Biogenesis of mitochondria in yeast Saccharomyces cerevisiae: Part I--Nuclear control of mitochondria biogenesis.
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Cell Nucleus↗
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Peroxisome biogenesis in Hansenula polymorpha: different mutations in genes, essential for peroxisome biogenesis, cause different peroxisomal mutant phenotypes.
In Hansenula polymorpha, different monogenic recessive mutations mapped in either of two previously identified genes, PER1 and PER3, produced different peroxisomal mutant phenotypes. Among five per1 mutants, four showed a Pim- phenotype: the cells contained few small peroxisomes while the bulk of the matrix enzymes resided in the cytosol. One of these mutants, per1-124 had an enhanced rate of peroxisome proliferation. The fifth mutant completely lacked peroxisomes (Per- phenotype). Of seven per3 mutants, four displayed a Pim- phenotype, two others a Per- phenotype, while one mutant showed pH-dependent growth on methanol and was affected in oligomerization of peroxisomal matrix protein. Thus, the protein products of both PER1 and PER3 genes appear to be essential in different aspects of peroxisome assembly/proliferation.
Genes, Fungal↗
Biogenesis of mitochondrial membranes in Neurospora crassa during cellular differentiation: ultrastructural changes accompanying differentiation.
The ultrastructural characteristics of Neurospora cells during dedifferentiation and redifferentiation of conidiospores into vegetative cells have been determined. This germination process occurs between 2 and 5 h after inoculation; by 3-5 h, approximately 50% of the cells have germinated. The cells enter the exponential phase of dry-weight gain between 4 and 5 h after inoculation. Several unusual structures are observed in Neurospora cells during germination. Whorled structures are frequently seen in the cytoplasm during germination, and occasionally at other times. They appear to be derived from the cytoplasmic membrane. Whorled structures of different appearance were observed in the mitochondria between 2 and 4 h after inoculation. Their number was related to the level of metabolizable carbohydrate, and was higher in 15% glucose-than in 2% sucrose-supplemented medium, and very low in medium containing 15% mannitol, or 2% sucrose+13% 2-deoxyglucose, or no added carbohydrate. The mitochondrial inclusions were osmiophilic and could be removed by treatment with 90% aqueous acetone in the cold, indicating that they were composed at least in part of lipid. The strong dependence of the number of mitochondrial inclusions on time and on carbohydrate supplementation, suggests that there is a physiological basis for these structures and that they reflect changes occurring in the mitochondria at times significant to cellular differentiation.
Carbohydrate Metabolism↗
[Biogenesis of steroid derivatives in the plant kingdom. 14. Hydroxylation in the 5-position during the biogenesis of hellebrigenin].
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Bufanolides↗
Stimulation of hepatic biogenesis of sterols on administration of adenosine compounds.
1. Re-feeding starved rats increased the biogenesis of sterols in livers, with highest activity at 6h after the start of food intake. 2. Complete deficiency of protein or fat and partial deficiency of carbohydrate in the diet had no effect on sterol biogenesis. 3. Glucose, citrate or pyruvate, when administered intraperitoneally to starved rats, stimulated the biogenesis of sterols only at high concentrations. 4. ATP given intraperitoneally at low concentrations (10mg/rat) stimulated biogenesis of sterols, but not of fatty acids, from [1-14C]acetate. This effect was also obtained with other adenosine compounds, but not with adenine or guanosine. 5. Administration of adenosine compounds to starved rats also increased the incorporation of [1-14C]acetate into sterols in liver slices and also the activity of microsomal 3-hydroxy-3-methylglutaryl-CoA reductase. The results suggest a regulatory role for adenosine compounds in the hepatic biogenesis of isoprenoid compounds.
Acetates↗
Mechanism of action of thyroxine (T4) on the biogenesis of mitochondria using antibiotic-free system: a gerontological survey.
For the biogenesis of mitochondria from rat liver two different genetic systems are responsible, the nucleo-cytoplasmic system, covering 85-90% of the protein, and the mitochondrial system (10-15%). These data have been confirmed by experiment. Both protein fractions were separated by phosphate buffer (pH 11.5), in which only one of them is soluble. The experiments were performed with 3 age groups of rat: 1, 3 and 24 months. The ratio of both protein fractions was not dependent on rat age. The activities of the two genetic systems were examined by the in-vivo incorporation rate of 14 C-leucine. For the mitochondrial genetic system this rate was approximately equal in all of the age groups, while that for the nucleo-cytoplasmic genetic system was reduced in the 24 month group. Hence an age-dependence is demonstrated for the nucleo-cytoplasmic genetic system. The results of our investigation permit the conclusion that the role of the mitochondrial genetic system increases at senescence. To investigate the effect of T4 on the biogenesis of mitochondria, both protein fractions were estimated also in liver of rats treated with T4. The result showed that there was an increase for all the age groups for protein only of nucleo-cytoplasmic origin. Since it is known that T4 stimulates the biogenesis of mitochondria and increases its protein content, it could be inferred that the action of T4 is channelled through the nucleo-cytoplasmic system independent on age, and that the nucleus plays the major regulatory role in the biogenesis of mitochondria.
