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Mitochondrial dynamics during the life cycle of S. cerevisiae. ( A ) Mitochondrial morphology and inheritance during mitotic cell division. Mitochondria are located near the cortex of the cell as a branched tubular network. They are partitioned continuously from the mother cell into the bud from early in S phase until cytokinesis. ( B ) Mitochondrial fusion during mating. Haploid yeast cells of different mating types form a diploid zygote by cellular and nuclear fusion. Prior to nuclear fusion, the parental mitochondrial networks in the zygote fuse to form one intercon- nected organelle. ( C ) Mitochondrial morphology and inheritance during meiosis and sporulation. Meiosis and sporulation in diploid yeast produces four haploid daughter cells enclosed within the mother cell (an ascus). Individual mitochondrial compartments in pre-meiotic stationary phase are dispersed at the cell cortex. In pre-meiotic S phase, these individual mitochondria fuse to form one large branched network. During meiotic nuclear divisions, the mitochondrial membrane remains closely associated with the nucleus. This association leads to the incorporation of part of the mitochondrial network into newly formed spores.
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Proteins that control mitochondrial dynamics in yeast are being identified at a rapid pace. These proteins include cytoskeletal elements that regulate organelle distribution and inheritance and several outer membrane proteins that are required to maintain the branched, mitochondrial reticulum. Interestingly, three of the high molecular weight GTPas...
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... review the relevant features of mitochondrial morphology and behavior in yeast during mitosis, mating and meiosis, and sporulation. The electron microscope was used in early studies to examine yeast mitochondrial ultrastructure and morphology after fixation and thin sectioning (Stevens 1977, 1981). More recently, investigators have begun to use a number of vi- tal dyes that preferentially accumulate in actively respiring organelles as well as targeted forms of the green fluorescent protein (GFP) (Bereiter-Hahn 1976, 1990, Johnson et al 1980, Chen 1989, Koning et al 1993, Nunnari et al 1997). In mitotically dividing cells, actively respiring mitochondria appear as a highly branched, tubular network located near the cell periphery (Hoffman & Avers 1973, Stevens 1981). Within this network, mitochondrial DNA (mtDNA nucleoids) stained with the DNA-specific dye DAPI (Williamson & Fennell 1979), are visualized as bright spots distributed at widely spaced intervals. Although it sometimes appears as if there is a single, continuous mitochondrial compartment in yeast cells, the actual number of mitochondria can range from one to ten because the organelles frequently fuse and divide (Stevens 1981, Koning et al 1993, Nunnari et al 1997). Yeast cells can survive without their mtDNA, which encodes gene products required for mitochondrial protein synthesis, electron transport, and oxidative phosphorylation. However, other metabolic functions that occur in the mitochondrial compartment such as reactions of the TCA cycle and amino acid and lipid biosynthesis are essential (Kovacova et al 1968, Gbelska et al 1983, Yaffe & Schatz 1984). As a consequence, yeast buds can only survive if they inherit part of the mitochondrial network from the mother cell during division. Mitochondrial inheritance begins early in the cell cycle (late G1/early S phase) when a portion of the network extends into the developing daughter cell or bud (Figure 1 A ) (Stevens 1981, McConnell et al 1990, Simon et al 1997). As the bud grows (S/G2 phase), additional mitochondrial membranes are transferred in from the mother cell. Mitochondria are reported to move in a linear and polarized fashion during this period (Simon et al 1995, 1997). A transient clustering of mitochondria at the bud tip is also observed (Simon et al 1997), suggesting that mitochondria can be captured and immobilized immediately after transfer to prevent their accidental return to the mother cell. Prior to cytokinesis, these immobilized mitochondria are redistributed throughout the bud. Haploid yeast cells exposed to mating pheromone develop mating projections, adhere to one another, and ultimately fuse to form a dumbbell-shaped zygote (Figure 1 B ) (Sprague & Thorner 1994). Prior to (or concomitant with) ...
