin system (RAS) is a hormonal system whose primary function is to regulate arterial pressure as well as water and sodium homeostasis [1]. The main effector of RAS is Angiotensin (Ang) II, which is produced by enzymatic sequential cleavage of peptides derived from the liver-produced angiotensinogen. Angiotensinogen is converted by renin to Ang I, which in turn is converted to Ang II by the action of the angiotensin-converting enzyme (ACE) [1]. Within the past 15 years, it has become evident that several RAS components are present in almost every organ (local RAS), where they exert diverse organ-specific physiological and pathophysiological functions through the action of de novo synthesized Ang II. Local RASs operate in concert with the systemic RAS, and independently [3,4]

Objectives

Methods

Results

Conclusion