The Mitochondrial GTPase Gem1 Contributes to the Cell Wall Stress Response and Invasive Growth of Candida albicans

Abstract

The interactions of mitochondria with the endoplasmic reticulum (ER) are crucial for maintaining proper mitochondrial morphology, function and dynamics. This enables cells to utilize their mitochondria optimally for energy production and anabolism, and it further provides for metabolic control over developmental decisions. In fungi, a key mechanism by which ER and mitochondria interact is via a membrane tether, the protein complex ERMES (ER-Mitochondria Encounter Structure). In the model yeast Saccharomyces cerevisiae, the mitochondrial GTPase Gem1 interacts with ERMES, and it has been proposed to regulate its activity. Here we report on the first characterization of Gem1 in a human fungal pathogen. We show that in Candida albicans Gem1 has a dominant role in ensuring proper mitochondrial morphology, and our data is consistent with Gem1 working with ERMES in this role. Mitochondrial respiration and steady state cellular phospholipid homeostasis are not impacted by inactivation of GEM1 in C. albicans. There are two major virulence-related consequences of disrupting mitochondrial morphology by GEM1 inactivation: C. albicans becomes hypersusceptible to cell wall stress, and is unable to grow invasively. In the gem1Δ/Δ mutant, it is specifically the invasive capacity of hyphae that is compromised, not the ability to transition from yeast to hyphal morphology, and this phenotype is shared with ERMES mutants. As a consequence of the hyphal invasion defect, the gem1Δ/Δ mutant is drastically hypovirulent in the worm infection model. Activation of the mitogen activated protein (MAP) kinase Cek1 is reduced in the gem1Δ/Δ mutant, and this function could explain both the susceptibility to cell wall stress and lack of invasive growth. This result establishes a new, respiration-independent mechanism of mitochondrial control over stress signaling and hyphal functions in C. albicans. We propose that ER-mitochondria interactions and the ER-Mitochondria Organizing Network (ERMIONE) play important roles in adaptive responses in fungi, in particular cell surface-related mechanisms that drive invasive growth and stress responsive behaviors that support fungal pathogenicity.

The Novel J-Domain Protein Mrj1 Is Required for Mitochondrial Respiration and Virulence in Cryptococcus neoformans

“…In particular, Mig1, Leu1, and Lys4 all influence cell wall-related phenotypes, and an observed capsule defect was attributed to cell wall changes in a leu1 mutant (42,58,59). The connection between mitochondrial function and cell wall integrity is well established in C. albicans (60)(61)(62)(63)(64)(65). For example, a screen of mutants hypersensitive to cell wall stress identified a role for the Ccr4 deadenylase in targeting transcripts for mitochondrial functions (62).…”

“…This observation led to the subsequent identification of connections for specific mitochondrial proteins including Sam37 and Gem1 (52,54). Sam37 is important for maintaining mitochondrial DNA (mtDNA), cell wall integrity, caspofungin tolerance, and ultimately virulence (61), while the mitochondrial GTPase, Gem1, plays a role in maintaining mitochondrial morphology and contributing to cell wall integrity in a Cek1-dependent manner (63). Recently, a role has been described for mitochondria in influencing the cell wall and contributing to a process called "masking" that results in avoidance of recognition by immune cells; the influence was attributed to modes of respiration or to hypoxia and connected to signaling via the cyclic AMP (cAMP)-protein kinase A (PKA) pathway (60,64).…”

The Emerging Role of RHOT1/Miro1 in the Pathogenesis of Parkinson's Disease

“…The relationship between Miro proteins and MERCs started to be investigated when, in 2011, two research groups identified Gem1p, the yeast ortholog of mammalian Miro1, as a crucial regulator of the ER-mitochondrial encounter structure (ERMES), a protein complex that tethers mitochondria and ER in yeast ( 15 , 80 ). Association of Gem1p to ERMES controls phospholipid exchange for lipid biosynthesis between mitochondria and ER ( 15 ) and regulates mitochondrial division and morphology ( 81 – 83 ). The localization of dMiro at MERCs was also demonstrated in Drosophila neural stem cells and dopaminergic neurons ( 17 , 84 ), as well as mammalian Miro1 in COS-7 cells, HeLa cells, MEFs, human fibroblasts, and human iPSC-derived neurons ( 14 , 15 , 67 , 84 , 85 ).…”

Mdivi-1 and mitochondrial fission: recent insights from fungal pathogens

“…a The worm C. elegans ( glp-4; sek-1 ) was infected with C. albicans strains as follows: wild type, a DNM1 deletion strain ∆∆dnm1 or a complemented mutant strain (+ DNM1 ). The strains are described in (Koch et al 2018), and the worm C. albicans infection method is described in detail in our previous publication (Koch et al 2017). Shown are representative images after 48 h of infection.…”