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... review the relevant features of mitochondrial morphology and behavior in yeast during mitosis, mating and meiosis, and sporulation. The electron microscope was used in early studies to examine yeast mitochondrial ultrastructure and morphology after fixation and thin sectioning (Stevens 1977, 1981). More recently, investigators have begun to use a number of vi- tal dyes that preferentially accumulate in actively respiring organelles as well as targeted forms of the green fluorescent protein (GFP) (Bereiter-Hahn 1976, 1990, Johnson et al 1980, Chen 1989, Koning et al 1993, Nunnari et al 1997). In mitotically dividing cells, actively respiring mitochondria appear as a highly branched, tubular network located near the cell periphery (Hoffman & Avers 1973, Stevens 1981). Within this network, mitochondrial DNA (mtDNA nucleoids) stained with the DNA-specific dye DAPI (Williamson & Fennell 1979), are visualized as bright spots distributed at widely spaced intervals. Although it sometimes appears as if there is a single, continuous mitochondrial compartment in yeast cells, the actual number of mitochondria can range from one to ten because the organelles frequently fuse and divide (Stevens 1981, Koning et al 1993, Nunnari et al 1997). Yeast cells can survive without their mtDNA, which encodes gene products required for mitochondrial protein synthesis, electron transport, and oxidative phosphorylation. However, other metabolic functions that occur in the mitochondrial compartment such as reactions of the TCA cycle and amino acid and lipid biosynthesis are essential (Kovacova et al 1968, Gbelska et al 1983, Yaffe & Schatz 1984). As a consequence, yeast buds can only survive if they inherit part of the mitochondrial network from the mother cell during division. Mitochondrial inheritance begins early in the cell cycle (late G1/early S phase) when a portion of the network extends into the developing daughter cell or bud (Figure 1 A ) (Stevens 1981, McConnell et al 1990, Simon et al 1997). As the bud grows (S/G2 phase), additional mitochondrial membranes are transferred in from the mother cell. Mitochondria are reported to move in a linear and polarized fashion during this period (Simon et al 1995, 1997). A transient clustering of mitochondria at the bud tip is also observed (Simon et al 1997), suggesting that mitochondria can be captured and immobilized immediately after transfer to prevent their accidental return to the mother cell. Prior to cytokinesis, these immobilized mitochondria are redistributed throughout the bud. Haploid yeast cells exposed to mating pheromone develop mating projections, adhere to one another, and ultimately fuse to form a dumbbell-shaped zygote (Figure 1 B ) (Sprague & Thorner 1994). Prior to (or concomitant with) ...
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... most dramatic changes in mitochondrial distribution and morphology occur during meiosis and sporulation in S. cerevisiae ( Figure 1 C ). Mitochondria in pre-meiotic cells appear as punctate structures dispersed at the cell cortex (Miyakawa et al 1984, Smith et al 1995). By early prophase, these discrete units have fused to form a tubular reticulum. The mtDNA nucleoids within this reticulum are highly condensed and resemble a series of beads on a string when stained with DAPI (Miyakawa et al 1984). The mitochondrial reticulum next migrates to the cell center where it remains associated with the nuclear membrane during the first and second meiotic divisions. At the end of meiosis II, four discrete mitochondrial tubules remain, each one located near an individual nuclear lobe. This intimate association of the mitochondrial and nuclear membranes ensures that mitochondria are included when each nuclear lobe is enclosed by the prospore cell membrane. Morphological screens are being used very successfully to identify genes required for Mitochondrial Distribution and Morphology (MDM) and Mitochondrial Morphology Maintenance (MMM) (McConnell et al 1990, Burgess et al 1994, Hermann et al 1997). By shifting temperature-sensitive yeast strains to 37 ◦ C and staining with fluorescent dyes to visualize the mitochondrial compartment, mutations have been isolated that fall into several different classes including ( a ) mutations that block mitochondrial inheritance but do not affect mitochondrial morphology, ( b ) mutations that alter mitochondrial morphology and block mitochondrial inheritance, and ( c ) mutations that alter mitochondrial morphology but do not block mitochondrial inheritance. The defects in most of the mutants appear to be specific for mitochondria and do not affect the morphology or inheritance of other cytoplasmic organelles that have been examined (e.g. nuclei and vacuoles). Independent selections for genes affecting Mitochondrial Genome Maintenance (MGM) (Jones & Fangman 1992) and Yeast Mitochondrial Escape (YME) (Thorsness & Fox 1993) have also yielded genes required for the maintenance of mitochondrial morphology and inheritance. Table 1 lists the published genes identified by the approaches cited above that are discussed in this review. Cell-free assays that recapitulate mitochondrial behaviors in vivo are also being used to understand the mechanisms regulating yeast mitochondrial dynamics. To date, these assays focus exclusively on the interactions of yeast mitochondria with actin filaments and actin-based mitochondrial motility (see ...