Aging↗
Nuclear functions required for cytochrome c oxidase biogenesis in Saccharomyces cerevisiae: multiple trans-acting nuclear genes exert specific effects on expression of each of the cytochrome c oxidase subunits encoded on mitochondrial DNA.
Fourteen nuclear complementation groups of mutants that specifically affect the three mitochondrially-encoded subunits of yeast cytochrome c oxidase have been characterized. Genes represented by these complementation groups are not required for mitochondrial transcription, transcript processing, or translation per se but are required for the expression of one of the three genes--COX1, COX2, or COX3--which encode the cytochrome c oxicase subunits I, II, or III, respectively. Five of these genes affect the biogenesis of cytochrome c oxidase subunit I, 3 affect the biogenesis of subunit II, 3 affect the biogenesis of subunit III and 3 affect the biogenesis of both cytochrome c oxidase subunit I and cytochrome b, the product of COB. Among the 5 complementation groups of mutants that affect the expression of COX1, 2 lack COX1 transcripts, 1 produces incompletely processed COX1 transcripts, and 2 contain normal levels of normal-sized COX1 transcripts. In contrast, all 3 complementation groups which affect the expression of COX2 and all 3 complementation groups which affect the expression of COX3 exhibit no, or little, detectable difference with respect to the wild type pattern of transcripts. The 3 complementation groups which affect the expression of both COX1 and COB all have aberrant COX1 and COB transcript patterns. These findings indicate that multiple trans-acting nuclear genes are required for specific expression of each COX gene encoded on mitochondrial DNA and suggest that their products act at different steps in the expression of these mitochondrial genes.
Cell Nucleus↗
Involvement of iron in the biogenesis of the cyanide-insensitive respiration in the yeast Saccharomycopsis lipolytica.
The involvement of iron in the biogenesis of the cyanide-insensitive respiration in the yeast Saccharomycopsis lipolytica has been established on the following basis: (1) endogenous metal chelation by either benzyl- or salicylhydroxamic acid, EDTA or nitrilotriacetate prevented the biogenesis of the cyanide-insensitive respiratory pathway in S. lipolytica. (2) Addition of Fe(III) during the biogenesis increased both the rate of the appearance of the alternative respiratory pathway and its extent. Neither Fe(II), nor Co(II), Cu(II), Al(III), La(III), Mn(II) or Mg(II) could substitute for Fe(III). (3) The biogenesis of the alternative respiratory pathway could be dissociated into two steps: (a) a first one, slow, cycloheximide-sensitive, temperature-dependent, iron-independent, leading to cells still fully cyanide-sensitive, presumably involving the de novo biosynthesis of an inactive protein moiety and (b) a second step, fast, iron-dependent, temperature-independent, cycloheximide-insensitive, leading to cells with a cyanide-insensitive respiration, presumably the activation by iron of the inactive precursor.
Chelating Agents↗
Thyroid hormone and not growth hormone is the principle regulator of mammalian mitochondrial biogenesis.
T3 and GH have been implicated in the regulation of mitochondrial biogenesis. Since thyroid hormone promotes the synthesis of growth hormone, its control of human mitochondrial biogenesis could arise through a permissive action on GH biosynthesis. This was studied in hypophysectomized rats treated with T3 and/or human GH by the continuous infusion of hormone for 6 days from mini-infusion pumps implanted sc. Increases in mitochondrial respiration, enzyme activities, and protein synthesis were found in isolated liver mitochondria from rats receiving T3. In contrast, GH alone had no effect, nor did it increase the response to T3. Since it has been argued that mitochondrial biogenesis results from a direct interaction (binding) of GH with mitochondria, GH-specific binding sites were measured with 125I-bGH, a specific somatogenic receptor ligand, in isolated mitochondrial membranes in vitro. In addition, the intracellular endocytic uptake of 125I-bGH injected in vivo was compared in purified subcellular membrane fractions and mitochondria. No evidence in favour of specific GH interaction on mitochondrial membranes was found by either test. It is concluded that T3 exerts a direct, rather than permissive, effect on mitochondrial biogenesis, and that high affinity binding sites for GH are not present in rat liver mitochondria.
