Sirtuin Control of Mitochondrial Dysfunction, Oxidative Stress, and Inflammation in Chagas Disease Models

Abstract

Trypanosoma cruzi is a digenetic parasite that requires triatomines and mammalian host to complete its life cycle. T. cruzi replication in mammalian host induces immune-mediated cytotoxic proinflammatory reactions and cellular injuries, which are the common source of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during the acute parasitemic phase. Mitochondrial dysfunction of electron transport chain has been proposed as a major source of superoxide release in the chronic phase of infection, which renders myocardium exposed to sustained oxidative stress and contributes to Chagas disease pathology. Sirtuin 1 (SIRT1) is a class III histone deacetylase that acts as a sensor of redox changes and shapes the mitochondrial metabolism and inflammatory response in the host. In this review, we discuss the molecular mechanisms by which SIRT1 can potentially improve mitochondrial function and control oxidative and inflammatory stress in Chagas disease.

Keywords: Chagas disease; mitochondrial dysfunction; peroxisome proliferator-activated receptor gamma coactivator 1; reactive oxygen species; sirtuin.

Figure 1

Schematic representation of human sirtuins. SIRT1–3 (class I), SIRT4 (class II), SIRT5 (class III), and SIRT6–7 (class IV) are shown. NAD⁺ binding region is presented in black. MTS, mitochondria-targeting sequence is shown in orange; N, nuclear; C, cytoplasmic; ADRT, ADP-ribosyltransferase. Catalytic histidine and zinc-coordinating cysteines are not shown.

Figure 2

Potential mechanism of mitochondrial dysfunction in Chagas disease. T. cruzi uptake by monocytes/macrophages activates NADPH oxidase-mediated superoxide and ROS production. T. cruzi induces intracellular Ca²⁺ flux that causes mitochondrial membrane permeability transition, respiratory complex inefficiency, and increased leakage of electron from electron transport chain to oxygen, resulting in superoxide production. ROS suppress mitochondrial biogenesis through inhibition of PGC-1α-mediated transcriptional activation of NRF1/2 and TFAM that maintain redox homeostasis and mtDNA replication and transcription.

Figure 3

Mitochondrial ROS contribute to cardiac damage, inflammation, and remodeling in chronic Chagas cardiomyopathy. Mitochondrial dysfunction of electron transport chain is sustained in chronically infected mice and humans that results in persistence of ROS production and a decline in oxidative phosphorylation and ATP production. ROS-induced oxidative adducts signal inflammatory responses. Antioxidants capable of scavenging ROS have a potential to control cardiac damage and remodeling in chronic CD.

Figure 4

Potential benefits of SIRT1 agonists in CD. ROS induced oxidative adducts cause PARP1 hyperactivation that suppresses mitochondrial DNA replication and transcription and signals inflammation. PARP1 suppresses SIRT1 activity in Chagasic heart through depletion of NAD⁺ pool. Pharmacological inhibitors of PARP1 or activators of SIRT1 will enhance SIRT1-mediated deacetylation and will have cytoprotective effects in Chagas disease through inhibition of oxidative stress and inflammation and induction of antioxidant response and mitochondrial biogenesis.