Title: ¡Viva la mitochondria!: harnessing yeast mitochondria for chemical production
ABSTRACT The mitochondria, often referred to as the powerhouse of the cell, offer a unique physicochemical environment enriched with a distinct set of enzymes, metabolites and cofactors ready to be exploited for metabolic engineering. In this review, we discuss how the mitochondrion has been engineered in the traditional sense of metabolic engineering or completely bypassed for chemical production. We then describe the more recent approach of harnessing the mitochondria to compartmentalize engineered metabolic pathways, including for the production of alcohols, terpenoids, sterols, organic acids and other valuable products. We explain the different mechanisms by which mitochondrial compartmentalization benefits engineered metabolic pathways to boost chemical production. Finally, we discuss the key challenges that need to be overcome to expand the applicability of mitochondrial engineering and reach the full potential of this emerging field. more »« less
Mendelsohn, Rachel; Garcia, Guadalupe C; Bartol, Thomas M; Lee, Christopher T; Khandelwal, P; Liu, Emily; Spencer, Donald J; Husar, Adam; Bushong, Eric A; Phan, Sebastien; et al
(, bioRxiv)
null
(Ed.)
In the highly dynamic metabolic landscape of a neuron, mitochondrial membrane architectures can provide critical insight into the unique energy balance of the cell. Current theoretical calculations of functional outputs like ATP and heat often represent mitochondria as idealized geometries and therefore can miscalculate the metabolic fluxes. To analyze mitochondrial morphology in neurons of mouse cerebellum neuropil, 3D tracings of complete synaptic and axonal mitochondria were constructed using a database of serial TEM tomographyimages and converted to watertight meshes with minimal distortion of the original microscopy volumes with agranularity of 1.6 nanometer isotropic voxels. The resulting in silico representations were subsequently quantified by differential geometry methods in terms of the mean and Gaussian curvatures, surface areas, volumes, and membrane motifs, all of which can alter the metabolic output of the organelle. Finally, we identify structural motifs that are present across this population of mitochondria; observations which may contribute to future modeling studies of mitochondrial physiology and metabolism in neurons.
Abstract Mitochondria play a crucial role in the regulation of cellular metabolism and signalling. Mitochondrial activity is modulated by the processes of mitochondrial fission and fusion, which are required to properly balance respiratory and metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at sites of contact between the endoplasmic reticulum (ER) and mitochondria, and is dependent on the formation of actin filaments that drive mitochondrial constriction and the recruitment and activation of the dynamin-related GTPase fission protein DRP1. The requirement for mitochondria- and ER-associated actin filaments in mitochondrial fission remains unclear, and the role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing the formation of actin filaments on either mitochondria or the ER disrupts both mitochondrial fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion are dependent on INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the dynamin family GTPase fusion protein MFN2. Together, our work introduces a novel method for perturbing organelle-associated actin filaments, and demonstrates a previously unknown role for actin in mitochondrial fusion.
The classic roles of mitochondria in energy production, metabolism, and apoptosis have been well defined. However, a growing body of evidence suggests that mitochondria are also active players in regulating stem cell fate decision and lineage commitment via signaling transduction, protein modification, and epigenetic modulations. This is particularly interesting for spermatogenesis, during which germ cells demonstrate changing metabolic requirements across various stages of development. It is increasingly recognized that proper male fertility depends on exquisitely controlled plasticity of mitochondrial features, activities, and functional states. The unique role of mitochondria in germ cell ncRNA processing further adds another layer of complexity to mitochondrial regulation during spermatogenesis. In this review, we will discuss potential regulatory mechanisms of how mitochondria swiftly reshape their features, activities, and functions to support critical germ cell fate transitions during spermatogenesis. In addition, we will also review recent findings of how mitochondrial regulators coordinate with germline proteins to participate in germ cell-specific activities.
Weaver, Ryan J
(, Integrative and Comparative Biology)
Abstract The environment in which eukaryotes first evolved was drastically different from what they experience today, and one of the key limiting factors was the availability of oxygen for mitochondrial respiration. During the transition to a fully oxygenated Earth, other compounds such as sulfide posed a considerable constraint on using mitochondrial aerobic respiration for energy production. The ancestors of animals, and those that first evolved from the simpler eukaryotes have mitochondrial respiratory components that are absent from later-evolving animals. Specifically, mitochondria of most basal metazoans have a sulfide-resistant alternative oxidase (AOX), which provides a secondary oxidative pathway to the classical cytochrome pathway. In this essay, I argue that because of its resistance to sulfide, AOX respiration was critical to the evolution of animals by enabling oxidative metabolism under otherwise inhibitory conditions. I hypothesize that AOX allowed for metabolic flexibility during the stochastic oxygen environment of early Earth which shaped the evolution of basal metazoans. I briefly describe the known functions of AOX, with a particular focus on the decreased production of reactive oxygen species (ROS) during stress conditions. Then, I propose three evolutionary consequences of AOX-mediated protection from ROS observed in basal metazoans: 1) adaptation to stressful environments, 2) the persistence of facultative sexual reproduction, and 3) decreased mitochondrial DNA mutation rates. Recognizing the diversity of mitochondrial respiratory systems present in animals may help resolve the mechanisms involved in major evolutionary processes such as adaptation and speciation.