Animals↗
Kin17 promotes rDNA transcription, ribosomal biogenesis, and cortical lamination.
During brain development, neural progenitor cells (NPCs) undergo rapid division, necessitating efficient ribosomal biogenesis for proliferation. Yet, the regulatory mechanisms remain largely elusive. Here, we report that the DNA binding protein Kin17 exhibits development-dependent expression and plays a vital role in embryonic development. Complete loss of Kin17 in mice leads to embryonic lethality, while Kin17 depletion specifically in NPCs allows embryonic survival but results in reduced brain size and cortical lamination defects. Our findings demonstrate that these cortical malformation stems from impaired NPC proliferation and differentiation. Mechanistically, we show that Kin17 binds to the promoter region of rDNA, sequentially recruiting NCL and Polr1a, thereby promoting rDNA transcription. Consequently, Kin17 facilitates ribosome biogenesis and protein translation in NPCs. This study underscores a critical role of Kin17 in promoting rDNA transcription and ribosomal biogenesis in NPCs during brain development, which is essential for proper cortical lamination.
Animals↗
Mitochondrial biogenesis during the activation of lymphocytes by mitogens: the immunosuppressive action of tetracyclines.
The role of mitochondrial biogenesis and function during mitogenic stimulation of rat thymocytes was investigated. The results show that mitochondrial biogenesis is required to provide the ATP for the energy-requiring processes occurring during blastogenesis. Impairment of mitochondrial biogenesis by inhibition of mitochondrial protein synthesis inhibits blast transformation. Since the tetracyclines impair mitochondrial protein synthesis, the results offer an explanation for the well-known immunosuppressive effects of these antibiotics.
Animals↗
An intricate functional relationship between NuA4 and Sfp1 regulates ribosome biogenesis in response to nutrient availability.
Ribosome biogenesis is a crucial process requiring enormous transcriptional output. In budding yeast, the expression of 138 ribosomal protein (RP) genes and over 200 ribosome biogenesis (RiBi) genes is regulated by an intricate network of factors, including the nutrient-sensitive transcription activator Sfp1 and the NuA4 coactivator/acetyltransferase complex. Nutrient starvation or inhibition of target of rapamycin complex 1 by rapamycin leads to repression of RP and RiBi genes, in part through blocking Sfp1 nuclear localization and NuA4-dependent chromatin acetylation. Here, we demonstrate that Sfp1 physically interacts with NuA4 in a target of rapamycin complex 1-dependent manner. Our results indicate that Sfp1, along with NuA4, regulate the transcription of RiBi and RP genes via distinct mechanisms depending on promoter architectures. Sfp1 promotes histone acetylation at the promoters without affecting NuA4 recruitment. In contrast, NuA4 does impact Sfp1 binding but specifically at two classes of RP genes. Importantly, NuA4 acetylates Sfp1 at lysines 655 and 657, regulating its function. Cells expressing Sfp1 with acetyl-mimicking mutations exhibit increased expression of RiBi genes while RP genes remain stable. However, the same mutants lead to the loss of Sfp1 binding/activity at RiBi genes when cells are under non-optimal growth conditions. Mimicking constitutive acetylation of Sfp1 also limits the transcriptional burst of RP genes upon addition of glucose. Altogether, these results draw an intricate functional relationship between Sfp1 and NuA4 to control ribosome biogenesis, fine-tuning transcription output in different growth conditions.
Saccharomyces cerevisiae Proteins↗
Genetic approaches to the study of mitochondrial biogenesis in yeast.
In contrast to most other organisms, the yeast Saccharomyces cerevisiae can survive without functional mitochondria. This ability has been exploited in genetic approaches to the study of mitochondrial biogenesis. In the last two decades, mitochondrial genetics have made major contributions to the identification of genes on the mitochondrial genome, the mapping of these genes and the establishment of structure-function relationships in the products they encode. In parallel, more than 200 complementation groups, corresponding to as many nuclear genes necessary for mitochondrial function or biogenesis have been described. Many of the latter are required for post-transcriptional events in mitochondrial gene expression, including the processing of mitochondrial pre-RNAs, the translation of mitochondrial mRNAs, or the assembly of mitochondrial translation products into the membrane. The aim of this review is to describe the genetic approaches used to unravel the intricacies of mitochondrial biogenesis and to summarize recent insights gained from their application.