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Citations
... Dynamin-related protein 1 LD: lipid droplet CJ: crista junction began in this species. In fact, screens conducted in the 1990s using temperature-sensitive mutants, as well as studies focusing on mitochondrial genome maintenance, led to the identification of molecular players regulating mitochondrial morphology (52,112). Thus, molecules regulating mitochondrial fission and fusion were discovered and validated by application of live-cell fluorescence microscopy, along with functional implications such as growth rates and loss of mitochondrial DNA (mtDNA) (53,145). ...
Mitochondria are essential organelles performing important cellular functions ranging from bioenergetics and metabolism to apoptotic signaling and immune responses. They are highly dynamic at different structural and functional levels. Mitochondria have been shown to constantly undergo fusion and fission processes and dynamically interact with other organelles such as the endoplasmic reticulum, peroxisomes, and lipid droplets. The field of mitochondrial dynamics has evolved hand in hand with technological achievements including advanced fluorescence super-resolution nanoscopy. Dynamic remodeling of the cristae membrane within individual mitochondria, discovered very recently, opens up a further exciting layer of mitochondrial dynamics. In this review, we discuss mitochondrial dynamics at the following levels: ( a) within an individual mitochondrion, ( b) among mitochondria, and ( c) between mitochondria and other organelles. Although the three tiers of mitochondrial dynamics have in the past been classified in a hierarchical manner, they are functionally connected and must act in a coordinated manner to maintain cellular functions and thus prevent various human diseases.
Expected final online publication date for the Annual Review of Biophysics, Volume 53 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... The findings from earlier studies reveal that OLE1, which encodes the ∆-9 fatty acid desaturase, catalyzes the double bonding between carbons 9 and 10 of stearoyl CoA and palmitoyl CoA (Mcdonough et al. 1992). In addition to its activity in fatty acid production, OLE1 is also essential for the formation and functioning of the mitochondria (Hermann et al. 1998). In this work, the OLE1 gene showed more than 2.3-fold change and a p-value of less than 0.05 in a time course study at the late stage of the lag phase. ...
Lignocellulosic biomass is still considered a feasible source of bioethanol production. Saccharomyces cerevisiae can adapt to detoxify lignocellulose-derived inhibitors, including furfural. Tolerance of strain performance has been measured by the extent of the lag phase for cell proliferation following the furfural inhibitor challenge. The purpose of this work was to obtain a tolerant yeast strain against furfural through overexpression of YPR015C using the in vivo homologous recombination method. The physiological observation of the overexpressing yeast strain showed that it was more resistant to furfural than its parental strain. Fluorescence microscopy revealed improved enzyme reductase activity and accumulation of oxygen reactive species due to the harmful effects of furfural inhibitor in contrast to its parental strain. Comparative transcriptomic analysis revealed 79 genes potentially involved in amino acid biosynthesis, oxidative stress, cell wall response, heat shock protein, and mitochondrial-associated protein for the YPR015C overexpressing strain associated with stress responses to furfural at the late stage of lag phase growth. Both up- and down-regulated genes involved in diversified functional categories were accountable for tolerance in yeast to survive and adapt to the furfural stress in a time course study during the lag phase growth. This study enlarges our perceptions comprehensively about the physiological and molecular mechanisms implicated in the YPR015C overexpressing strain’s tolerance under furfural stress.
Construction illustration of the recombinant plasmid. a) pUG6-TEF1p-YPR015C, b) integration diagram of the recombinant plasmid pUG6-TEF1p-YPR into the chromosomal DNA of Saccharomyces cerevisiae .
... Previous reports have pinpointed the role of nuclear genes in mitochondrial genome integrity, emphasising the indispensability of proper nuclear-mitochondrial communication for healthy cell development and viability [96][97][98]. Many nuclear genome-encoded proteins regulate mitochondrial morphology and function, e.g., the replication and transcription of the mitochondrial genome, which is entirely dependent on nuclear gene products [96,[99][100][101]. ...
