Inflammatory bowel diseases (IBDs) are a group of chronic autoinflammatory diseases including Crohn’s disease and ulcerative colitis. Although the molecular mechanisms governing the pathogenesis of gastrointestinal inflammation are not completely clear, the main factors are presumed to be genetic predisposition, environmental exposure, and the intestinal microbiome. Hitherto, most of the studies focusing on the role of the microbiome studied the action and effect of bacteria. However, the intestinal microbiome comprises other members of the microbial community as well, namely, fungi, protozoa, and viruses. We believe that bacteriophages are among the main orchestrators of the effect of microbiota on the gut mucosa. Therefore, this review aims to summarize the knowledge of the role of intestinal phageome in IBD and to discuss the concept of phage therapy and its future applications.

Lon is an essential, multitasking AAA + protease regulating many cellular processes in species across all kingdoms of life. Altered expression levels of the human mitochondrial Lon protease (hLon) are linked to serious diseases including myopathies, paraplegia, and cancer. Here, we present the first 3D structure of full-length hLon using cryo-electron microscopy. hLon has a unique three-dimensional structure, in which the proteolytic and ATP-binding domains (AP-domain) form a hexameric chamber, while the N-terminal domain is arranged as a trimer of dimers. These two domains are linked by a narrow trimeric channel composed likely of coiled-coil helices. In the presence of AMP-PNP, the AP-domain has a closedring conformation and its N-terminal entry gate appears closed, but in ADP binding, it switches to a lock-washer conformation and its N-terminal gate opens, which is accompanied by a rearrangement of the N-terminal domain. We have also found that both the enzymatic activities and the 3D structure of a hLon mutant lacking the first 156 amino acids are severely disturbed, showing that hLon's N-terminal domains are crucial for the overall structure of the hLon, maintaining a conformation allowing its proper functioning.Human Lon (hLon, P36776) is a mitochondrial AAA + protein (ATPases Associated with diverse cellular Activities) belonging to the LonA protease subfamily 1 , which plays a crucial role in the maintenance of mitochondrial homeostasis. Its primary function is the degradation of misfolded, oxidatively modified and regulatory proteins 2 , but it also participates in the maintenance of mitochondrial DNA 3 and possesses a chaperone activity important for the proper assembly of protein complexes 4 . Changes in hLon expression have been linked to severe diseases, including epilepsy, myopathy, paraplegia, and cancer 5 . In several cancerous tissues, overexpression of hLon promoted proliferation of cancer cells 6 by remodeling their mitochondrial functions 7 while its down-regulation led to apoptosis and cell death 8 . Silencing of hLon or pharmacologically inhibiting its activity has therefore been considered as a new target for the development of anticancer drugs 9 .Like other ATPases, Lon's activities are accompanied by conformational changes induced by ATP binding and hydrolysis 10,11 . Early biochemical studies revealed that the binding of protein substrates by Lon stimulates its ATPase and peptidase activities and that this activation is likely to be allosteric 12,13 . Menon and Goldberg 12 first suggested a substrate-induced proteolytic mechanism, in which the default state of Lon is its inactive, ADP-bound form preventing accidental degradation of cellular proteins. Upon substrate binding, this form releases its ADP molecules and binds ATP, which is followed by its rapid hydrolysis and the cleavage of peptide bonds. In this mechanism, Lon can bind and hydrolyze ATP as long as the substrate binding sites are occupied. More recently, the idea that Lon's ATPase and protease activities are under allosteric...

Mitochondrial nucleoids consist of several different groups of proteins, many of which are involved in essential cellular processes such as the replication, repair and transcription of the mitochondrial genome. The eukaryotic, ATP-dependent protease Lon is found within the central nucleoid region, though little is presently known about its role there. Aside from its association with mitochondrial nucleoids, human Lon also specifically interacts with RNA. Recently, Lon was shown to regulate TFAM, the most abundant mtDNA structural factor in human mitochondria. To determine whether Lon also regulates other mitochondrial nucleoid- or ribosome-associated proteins, we examined the in vitro digestion profiles of the Saccharomyces cerevisiae TFAM functional homologue Abf2, the yeast mtDNA maintenance protein Mgm101, and two human mitochondrial proteins, Twinkle helicase and the large ribosomal subunit protein MrpL32. Degradation of Mgm101 was also verified in vivo in yeast mitochondria. These experiments revealed that all four proteins are actively degraded by Lon, but that three of them are protected from it when bound to a nucleic acid; the Twinkle helicase is not. Such a regulatory mechanism might facilitate dynamic changes to the mitochondrial nucleoid, which are crucial for conducting mitochondrial functions and maintaining mitochondrial homeostasis.