BBA - Molecular Cell Research (v.1833, #2)
Editorial Board (i).
What comes around goes around: Protein import and quality control in mitochondria and plastids by Enrico Schleiff; Martin van der Laan (243-244).
Cytosolic events involved in chloroplast protein targeting by Dong Wook Lee; Chanjin Jung; Inhwan Hwang (245-252).
Chloroplasts are unique organelles that are responsible for photosynthesis. Although chloroplasts contain their own genome, the majority of chloroplast proteins are encoded by the nuclear genome. These proteins are transported to the chloroplasts after translation in the cytosol. Chloroplasts contain three membrane systems (outer/inner envelope and thylakoid membranes) that subdivide the interior into three soluble compartments known as the intermembrane space, stroma, and thylakoid lumen. Several targeting mechanisms are required to deliver proteins to the correct chloroplast membrane or soluble compartment. These mechanisms have been extensively studied using purified chloroplasts in vitro. Prior to targeting these proteins to the various compartments of the chloroplast, they must be correctly sorted in the cytosol. To date, it is not clear how these proteins are sorted in the cytosol and then targeted to the chloroplasts. Recently, the cytosolic carrier protein AKR2 and its associated cofactor Hsp17.8 for outer envelope membrane proteins of chloroplasts were identified. Additionally, a mechanism for controlling unimported plastid precursors in the cytosol has been discovered. This review will mainly focus on recent findings concerning the possible cytosolic events that occur prior to protein targeting to the chloroplasts. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► Various cytosolic events are required for protein targeting into interior regions of chloroplasts. ► Unimported precursor response plays a crucial role in regulation of cytosolic levels of chloroplast preproteins. ► Various cytosolic events are required for targeting to the outer envelope of chloroplasts. ► AKR2 and Hsp17.8 function as a cytosolic factor and cofactor for targeting to chloroplast outer membrane.
Keywords: Chloroplast targeting signal; Cytosolic import factors; Outer envelope membrane; Chloroplast precursors in cytosol;
A reevaluation of dual-targeting of proteins to mitochondria and chloroplasts by Christopher Carrie; Ian Small (253-259).
Over 100 proteins are found in both mitochondria and chloroplasts, via a variety of processes known generally as ‘dual-targeting’. Dual-targeting has attracted interest from many different research groups because of its profound implications concerning the mechanisms of protein import into these organelles and the evolution of both the protein import machinery and the targeting sequences within the imported proteins. Beyond these aspects, dual-targeting is also interesting for its implications concerning shared functions between mitochondria and chloroplasts, and especially the control of the activities of these two very different energy organelles. We discuss each of these points in the light of the latest relevant research findings and make some suggestions for where research might be most illuminating in the near future. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► Over 100 proteins are now known to be dual-targeted to mitochondria and plastids. ► Dual-targeted proteins are biased towards soluble proteins implicated in DNA and RNA metabolism and/or translation. ► Targeting specificity for both organelles tends to physically overlap within targeting sequences. ► The dual-targeted state tends to persist over evolutionary timescales, implying a selective advantage.
Keywords: Mitochondrion; Plastid; Protein targeting; Protein import; Dual-targeting;
Protein targeting to subcellular organelles via mRNA localization by Benjamin L. Weis; Enrico Schleiff; William Zerges (260-273).
Cells have complex membranous organelles for the compartmentalization and regulation of most intracellular processes. Organelle biogenesis and maintenance requires newly synthesized proteins, each of which needs to go from the ribosome translating its mRNA to the correct membrane for insertion or translocation to an organellar subcompartment. Decades of research have revealed how proteins are targeted to the correct organelle and translocated across one or more organelle membranes to the compartment where they function. The paradigm examples involve interactions between a peptide sequence in the protein, localization factors, and various membrane-embedded translocation machineries. Membrane translocation is either cotranslational or posttranslational depending on the protein and target organelle. Meanwhile, research in embryos, neurons and yeast revealed an alternative targeting mechanism in which the mRNA is localized and only then translated to synthesize the protein in the correct location. In these cases, the targeting information is encoded by cis-acting sequences in the mRNA (“Zipcodes”) that interact with localization factors and, in many cases, are transported by molecular motors on cytoskeletal filaments. Recently, evidence has been found for this “mRNA-based” mechanism in organelle protein targeting to endoplasmic reticulum, mitochondria, and the photosynthetic membranes within chloroplasts. Here we review known and potential roles of mRNA localization in protein targeting to and within organelles. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► mRNA distribution in cellular systems is essential for cellular function. ► mRNA and protein elements are signals for the differential distribution. ► Multiple modes for the association of mRNAs with membranes exist. ► mRNA localization is one important way for regulation of protein translocation.
