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Chapter 21 : Back to the Future: Mitochondria and Energetics

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Abstract:

This chapter reviews the role of mitochondria in human fungal pathogens, focusing upon , , and . The respiratory pathways of species are highlighted along with the roles of mitochondria in morphogenesis, adaptive responses to oxidant stress and carbon depletion, and antifungal drug resistance and sensitivity. The focus therefore is on the role of mitochondria in the pathogenesis of candidiasis and developing the concept that there are differences in mitochondria of mammalian cells versus pathogens. The study of mitochondria in species first followed those that were of industrial importance, examples being and . The morphogenesis of has long been featured as critical to the establishment of candidiasis. Mitochondria play an active role in detoxifying reactive oxidant species (ROS) produced during cell metabolism. This has been convincingly shown through the use of inhibitors of respiratory complexes. 7-Chlorotetrazolo[5,1-c]benzo[1,2,4]triazine (CTBT) increases the activity of several antimycotics, including flucytosine as well as azoles. The target of histatin 5, a human basic salivary peptide that has demonstrated antifungal activity, was initially shown to be the energized mitochondria. There is ample proof that mitochondrial functions as well as regulation of these functions vary among pathogenic and model fungi, and that mammalian mitochondria have less complexity with regard to respiratory pathways.

Citation: Alex D, Calderone R, Li D. 2012. Back to the Future: Mitochondria and Energetics, p 331-341. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch21
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Image of FIGURE 1
FIGURE 1

The respiratory pathway of and . Complexes I, II, III, and IV are part of the classical respiratory pathway. Protons are transported to the IMS as a result of electron transfer across complexes in the respiratory pathways, thereby building a potential across the membrane. CoQ is the hub for transfer of electrons from complex I and complex II. Additionally, there are alternative NADH dehydrogenases that can separately sequester NADH from internal and external sources and feed electrons to CoQ. The AOX pathway branches at the level of CoQ and is able to reduce oxygen and produce ATP. The PAR pathway also branches at the level of CoQ but is also able to accept electrons from cytochrome (cyt ) of the classical pathway, which is further downstream of CoQ. Inhibitors of the complexes are shown. Of importance to energetics, the potential that is built up by the transfer of protons is used to generate ATP as the protons are pumped back into the matrix. oxi c, cytochrome oxidase. Adapted from reference . doi:10.1128/9781555817176.ch21.f1

Citation: Alex D, Calderone R, Li D. 2012. Back to the Future: Mitochondria and Energetics, p 331-341. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch21
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Image of FIGURE 2
FIGURE 2

Pathways of mitochondrial protein import and distribution to the mitochondria. Translocases are of two types, TOM (of the OM) and TIM (of the IM). SAM, sorting and assembling machinery; MDM, mitochondrial distribution and morphology; PAM, presequence translocase-associated motors; MIA, mitochondrial IMS assembly; MPP, mitochondrial processing peptidase. See reference . doi:10.1128/9781555817176.ch21.f2

Citation: Alex D, Calderone R, Li D. 2012. Back to the Future: Mitochondria and Energetics, p 331-341. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch21
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Image of FIGURE 3
FIGURE 3

Possible roles of Goa1p in mitochondrial function. CRC complexes I to IV as well as AOX and PAR are represented as circles. Since strain GOA31 () is defective in building a membrane potential and ATP formation, we hypothesize that the lesion could be associated with several dysfunctions, including inhibition of complex I, III, or IV, that may lead to the phenotypic traits seen in this mutant. Mitochondrial functions that are affected in the mutant are shown (see also reference ). doi:10.1128/9781555817176.ch21.f3

Citation: Alex D, Calderone R, Li D. 2012. Back to the Future: Mitochondria and Energetics, p 331-341. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch21
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Tables

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TABLE 1

Differences in respiratory pathways among organisms

Citation: Alex D, Calderone R, Li D. 2012. Back to the Future: Mitochondria and Energetics, p 331-341. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch21

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