Cell Nucleus↗
Biogenesis of transverse tubules and triads: immunolocalization of the 1,4-dihydropyridine receptor, TS28, and the ryanodine receptor in rabbit skeletal muscle developing in situ.
Our previous immunofluorescence studies support the conclusion that the temporal appearance and subcellular distribution of TS28 (a marker of transverse (T) tubules and caveolae in adult skeletal muscle [Jorgensen, A. O., W. Arnold, A. C.-Y. Shen. S. Yuan, M. Gover, and K. P. Campbell, 1990, J. Cell Biol. 110:1173-1185]), correspond very closely to those of T-tubules forming de novo in developing rabbit skeletal muscle (Yuan, S., W. Arnold, and A. O. Jorgensen, 1990, J. Cell Biol. 110:1187-1198). To extend our morphological studies of the biogenesis of T-tubules and triads, the temporal appearance and subcellular distribution of the alpha 1-subunit of the 1,4-dihydropyridine receptor (a marker of the T-tubules and caveolae) was compared to (a) that of TS28; and (b) that of the ryanodine receptor (a marker of the junctional sarcoplasmic reticulum) in rabbit skeletal muscle cells developing in situ (day 19 of gestation to 10 d newborn) by double immunofluorescence labeling. The results presented show that the temporal appearance and relative subcellular distribution of the alpha 1-subunit of the 1,4-dihydropyridine receptor (alpha 1-DHPR) are distinct from those of TS28 at the onset of the biogenesis of T-tubules. Thus, in a particular developing myotube the alpha 1-DHPR appeared before TS28 (secondary myotubes; day 19-24 of gestation). Furthermore, the alpha 1-DHPR was distributed in discrete foci at the outer zone of the cytosol, while TS28 was confined to foci and rod-like structures at the cell periphery. As development proceeded (primary myotubes; day 24 of gestation) approximately 50% of the foci were positively labeled for both TS28 and the alpha 1-DHPR, while approximately 20 and 30% of the foci were uniquely labeled for TS28 and the alpha 1-DHPR, respectively. The foci labeled for both TS28 and the alpha 1-DHPR and the foci uniquely labeled for TS28 were generally confined to the cell periphery, while the foci uniquely labeled for the alpha 1-DHPR were mostly confined to the outer zone of the cytosol. 1-2 d after birth, TS28 was distributed in a chickenwire-like network throughout the cytosol, while the alpha 1-DHPR was confined to cytosolic foci. In contrast, the temporal appearance and subcellular distribution of the alpha 1-DHPR and the ryanodine receptor were very similar, if not identical, throughout all the stages of the de novo biogenesis of T-tubules and triads examined.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Single-nucleus profiling of postmortem diffuse midline gliomas identifies mitochondrial biogenesis as a resistance mechanism to imipridone therapy.
BACKGROUND: Imipridone ONC201 is the first FDA-approved therapy for H3K27-altered diffuse midline glioma; however, clinical responses remain limited. Defining tumor-intrinsic determinants and microenvironmental, extrinsic factors that shape sensitivity or resistance to imipridones will identify actionable therapeutic opportunities and inform improved clinical strategies. METHODS: To identify mechanisms of imipridone resistance, we obtained postmortem brain tissue from DMG patients who had received imipridones and/or standard care. Single-nucleus RNA and open-chromatin sequencing were performed on N = 22 cases. Immunofluorescence-based myeloid phenotyping was performed on N = 46 cases. Mitochondrial copy-number analysis was performed on N = 19 cases. Validation of imipridone sensitivity, its effect on mitochondrial density, and its synergy with inhibition of mitochondrial biogenesis were assessed in DMG primary cells. RESULTS: We established a single-cell RNA/open-chromatin atlas from postmortem DMG cases and found imipridone treatment resulting in regressed mesenchymal transition, reduced myeloid-derived suppressive cells, and reversed aberrant H3K27-altered enhancer activity. Resistant tumors showed increased mitochondrial density, turnover, and membrane potential. Mitochondrial biogenesis and PPARGC1A emerged as resistance biomarkers and actionable targets. CONCLUSIONS: These studies implicate mitochondrial biogenesis as a biomarker of imipridone resistance and a focus for the development of combinatorial strategies to provide effective therapeutic options for a challenging pediatric brain tumor.
Humans↗
Biogenesis of the ciliary roots: participation of the dictyosomes of Golgi's complex.
