Alternative Oxidase – Aid or obstacle to combat the rise of fungal pathogens?

Fungal pathogens present a growing threat to both humans and global health security alike. Increasing evidence of antifungal resistance in fungal populations that infect both humans and plant species has increased reliance on combination therapies and shown the need for new antifungal therapeutic targets to be investigated. Here, we review the roles of mitochondria and fungal respiration in pathogenesis and discuss the role of the Alternative Oxidase enzyme (Aox) in both human fungal pathogens and phytopathogens. Increasing evidence exists for Aox within mechanisms that underpin fungal virulence. Aox also plays important roles in adaptability that may prove useful within dual targeted fungal-specific therapeutic approaches. As improved fungal specific mitochondrial and Aox inhibitors are under development we may see this as an emerging target for future approaches to tackling the growing challenge of fungal infection

Localization and Functional Characterization of the Alternative Oxidase in Naegleria

The Alternative oxidase (AOX) is a protein involved in maintaining the Krebs cycle in instances where the respiratory chain has been inhibited, while allowing for the maintenance of cell growth and necessary metabolic processes for survival. Among eukaryotes, alternative oxidases have disperse distribution and are found in plants, fungi and a few protists, including Naegleria ssp. Naegleria species are free-living unicellular amoeboflagellates, and include the pathogenic species of N. fowleri, the so-called brain eating amoeba. Using a multidisciplinary approach, we aimed to understand the evolution, localization and function of AOX and the role that plays in Naegleria’s biology. Our analyses suggest that the protein was present in last common ancestor of the genus and structure prediction showed that all functional residues are also present in Naegleria species. Using a combination of cellular and biochemical techniques, we also functionally characterize N. gruberi’s AOX in its mitochondria and we demonstrate that its inactivation affects its proliferation. Consequently, we discuss the benefits of the presence of this protein in Naegleria species, along with its potential pathogenicity role in N. fowleri. We predict that our findings will spearhead new explorations to understand the cell biology, metabolism and evolution of Naegleria and other free-living relatives

Porin 1 Modulates Autophagy in Yeast

Autophagy is a cellular recycling program which efficiently reduces the cellular burden of ageing. Autophagy is characterised by nucleation of isolation membranes, which grow in size and further expand to form autophagosomes, engulfing cellular material to be degraded by fusion with lysosomes (vacuole in yeast). Autophagosomal membranes do not bud from a single cell organelle, but are generated de novo. Several lipid sources for autophagosomal membranes have been identified, but the whole process of their generation is complex and not entirely understood. In this study, we investigated how the mitochondrial outer membrane protein porin 1 (Por1), the yeast orthologue of mammalian voltage-dependent anion channel (VDAC), affects autophagy in yeast. We show that POR1 deficiency reduces the autophagic capacity and leads to changes in vacuole and lipid homeostasis. We further investigated whether limited phosphatidylethanolamine (PE) availability in por1∆ was causative for reduced autophagy by overexpression of the PE-generating phosphatidylserine decarboxylase 1 (Psd1). Altogether, our results show that POR1 deficiency is associated with reduced autophagy, which can be circumvented by additional PSD1 overexpression. This suggests a role for Por1 in Psd1-mediated autophagy regulation

Time to Osteoporosis and Major Fracture in Older Men

For older men who undergo bone mineral density (BMD) testing, the optimal osteoporosis screening schedule is unknown. Time-to-disease estimates are necessary to inform screening intervals

Time to Osteoporosis and Major Fracture in Older Men

For older men who undergo bone mineral density (BMD) testing, the optimal osteoporosis screening schedule is unknown. Time-to-disease estimates are necessary to inform screening intervals

A dynamic actin cytoskeleton is required to prevent constitutive VDAC-dependent MAPK-signalling and aberrant lipid homeostasis.

The dynamic nature of the actin cytoskeleton is required to coordinate many cellular processes and a loss of its plasticity has been linked to accelerated cell ageing and attenuation of adaptive response mechanisms. Cofilin is an actin-binding protein that controls actin dynamics and has been linked to mitochondrial signalling pathways that control drug resistance and cell death. Here we show that cofilin-driven chronic depolarisation of the actin cytoskeleton activates cell wall integrity MAPK-signalling and disrupts lipid homeostasis in a VDAC-dependent manner. Expression of the cof1-5 mutation, which reduces the dynamic nature of actin, triggers loss of cell wall integrity, vacuole fragmentation, disruption of lipid homeostasis, lipid droplet (LD) accumulation and the promotion of cell death. The integrity of the actin cytoskeleton is therefore essential to maintain the fidelity of MAPK signalling, lipid homeostasis and cell health in S. cerevisiae. Graphical abstrac