Maintenance of Mitochondrial Morphology in Cryptococcus neoformans Is Critical for Stress Resistance and Virulence

Abstract

C. neoformans is a yeast that causes fatal brain infection in close to 200,000 people worldwide every year, mainly afflicting individuals with AIDS or others who are severely immunocompromised. One feature of this microbe that helps it cause disease is that it is able to withstand toxic molecules it encounters when host cells engulf it in their efforts to control the infection. Mitochondria are important organelles responsible for energy production and other key cellular processes. They typically exist in a complex network that changes morphology by fusing and dividing; these alterations also influence mitochondrial function. Using genetic approaches, we found that changes in mitochondrial morphology dramatically influence cryptococcal virulence. We showed that this occurs because the altered mitochondria are less able to eliminate the harmful molecules that host cells produce to kill invading microbes. These findings are important because they elucidate fundamental biology and virulence and may suggest avenues for therapy.

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

“…Mitochondria are dynamic organelles that constantly undergo fusion and fission to maintain mitochondrial function during healthy growth and in stress conditions [ 52 , 53 ]. Recently, the fusion and fission of mitochondria have emerged as important contributors to the fungal virulence in a variety of fungal pathogens [ 52 , 54 ]. Furthermore, molecular mechanisms by which mitochondrial morphology affects fungal virulence have been elaborated in detail ( Figure 4 ).…”

“…The fusion of mitochondria can help cells cope with various stress conditions by forming what is termed tubular morphology that can share genetic material and resources to aid survival [ 52 , 55 ]. In Saccharomyces cerevisiae , fusion of mitochondria is mediated by three dynamin-related proteins (DRPs), Fzo1, Mgm1, and Ugo1 [ 26 , 52 , 54 ], which are conserved and have been characterized in fungal pathogens. For example, in C. albicans , deletion of the mitofusin Fzo1 results in decreased ability to adopt tubular morphology, which in turn decreases the ability of cells to resist peroxide stress that is encountered during infection of a host by the fungus ( Figure 4 ) [ 54 ].…”

“…In Saccharomyces cerevisiae , fusion of mitochondria is mediated by three dynamin-related proteins (DRPs), Fzo1, Mgm1, and Ugo1 [ 26 , 52 , 54 ], which are conserved and have been characterized in fungal pathogens. For example, in C. albicans , deletion of the mitofusin Fzo1 results in decreased ability to adopt tubular morphology, which in turn decreases the ability of cells to resist peroxide stress that is encountered during infection of a host by the fungus ( Figure 4 ) [ 54 ]. Mgm1 has an important role in the regulation of mitochondrial fusion, mtDNA (i.e., mitochondrial genome) maintenance, and hyphal development in C. albicans .…”

“…When examined for virulence, a strain of A. fumigatus with a conditional mutation in the essential gene Mgm1 was avirulent in the Galleria mellonella infection model. Similar to C. albicans and A. fumigatus , recent research has found that mitochondrial fusion is also involved in Cryptococcus neoformans virulence in hosts, implying that mitochondrial fusion may play a general role in fungal virulence [ 54 ]. C. neoformans is a facultative intracellular pathogen that is exposed to oxidative stress within host cells.…”

Mitochondrial dynamics and mitophagy are necessary for proper invasive growth in Rice Blast

“…Maintaining the mitochondrial morphology in steady state by the balance of fusion and fission activities is critical for living cells. When this equilibrium is broken, mitochondrial shape and dynamics are disturbed leading to important physiological consequences including increased cellular stress and various diseases (Zemirli & Morel, 2018, Rapaport et al , 1998, Guan et al , 1993, Sesaki & Jensen, 2001, Chang & Doering, 2018, Ma et al , 2009, Mozdy et al , 2000, Delettre et al , 2000, Kijima et al , 2005).…”