In this study, the hypothesis of a possible biogenesis of the ciliary roots is suggested, after observing the cilia neurons under the electron microscope, which were found as an exception in the periaqueductal nucleus of the mesencephalon in the domestic cat, conserving the potential to differentiate the cilia, basal bodies and ciliary roots. The dictyosomes of Golgi's complex and Golgi's vesicles participated in this biogenesis. Vesicles of approximately 71.6 nm in diameter had become separated from the periphery of the flattened discoid cisterns of the dictyosome and were aligned normally, in tangential contact with each other, forming rows of vesicles or 'ringed chains', whose points of contact formed the beginning of the 'periodic striation' of a thin ciliary root. Later, the lateral walls of the vesicles and the molecules of the intracisternal proteins gave rise to the interperiodic microfilaments, when the carrier proteins were transformed into structural proteins of the ciliary roots. The parallel apposition of several ringed chains or thin ciliary roots, with their rings joined at the same level (or transversal striations), gave rise to thicker striated roots. This hypothesis of an ultrastructural biogenesis of the striated ciliary roots involves the following six stages: stage I = separation of Golgi's vesicles from the periphery of the flattened disk of dictyosomes near the basal body, with a diameter of over 71.6 nm; stage II = reinforcement of the membrane of the vesicles at the two opposite polar ends of its larger diameter; stage III = alignment of vesicles to form ringed chains, due to the tangential contact between their reinforced points; initiation of the 71.6-nm striation period, roots ringed linearly; stage IV = formation of joining microfilaments between periods (69.2 nm) with the lateral walls of the vesicles and the molecules of the proteins in their content; stage V = lengthening of the thin ciliary roots due to the coupling of new Golgi's vesicles at their ends so that their length increases as a result of the addition of terminal vesicles; stage VI = increase in thickness of the thin ciliary roots, due to the parallel apposition of several ringed chains or thin ringed ciliary roots, at the point where their transversal striation points coincide.
Animals↗
On some of the in organello processes involved in the biogenesis of chlorophyll-protein complexes.
The biogenesis and assembly of chlorophyll-protein complexes consist of many steps. These are initiated with the transcription and translation of the different polypeptide components constituting the complexes. For the nuclear-encoded subunits the synthesis takes place in the cytoplasm, and they are synthesized as precursors, which are later imported into the chloroplast. Within the organelle, the precursors are inserted into the thylakoid membranes, as well as being processed to their mature forms. The different nuclear- and chloroplast-encoded subunits assemble together, and bind the pigments and other cofactors to form the active pigmented-complex. In the present article, we discuss only the in organello processes of the biogenesis. We describe the pathways taken by two nuclear-encoded thylakoid proteins, the precursor of the main light-harvesting chlorophyll-protein of photosystem II (pLHCP) and the precursor of photosystem I subunit II (pre subunit II). These polypeptide subunits, that are located in two different photosynthetic complexes, differ from each other. While pLHCP is an integral membrane protein, which binds pigments, photosystem I-subunit II is a peripheral membrane protein, located on the stromal side of the thylakoids, and is not predicted to span it. The differences and the common features of the in organello biogenesis pathways of these two proteins are discussed.
Apoproteins↗
Surface architecture of the plant cell: biogenesis of the cell wall, with special emphasis on the role of the plasma membrane in cellulose biosynthesis.
Cell wall structure and biogenesis in the unicellular green alga, Oocystis apiculata, is described. The wall consists of an outer amorphous primary layer and an inner secondary layer of highly organized cellulosic microfibrils. The primary wall is deposited immediately after cytokinesis. Golgi-derived products contribute to this layer. Cortical microtubules underlie the plasma membrane immediately before and during primary wall formation. They function in maintaining the elliptical cell shape. Following primary wall synthesis, Golgi-derived materials accumulate on the cell surface to form the periplasmic layer. This layer functions in the deposition of coating and cross-linking substances which associate with cellulosic microfibrils of the incipient secondary wall. Secondary wall microfibrils are assembled in association with the plasma membrane. Freeze-etch preparations of untreated, living cells reveal linear terminal complexes in association with growing cellulosic microfibrils. These complexes are embedded in the EF fracture face of the plasma membrane. The newly synthesized microfibril lies in a groove of the outer leaflet of the plasma membrane. The groove is decorated on the EF fracture face by perpendicular structures termed "ridges". The ridges interlink with definitive rows of particles associated withe PF fracture face of the innter leaflet of the plasma membrane. These particles are termed "granule bands", and they function in the orientation of the newly synthesized microfibrils. Microfibril development in relation to a coordinated multienzyme complex is discussed. The process of cell wall biogenesis in Oocystis is compared to that in higher plants.
Cell Membrane↗