Metabolome-Driven Regulation of Adenovirus-Induced Cell Death

Abstract

A viral infection that involves virus invasion, protein synthesis, and virion assembly is typically accompanied by sharp fluctuations in the intracellular levels of metabolites. Under certain conditions, dramatic metabolic shifts can result in various types of cell death. Here, we review different types of adenovirus-induced cell death associated with changes in metabolic profiles of the infected cells. As evidenced by experimental data, in most cases changes in the metabolome precede cell death rather than represent its consequence. In our previous study, the induction of autophagic cell death was observed following adenovirus-mediated lactate production, acetyl-CoA accumulation, and ATP release, while apoptosis was demonstrated to be modulated by alterations in acetate and asparagine metabolism. On the other hand, adenovirus-induced ROS production and ATP depletion were demonstrated to play a significant role in the process of necrotic cell death. Interestingly, the accumulation of ceramide compounds was found to contribute to the induction of all the three types of cell death mentioned above. Eventually, the characterization of metabolite analysis could help in uncovering the molecular mechanism of adenovirus-mediated cell death induction and contribute to the development of efficacious oncolytic adenoviral vectors.

Keywords: autophagy; metabolites; viruses.

Figure 1

Schematic representation of the tentative cell death mechanism operating through a ceramide-mediated mitophagy. Adenoviral infection induces ceramide accumulation through de novo synthesis from palmitoyl CoA and serine [19]. Subsequently, ceramide mediates the LC3 binding to the mitochondrial membrane and promotes lethal mitophagy leading to autophagic cell death [25].

Figure 2

Calcium influx contributes to the induction of necrotic cell death. Calcium influx is promoted by many factors, including endoplasmic reticulum stress, acidosis (due to lactate accumulation) [70,71], and ATP depletion (particularly due to assembly of virions and RIPK1-dependent inhibition of ANT in the mitochondrial membrane mediated by ceramide accumulation). Subsequently, an elevated concentration of calcium induces ROS production through increasing mitochondrial permeability [56,72,73]. A simultaneous decrease in ATP levels and the induced ROS production result in necrotic cell death. Abbreviations: ER—endoplasmic reticulum, ANT—adenosine nucleotide translocase, MCI—mitochondrial complex I, LDH—lactate dehydrogenase, “+”—increase effect.

Figure 3

Metabolome fluctuations that trigger different types of cell death. Elevated acetate levels stimulating uptake of glucose and lactate along with asparagine deficiency can be linked to the induction of apoptosis. Calcium influx, production of reactive oxygen species (ROS), increased glucose uptake and lactate secretion as well as an elevation in acetyl-CoA concentration are all capable of triggering autophagic cell death. In addition, ROS production, calcium elevation and ATP depletion are known to induce necroptosis. Furthermore, accumulation of ceramide species is capable of triggering all three types of cell death described in this review. Up arrow means it increases and down arrow means it decreases.