... Previous reports have pinpointed the role of nuclear genes in mitochondrial genome integrity, emphasising the indispensability of proper nuclear-mitochondrial communication for healthy cell development and viability [96][97][98]. Many nuclear genome-encoded proteins regulate mitochondrial morphology and function, e.g., the replication and transcription of the mitochondrial genome, which is entirely dependent on nuclear gene products [96,[99][100][101]. Several lines of evidence suggest that decreased mitochondria biogenesis, mitochondrial dysfunction and the level of mtDNA content in yeast may be associated with defects in genes that regulate the cell division cycle [102][103][104]. ...
Mitochondria are multifunctional, dynamic organelles important for stress response, cell longevity, ageing and death. Although the mitochondrion has its genome, nuclear-encoded proteins are essential in regulating mitochondria biogenesis, morphology, dynamics and function. Moreover, chromatin structure and epigenetic mechanisms govern the accessibility to DNA and control gene transcription, indirectly influencing nucleo-mitochondrial communications. Thus, they exert crucial functions in maintaining proper chromatin structure, cell morphology, gene expression, stress resistance and ageing. Here, we present our studies on the mtDNA copy number in Saccharomyces cerevisiae chromatin mutants and investigate the mitochondrial membrane potential throughout their lifespan. The mutants are arp4 (with a point mutation in the ARP4 gene, coding for actin-related protein 4-Arp4p), hho1∆ (lacking the HHO1 gene, coding for the linker histone H1), and the double mutant arp4 hho1∆ cells with the two mutations. Our findings showed that the three chromatin mutants acquired strain-specific changes in the mtDNA copy number. Furthermore, we detected the disrupted mitochondrial membrane potential in their chronological lifespan. In addition, the expression of nuclear genes responsible for regulating mitochondria biogenesis and turnover was changed. The most pronounced were the alterations found in the double mutant arp4 hho1∆ strain, which appeared as the only petite colony-forming mutant, unable to grow on respiratory substrates and with partial depletion of the mitochondrial genome. The results suggest that in the studied chromatin mutants, hho1∆, arp4 and arp4 hho1∆, the nucleus-mitochondria communication was disrupted, leading to impaired mitochondrial function and premature ageing phenotype in these mutants, especially in the double mutant.
... Dramatic progress in mitochondrial dynamics research especially in the last decade was analyzed in our study. Mitochondrial dynamics were first studied in single-celled organisms (Sedar and Porter 1955;Hermann and Shaw 1998) and in Drosophila (Watanabe and Williams 1953), and later expanded to human-related diseases and cells, as retrieved from the WOS database. Mitochondria had previously served as organelles for cellular energy production and fatty acid oxidation until researchers discovered that mitochondria can retain their own DNA (mtDNA) as well as transcription and translation (Friedman and Nunnari 2014), and have kinetic characteristics of fusion and breakage as well as mitophagy (Ruan et al. 2020). ...
... Based on the results of the analysis about contributions of countries, USA was the most contributor to publications.Also, according to the search, the earliest study of mitochondrial dynamics in eukaryotes was published by the American researcher Pinkert,CA (Hermann and Shaw 1998), and was funded by NIH and HHS. This shows that the U.S. research in mitochondrial dynamics started earlier than other countries, and has a lot of experience and attention. ...
Background
Mitochondria are remarkably dynamic organelles encapsulated by bilayer membranes. The dynamic properties of mitochondria are critical for energy production.
Aims
The aim of our study is to investigate the global status and trends of mitochondrial dynamics research and predict popular topics and directions in the field.
Methods
Publications related to the studies of mitochondrial dynamics from 2002 to 2021 were retrieved from Web of Science database. A total of 4,576 publications were included. Bibliometric analysis was conducted by visualization of similarities viewer and GraphPadPrism 5 software.
