Toxoplasma gondii GRA8 induces ATP5A1–SIRT3-mediated mitochondrial metabolic resuscitation: a potential therapy for sepsis

Abstract

The intracellular parasite Toxoplasma gondii has unique dense granule antigens (GRAs) that are crucial for host infection. Emerging evidence suggests that GRA8 of T. gondii is a promising serodiagnostic marker in toxoplasmosis. However, little is known about the intracellular regulatory mechanisms involved in GRA8-induced host responses. We found that GRA8 interacts with host proteins involved in mitochondria activation and might be useful as a therapeutic strategy for sepsis. Here, we show that protein kinase-Cα (PKCα)-mediated phosphorylation of T. gondii GRA8 (Thr220) is required for mitochondrial trafficking and regulates the interaction of C terminal of GRA8 with nucleotide binding domain of ATP5A1. Furthermore, GRA8 interacts with SIRT3 in mitochondria, facilitating ATP5A1 deacetylation (K506 and K531), adenosine triphosphate production and subsequent anti-septic activity in vivo. Taken together, these results demonstrate a new anti-sepsis therapeutic strategy using T. gondii GRA8-induced mitochondrial metabolic resuscitation. This strategy represents an urgently needed paradigm shift for therapeutic intervention.

Toxoplasma gondii GRA8-derived peptide immunotherapy improves tumor targeting of colorectal cancer

“…PKCα-phosphorylated GRA8 associates with mitochondrial SIRT3; SIRT3 associates with ATP5A1 and controls its activity by affecting acetylation status [8,9]. Deacetylated ATP5A1 participates in several mitochondrial functions, and SIRT3 can orchestrate the overall changes in mitochondrial function, that are critical for cancer growth [14,22].…”

“…Therapeutic approaches that target mitochondria are considered to provide novel means to combat cancer and to reduce associated mortality and even to reverse the oncogenic process. Such metabolic intervening measures, called "metabolic resuscitation", employ either nutritional or pharmacological agents to improve mitochondrial function [2,4,7,8]. However, the underlying mechanisms for the metabolic resuscitation induced by the dense granule protein GRA8 of Toxoplasma gondii (T. gondii) in tumor cells are yet to be investigated [8].…”

“…We previously discovered that protein kinase Cα (PKCα)-phosphorylated T. gondii GRA8 is transferred to the mitochondria and interacts with mitochondrial SIRT3. SIRT3 undergoes deacetylation with ATP synthase F1 Research Paper www.oncotarget.com subunit alpha (ATP5A1) and regulates mitochondrial activity to contribute to antiseptic activities in vivo [8,9].…”

“…SIRT3 can act like a tumor suppressor as well as an oncogene, and thus modulate cell death by affecting the main regulatory factors and their signaling pathways in cancer [5,6,14,15]. Thus, the GRA8-mediated cellular mechanisms that regulate mitochondrial metabolism could be exploited in therapeutic approaches against tumors similar to strategies that have been used against sepsis [2,8,16].…”

“…In addition, enhanced selectivity has the potential to lower toxicity and side effects. Inasmuch as it is possible to design peptides to affect a wide range of targets, there are numerous possibilities of applying peptide therapeutics in several fields including endocrinology, immunology, oncology, and infectious disease [8,18,19]. In this study, we built upon the discoveries of the minimal peptide moieties for mitochondrial targeting and ATP5A1/SIRT3 binding, previously reported to be important in therapeutic approaches [8].…”