Leishmania donovani restricts mitochondrial dynamics to enhance miRNP stability and target RNA repression in host
Yogaditya Chakrabarty1, Suvendra N Bhattacharyya2
1RNA Biology Research Laboratories, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India.
Abstract:
MicroRNAs (miRNAs), the tiny regulatory RNAs, form complexes with Argonaute (Ago) proteins and inhibit gene expression in metazoan cells. While studying parasite-invaded macrophages, we identify a unique mode of gene regulation in which the parasite Leishmania donovani (Ld) causes mitochondrial depolarization, reduces mitochondrial dynamics, and restricts turnover of cellular microRNA ribonucleoprotein (miRNP) complexes in infected host cells. This leads to increased stability of miRNPs along with elevated levels of Ago2-bound cytokine mRNA in Ld-infected macrophages. Thus the increase of miRNP stability in Ld-infected cells curtails production of proinflammatory cytokines, which are otherwise detrimental for survival of the parasite within the infected macrophages. Loss of mitochondrial membrane potential is accompanied by reduced juxtaposition of endoplasmic reticulum (ER) and mitochondria as well as endosomes. This is likely coupled with enhanced sequestration and stabilization of ER- associated miRNPs observed in infected macrophage cells. Mitofusin 2 (Mfn2), a membrane protein implicated in ER-mitochondria tethering, also shows reduced expression in Ld-infected cells. A mitochondrial role in Ld-induced alteration of miRNA activity and stability is further corroborated by impaired compartmentalization and stabilization of miRNP components in Mfn2-depleted mammalian cells.
Insights
The parasite Leishmania donovani stabilizes microRNA ribonucleoprotein (miRNP) complexes in host macrophages by disrupting mitochondrial function. This mechanism suppresses proinflammatory cytokines, aiding parasite survival.
Area of Science:
- Molecular Biology
- Cell Biology
- Parasitology
Background:
- MicroRNAs (miRNAs) are small regulatory RNAs that form complexes with Argonaute (Ago) proteins to regulate gene expression.
- Parasitic infections can manipulate host cell machinery to ensure pathogen survival.
Purpose of the Study:
- To investigate the unique gene regulation mechanisms employed by Leishmania donovani (Ld) in infected host macrophages.
- To elucidate the role of mitochondria and microRNA ribonucleoprotein (miRNP) complexes in Ld pathogenesis.
Main Methods:
- Analysis of mitochondrial function, dynamics, and ER-mitochondria juxtaposition in Ld-infected macrophages.
- Assessment of miRNP complex stability and Ago2-bound cytokine mRNA levels.
- Investigation using Mitofusin 2 (Mfn2) depletion in mammalian cells.
Main Results:
- Ld infection induces mitochondrial depolarization and reduces mitochondrial dynamics in host cells.
- miRNP turnover is restricted, leading to increased miRNP stability and elevated Ago2-bound cytokine mRNA.
- Reduced ER-mitochondria juxtaposition and Mfn2 expression are observed in infected cells, impacting miRNP compartmentalization.
Conclusions:
- Leishmania donovani manipulates host mitochondrial function to stabilize miRNPs, thereby suppressing essential proinflammatory cytokines.
- This parasite-induced suppression of host immunity is crucial for Ld survival within macrophages.
- Mitochondrial integrity and ER-mitochondria tethering, mediated by proteins like Mfn2, are critical for regulating miRNA activity during infection.