Results
There is an increasing trend of mitochondrial dynamics research during the last 20 years. The cumulative number of publications about mitochondrial dynamics research followed the logistic growth model f(x)=a/1+e(b-cx)\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mathrm{f}(x)=\mathrm{a}/\left[1+{e}^{(b-cx)}\right]$$\end{document}. The USA made the highest contributions to the global research. The journal Biochimica et Biophysica Acta (BBA)—Molecular Cell Research had the largest publication numbers. Case Western Reserve University is the most contributive institution. The main research orientation and funding agency were cell biology and HHS. All keywords related studies could be divided into three clusters: “Related disease research”, “Mechanism research” and “Cell metabolism research”.
Conclusions
Attention should be drawn to the latest popular research and more efforts will be put into mechanistic research, which may inspire new clinical treatments for the associated diseases.
... In the Baker's yeast Saccharomyces cerevisiae, there is a large body of data showing evidence of heteroplasmy and recombination in laboratory crosses. However, mitochondrial heterogeneity was always transient, with the offspring of the zygote becoming completely homozygous within 20 mitotic cell divisions (Hermann and Shaw, 1998). A few other studies have also provided evidence of mtDNA recombination in natural populations of certain fungal species, such as Armillaria gallica (Saville et al., 1998), Cryptococcus gattii (Xu et al., 2009), Agaricus bisporus (Xu et al., 2013) and recently, Thelephora ganbajun (Wang et al., 2017). ...
Mitochondrial genes and genomes have patterns of inheritance that are distinctly different from those of nuclear genes and genomes. In nature, the mitochondrial genomes in eukaryotes are generally considered non-recombining and homoplasmic. If heteroplasmy and recombination exist, they are typically very limited in both space and time. Here we show that mitochondrial heteroplasmy and recombination may not be limited to a specific population nor exit only transiently in the basidiomycete Cantharellus cibarius and related species. These edible yellow chanterelles are an ecologically very important group of fungi and among the most prominent wild edible mushrooms in the Northern Hemisphere. At present, very little is known about the genetics and population biology of these fungia cross large geographical distances. Our study here analyzed a total of 363 specimens of edible yellow chanterelles from 24 geographic locations in Yunnan in southwestern China and six geographic locations in five countries in Europe. For each mushroom sample, we obtained the DNA sequences at two genes, one in the nuclear genome and one in the mitochondrial genome. Our analyses of the nuclear gene, translation elongation factor 1-alpha (tef-1) and the DNA barcode of C. cibarius and related species, suggested these samples belong to four known species and five potential new species. Interestingly, analyses of the mitochondrial ATP synthase subunit 6 (atp6) gene fragment revealed evidence of heteroplasmy in two geographic samples in Yunnan and recombination within the two new putative species in Yunnan. Specifically, all four possible haplotypes at two polymorphic nucleotide sites within the mitochondrial atp6 gene were found distributed across several geographic locations in Yunnan. Furthermore, these four haplotypes were broadly distributed across multiple phylogenetic clades constructed based on nuclear tef-1 sequences. Our results suggest that heteroplasmy and mitochondrial recombination might have happened repeatedly during the evolution of the yellow chanterelles. Together, our results suggest that the edible yellow chanterelles represent an excellent system from which to study the evolution of mitochondrial-nuclear genome relationships.
... Ogata and Yamasaki, 1985;Kirkwood et al., 1986;Weibel and Kayar, 1988;Glancy et al., 2015;Bleck et al., 2018). Likely in pancreatic cells and HL-1 cells with a cardiac phenotype, yeast cells show a dynamic mitochondria reticulum of branched tubules surrounding the nucleus (Hermann and Shaw, 1998;Egner et al., 2002;Karbowski and Youle, 2003). In neurons, where there is high energetic demands, there is a constant movement of mitochondria from cell body to synaptic sites with heterogeneous mitochondrial networks (Ligon and Steward, 2000;Miller and Sheetz, 2004;Miller et al., 2006). ...
