Mitochondrial proline catabolism activates Ras1/cAMP/PKA-induced filamentation in Candida albicans

Abstract

Amino acids are among the earliest identified inducers of yeast-to-hyphal transitions in Candida albicans , an opportunistic fungal pathogen of humans. Here, we show that the morphogenic amino acids arginine, ornithine and proline are internalized and metabolized in mitochondria via a PUT1 - and PUT2 -dependent pathway that results in enhanced ATP production. Elevated ATP levels correlate with Ras1/cAMP/PKA pathway activation and Efg1-induced gene expression. The magnitude of amino acid-induced filamentation is linked to glucose availability; high levels of glucose repress mitochondrial function thereby dampening filamentation. Furthermore, arginine-induced morphogenesis occurs more rapidly and independently of Dur1,2-catalyzed urea degradation, indicating that mitochondrial-generated ATP, not CO 2 , is the primary morphogenic signal derived from arginine metabolism. The important role of the SPS-sensor of extracellular amino acids in morphogenesis is the consequence of induced amino acid permease gene expression, i.e., SPS-sensor activation enhances the capacity of cells to take up morphogenic amino acids, a requisite for their catabolism. C . albicans cells engulfed by murine macrophages filament, resulting in macrophage lysis. Phagocytosed put1-/- and put2 -/- cells do not filament and exhibit reduced viability, consistent with a critical role of mitochondrial proline metabolism in virulence.

Role of Amino Acid Metabolism in the Virulence of Human Pathogenic Fungi

“…Although CaSsy1 and ScSsy1 share a high degree of homology in the C-terminal domains, their N-terminal-sensing domains are highly divergent [52]. It is likely that this explains the altered CaSsy1 substrate specificity: the highest induction occurs in the presence of Arg, Asn, Asp, Gln, Glu, His, Lys, and Ser, while the other amino acids fail to stimulate the sensor [22,52]. Further differences can be found in the downstream effectors CaStp1 and CaStp2 which, contrary to S. cerevisiae, exhibit a clear dichotomy in their regulatory activity: while the CaStp1 regulon contains genes required for protein utilization; like secreted aspartyl proteases (SAP) and oligopeptide transporters (OPT), CaStp2 is required for the expression of AAPs [53].…”

Mitochondria-Mediated Azole Drug Resistance and Fungal Pathogenicity: Opportunities for Therapeutic Development

“…On the one hand, mitochondrial respiration can affect the morphogenesis of fungi. For instance, high ATP levels resulting from mitochondrial respiratory activity have been shown to be crucial for C. albicans to switch from yeast cells to mycelium growth [ 20 , 64 , 65 ]. Because this morphogenetic transition is thought to be related to C. albicans virulence [ 66 ], this result shows that mitochondrial respiration can mediate C. albicans virulence by affecting morphogenetic transition.…”

Alternative Oxidase: A Potential Target for Controlling Aflatoxin Contamination and Propagation of Aspergillus flavus

“…For example, Grahl et al (2015) reported that in C. albicans, the disease-associated morphological switch from yeast to hyphal growth is affected by mitochondrial functions, as mitochondrial inhibitors potently suppress the Ras1-Cyr1-PKA pathway, a major regulator of C. albicans morphogenesis, biofilm formation, and white-opaque switching. Furthermore, Silao et al (2019) reported that induced respiration is critical for morphogenesis during the catabolism of morphogenic amino acids, which is an important feature for C. albicans to evade macrophages. C. albicans cells are highly adaptive to the inhibition of classical respiration; however, a recent study reported that a combination of AOX inhibitor salicylhydroxamic acid (SHAM) and sodium nitroprusside lead to fitness defects and the loss of viability in C. albicans (Duvenage et al, 2019).…”