Abstract
Upon invasion of host cells, the ubiquitous pathogen Toxoplasma gondii manipulates several host processes, including re-organization of host organelles, to create a replicative niche. Host mitochondrial association to T. gondii parasitophorous vacuoles is rapid and has roles in modulating host immune responses. Here gene expression profiling of T. gondii infected cells reveals enrichment of genes involved in oxidative phosphorylation (OXPHOS) and mitochondrial dysfunction 6 h post-infection. We identified 11 hub genes (HIF-1α, CASP8, FN1, POU5F1, CD44, ISG15, HNRNPA1, MDM2, RPL35, VHL, and NUPR1) and 10 predicted upstream regulators, including 4 endogenous regulators RICTOR, KDM5A, RB1, and D-glucose. We characterized a number of mitochondrial parameters in T. gondii infected human foreskin fibroblast cells over a 36 h time-course. In addition to the usual rapid recruitment and apparent enlargement of mitochondria around the parasitophorous vacuole we observed fragmented host mitochondria in infected cells, not linked to cellular apoptosis, from 24 h post-infection. An increase in mitochondrial superoxide levels in T. gondii infected cells was observed that required active parasite invasion and peaked at 30 h post-infection. Measurement of OXPHOS proteins showed decreased expression of Complex IV in infected cells at 24 h post-infection, followed by decreased expression of Complexes I and II at 36 h post-infection. No change occurred in Complex V. No difference in host mitochondrial membrane potential between infected and mock-infected cells was observed at any time. Our results show perturbation of host mitochondrial function following T. gondii infection that likely impacts on pathogenesis of disease.
Highlights
Mitochondria are powerhouses of the cell, generating most of the cellular energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS)
Host mitochondrial association to T. gondii’s parasitophorous vacuole membrane (PVM) has been described for several decades, studies on how T. gondii interacts with the host mitochondria and the role it plays during infection are only recently emerging
Since T. gondii closely interacts with the host mitochondria during infection, we wanted to study in more detail the functional changes of host mitochondria in the acute stages of infection
Summary
Mitochondria are powerhouses of the cell, generating most of the cellular energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). This process occurs at the electron transport chain found on the inner mitochondrial membrane comprising of the OXPHOS complexes. ATP synthase (Complex V) uses the proton gradient to generate ATP. In addition to their central role in metabolism, mitochondria regulate cellular processes such as cell cycle (Antico Arciuch et al, 2012), innate immunity (West et al, 2011), and apoptosis (Wang and Youle, 2009).
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