Mitochondria are key determinants of cellular health. However, the functional role of mitochondria varies from cell to cell depending on the relative demands for energy distribution, metabolite biosynthesis, and/or signaling. In order to support the specific needs of different cell types, mitochondrial functional capacity can be optimized in part by modulating mitochondrial structure across several different spatial scales. Here we discuss the functional implications of altering mitochondrial structure with an emphasis on the physiological trade-offs associated with different mitochondrial configurations. Within a mitochondrion, increasing the amount of cristae in the inner membrane improves capacity for energy conversion and free radical-mediated signaling but may come at the expense of matrix space where enzymes critical for metabolite biosynthesis and signaling reside. Electrically isolating individual cristae could provide a protective mechanism to limit the spread of dysfunction within a mitochondrion but may also slow the response time to an increase in cellular energy demand. For individual mitochondria, those with relatively greater surface areas can facilitate interactions with the cytosol or other organelles but may be more costly to remove through mitophagy due to the need for larger phagophore membranes. At the network scale, a large, stable mitochondrial reticulum can provide a structural pathway for energy distribution and communication across long distances yet also enable rapid spreading of localized dysfunction. Highly dynamic mitochondrial networks allow for frequent content mixing and communication but require constant cellular remodeling to accommodate the movement of mitochondria. The formation of contact sites between mitochondria and several other organelles provides a mechanism for specialized communication and direct content transfer between organelles. However, increasing the number of contact sites between mitochondria and any given organelle reduces the mitochondrial surface area available for contact sites with other organelles as well as for metabolite exchange with cytosol. Though the precise mechanisms guiding the coordinated multi-scale mitochondrial configurations observed in different cell types have yet to be elucidated, it is clear that mitochondrial structure is tailored at every level to optimize mitochondrial function to meet specific cellular demands.
... The mitochondrial dynamics are tightly regulated by maintaining in a balance between the fusion and fission process and regulates the mitochondrial morphology, size, numbers, and physiological function (Scott and Youle, 2010;Toyama et al., 2016;McInnes, 2013). As mitochondria are the sole ATP producing organelle, the maintenance of its morphology and dynamics is crucial for its proper physiological functions (Frederick et al., 2004;Hermann and Shaw, 1998;McInnes, 2013). Several studies have shown that defective mitochondrial dynamics induces several NDs like AD, PD, ALS and HD related pathologies including hampered metabolic state, reduced ATP production and enhanced oxidative stress (Gao et al., 2017;Panchal and Tiwari, 2019;Su et al., 2010;Zhu et al., 2018). ...
Miro (mitochondrial Rho GTPases) a mitochondrial outer membrane protein, plays a vital role in the microtubule-based mitochondrial axonal transport, mitochondrial dynamics (fusion and fission) and Mito-Ca²⁺ homeostasis. It forms a major protein complex with Milton (an adaptor protein), kinesin and dynein (motor proteins), and facilitates bidirectional mitochondrial axonal transport such as anterograde and retrograde transport. By forming this protein complex, Miro facilitates the mitochondrial axonal transport and fulfills the neuronal energy demand, maintain the mitochondrial homeostasis and neuronal survival. It has been demonstrated that altered mitochondrial biogenesis, improper mitochondrial axonal transport, and mitochondrial dynamics are the early pathologies associated with most of the neurodegenerative diseases (NDs). Being the sole mitochondrial outer membrane protein associated with mitochondrial axonal transport-related processes, Miro proteins can be one of the key players in various NDs such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis(ALS) and Huntington's disease (HD). Thus, in the current review, we have discussed the evolutionarily conserved Miro proteins and its role in the pathogenesis of the various NDs. From this, we indicated that Miro proteins may act as a potential target for a novel therapeutic intervention for the treatment of various NDs.
... Mitochondrial length is determined through a balance of fission and fusion events (20). Interestingly, a gene identified in the synthetic sick/lethal screen, the GTPase FZO1 (mitofusin), is required for mitochondrial fusion (21,22). Using high content-screening (23) together with electron microscopy (Fig 2C), we determined mean mitochondrial length in NPC1 patient cells and confirmed that there was a significant increase in length in comparison with controls (GM3123, 2.59 μm ± 0.077; NPC1 +/+ , 1.74 μm ± 0.043 **P < 0.01, n = 100; Fig 2D). ...