Lee, Wei-Hua; Bhute, Vijesh J; Higuchi, Hitoshi; Ikeda, Sakae; Palecek, Sean P; Ikeda, Akihiro
(, Experimental Biology and Medicine)
null
(Ed.)
Mitochondria are dynamic organelles that undergo fission and fusion. While they are essential for cellular metabolism, the effect of dysregulated mitochondrial dynamics on cellular metabolism is not fully understood. We previously found that transmembrane protein 135 ( Tmem135) plays a role in the regulation of mitochondrial dynamics in mice. Mice homozygous for a Tmem135 mutation ( Tmem135 FUN025/FUN025 ) display accelerated aging and age-related disease pathologies in the retina including the retinal pigment epithelium (RPE). We also generated a transgenic mouse line globally overexpressing the Tmem135 gene ( Tmem135 TG). In several tissues and cells that we studied such as the retina, heart, and fibroblast cells, we observed that the Tmem135 mutation causes elongated mitochondria, while overexpression of Tmem135 results in fragmented mitochondria. To investigate how abnormal mitochondrial dynamics affect metabolic signatures of tissues and cells, we identified metabolic changes in primary RPE cell cultures as well as heart, cerebellum, and hippocampus isolated from Tmem135 FUN025/FUN025 mice (fusion > fission) and Tmem135 TG mice (fusion < fission) using nuclear magnetic resonance spectroscopy. Metabolomics analysis revealed a tissue-dependent response to Tmem135 alterations, whereby significant metabolic changes were observed in the heart of both Tmem135 mutant and TG mice as compared to wild-type, while negligible effects were observed in the cerebellum and hippocampus. We also observed changes in Tmem135 FUN025/FUN025 and Tmem135 TG RPE cells associated with osmosis and glucose and phospholipid metabolism. We observed depletion of NAD + in both Tmem135 FUN025/FUN025 and Tmem135 TG RPE cells, indicating that imbalance in mitochondrial dynamics to both directions lowers the cellular NAD + level. Metabolic changes identified in this study might be associated with imbalanced mitochondrial dynamics in heart tissue and RPE cells which can likely lead to functional abnormalities. Impact statement Mitochondria are dynamic organelles undergoing fission and fusion. Proper regulation of this process is important for healthy aging process, as aberrant mitochondrial dynamics are associated with several age-related diseases/pathologies. However, it is not well understood how imbalanced mitochondrial dynamics may lead to those diseases and pathologies. Here, we aimed to determine metabolic alterations in tissues and cells from mouse models with over-fused (fusion > fission) and over-fragmented (fusion < fission) mitochondria that display age-related disease pathologies. Our results indicated tissue-dependent sensitivity to these mitochondrial changes, and metabolic pathways likely affected by aberrant mitochondrial dynamics. This study provides new insights into how dysregulated mitochondrial dynamics could lead to functional abnormalities of tissues and cells.
Duran, Lisset, López, José Montaño, and Avalos, José L. ¡Viva la mitochondria!: harnessing yeast mitochondria for chemical production. Retrieved from https://par.nsf.gov/biblio/10285253. FEMS Yeast Research 20.6 Web. doi:10.1093/femsyr/foaa037.
Duran, Lisset, López, José Montaño, & Avalos, José L. ¡Viva la mitochondria!: harnessing yeast mitochondria for chemical production. FEMS Yeast Research, 20 (6). Retrieved from https://par.nsf.gov/biblio/10285253. https://doi.org/10.1093/femsyr/foaa037
@article{osti_10285253,
place = {Country unknown/Code not available},
title = {¡Viva la mitochondria!: harnessing yeast mitochondria for chemical production},
url = {https://par.nsf.gov/biblio/10285253},
DOI = {10.1093/femsyr/foaa037},
abstractNote = {ABSTRACT The mitochondria, often referred to as the powerhouse of the cell, offer a unique physicochemical environment enriched with a distinct set of enzymes, metabolites and cofactors ready to be exploited for metabolic engineering. In this review, we discuss how the mitochondrion has been engineered in the traditional sense of metabolic engineering or completely bypassed for chemical production. We then describe the more recent approach of harnessing the mitochondria to compartmentalize engineered metabolic pathways, including for the production of alcohols, terpenoids, sterols, organic acids and other valuable products. We explain the different mechanisms by which mitochondrial compartmentalization benefits engineered metabolic pathways to boost chemical production. Finally, we discuss the key challenges that need to be overcome to expand the applicability of mitochondrial engineering and reach the full potential of this emerging field.},
journal = {FEMS Yeast Research},
volume = {20},
number = {6},
author = {Duran, Lisset and López, José Montaño and Avalos, José L},
editor = {null}
}
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