Niemann–Pick disease type C (NPC) is a rare lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Mutations in the NPC1 gene lead to the majority of clinical cases (95%); however, the function of NPC1 remains unknown. To gain further insights into the biology of NPC1, we took advantage of the homology between the human NPC1 protein and its yeast orthologue, Niemann–Pick C–related protein 1 (Ncr1). We recreated the NCR1 mutant in yeast and performed screens to identify compensatory or redundant pathways that may be involved in NPC pathology, as well as proteins that were mislocalized in NCR1 -deficient yeast. We also identified binding partners of the yeast Ncr1 orthologue. These screens identified several processes and pathways that may contribute to NPC pathogenesis. These included alterations in mitochondrial function, cytoskeleton organization, metal ion homeostasis, lipid trafficking, calcium signalling, and nutrient sensing. The mitochondrial and cytoskeletal abnormalities were validated in patient cells carrying mutations in NPC1 , confirming their dysfunction in NPC disease.
... Mechanistic insight into mitochondrial morphosis was initially obtained in yeast and, more recently, in neuronal cells [74][75][76][77][78][79][80][81][82][83][84][85][86][87], with genetic manipulation of yeast homologues of the mammalian guanosine triphosphates (GTPases) providing the foundation for our current understanding of the molecular mediators of fission and fusion [63,65,74,88]. In a process that is highly conserved across species, mitochondrial fission, when balanced with fusion, is a normal physiologic process that: (1) serves as the first step in the culling of damaged and dysfunctional organelles from the mitochondrial network, and (2) fragments the network to facilitate trafficking of mitochondria to microdomains within the cell [62, 87,[89][90][91][92][93][94] (Figure 3). ...
The current standard of care for acute myocardial infarction or ‘heart attack’ is timely restoration of blood flow to the ischemic region of the heart. While reperfusion is essential for the salvage of ischemic myocardium, re-introduction of blood flow paradoxically kills (rather than rescues) a population of previously ischemic cardiomyocytes—a phenomenon referred to as ‘lethal myocardial ischemia-reperfusion (IR) injury’. There is long-standing and exhaustive evidence that mitochondria are at the nexus of lethal IR injury. However, during the past decade, the paradigm of mitochondria as mediators of IR-induced cardiomyocyte death has been expanded to include the highly orchestrated process of mitochondrial quality control. Our aims in this review are to: (1) briefly summarize the current understanding of the pathogenesis of IR injury, and (2) incorporating landmark data from a broad spectrum of models (including immortalized cells, primary cardiomyocytes and intact hearts), provide a critical discussion of the emerging concept that mitochondrial dynamics and mitophagy (the components of mitochondrial quality control) may contribute to the pathogenesis of cardiomyocyte death in the setting of ischemia-reperfusion.
... Described as early as 1914 [103] and rediscovered later [104,105], mitochondria are highly dynamic organelles that constantly undergo fusion and fission events and move within cells. By using the power of yeast genetics, initial pioneering studies led to identification of several proteins localized both on the OM and IM responsible for fusion and fission [106][107][108]. In mammals, mitochondria undergo fusion with the help of large GTPases, Mitofusins 1 and 2 (Mfn1 and Mfn2) for the OM and OPA1 for the IM. ...
Mitochondria are vital cellular organelles involved in a plethora of cellular processes such as energy conversion, calcium homeostasis, heme biogenesis, regulation of apoptosis and ROS reactive oxygen species (ROS) production. Although they are frequently depicted as static bean-shaped structures, our view has markedly changed over the past few decades as many studies have revealed a remarkable dynamicity of mitochondrial shapes and sizes both at the cellular and intra-mitochondrial levels. Aberrant changes in mitochondrial dynamics and cristae structure are associated with ageing and numerous human diseases (e.g., cancer, diabetes, various neurodegenerative diseases, types of neuro- and myopathies). Another unique feature of mitochondria is that they harbor their own genome, the mitochondrial DNA (mtDNA). MtDNA exists in several hundreds to thousands of copies per cell and is arranged and packaged in the mitochondrial matrix in structures termed mt-nucleoids. Many human diseases are mechanistically linked to mitochondrial dysfunction and alteration of the number and/or the integrity of mtDNA. In particular, several recent studies identified remarkable and partly unexpected links between mitochondrial structure, fusion and fission dynamics, and mtDNA. In this review, we will provide an overview about these recent insights and aim to clarify how mitochondrial dynamics, cristae ultrastructure and mtDNA structure influence each other and determine mitochondrial functions.