Keywords: mRNA localization; cotranslational and post-translational import; signal recognition particle; mitochondria; chloroplast; endoplasmic reticulum;
Mitochondrial protein import: Common principles and physiological networks by Jan Dudek; Peter Rehling; Martin van der Laan (274-285).
Most mitochondrial proteins are encoded in the nucleus. They are synthesized as precursor forms in the cytosol and must be imported into mitochondria with the help of different protein translocases. Distinct import signals within precursors direct each protein to the mitochondrial surface and subsequently onto specific transport routes to its final destination within these organelles. In this review we highlight common principles of mitochondrial protein import and address different mechanisms of protein integration into mitochondrial membranes. Over the last years it has become clear that mitochondrial protein translocases are not independently operating units, but in fact closely cooperate with each other. We discuss recent studies that indicate how the pathways for mitochondrial protein biogenesis are embedded into a functional network of various other physiological processes, such as energy metabolism, signal transduction, and maintenance of mitochondrial morphology. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► Multiple import machineries mediate the sorting and assembly of nuclear encoded mitochondrial precursor proteins. ► Mitochondrial protein translocases operate as highly dynamic molecular machines. ► Close cooperation between translocation machineries of inner and outer membrane is crucial for mitochondrial protein sorting. ► Mitochondrial protein import is embedded into large-scale physiological networks.
Keywords: Mitochondria; Import motor; Protein import; Signal sequence; TOM complex; TIM23 complex;
Control of protein synthesis in yeast mitochondria: The concept of translational activators by Johannes M. Herrmann; Michael W. Woellhaf; Nathalie Bonnefoy (286-294).
Mitochondria contain their own genome which codes for a small number of proteins. Most mitochondrial translation products are part of the membrane-embedded reaction centers of the respiratory chain complexes. In the yeast Saccharomyces cerevisiae, the expression of these proteins is regulated by translational activators that bind mitochondrial mRNAs, in most cases to their 5′-untranslated regions, and each mitochondrial mRNA appears to have its own translational activator(s). Recent studies showed that these translational activators can be part of feedback control loops which only permit translation if the downstream assembly of nascent translation products can occur. In several cases, the accumulation of a non-assembled protein prevents further synthesis of this protein but not translation in general. These control loops prevent the synthesis of potentially harmful assembly intermediates of the reaction centers of mitochondrial enzymes. Since such regulatory feedback loops only work if translation occurs in the compartment in which the complexes of the respiratory chain are assembled, these control mechanisms require the presence of a translation machinery in mitochondria. This might explain why eukaryotic cells maintained DNA in mitochondria during the last two billion years of evolution. This review gives an overview of the mitochondrial translation system and summarizes the current knowledge on translational activators and their role in the regulation of mitochondrial protein synthesis. This article is part of a Special Issue entitled: Protein import and quality control in mitochondria and plastids.► The mitochondrial translation system is very different from that of bacteria or eukaryotic cytosol. ► In yeast, protein synthesis depends on mRNA-specific translational activators. ► Feedback loops ensure that only proteins that can be assembled are synthesized. ► This avoids the accumulation of potentially harmful assembly intermediates.
Keywords: Cytochrome c oxidase; Mitochondrial translation; Protein insertion; Ribosome; Translational activator;
Back to basics: A revealing secondary reduction of the mitochondrial protein import pathway in diverse intracellular parasites by Eva Heinz; Trevor Lithgow (295-303).
Mitochondria are present in all eukaryotes, but remodeling of their metabolic contribution has in some cases left them almost unrecognizable and they are referred to as mitochondria-like organelles, hydrogenosomes or, in the case where evolution has led to a great deal of simplification, as mitosomes. Mitochondria rely on the import of proteins encoded in the nucleus and the protein import machinery has been investigated in detail in yeast: several sophisticated molecular machines act in concert to import substrate proteins across the outer mitochondrial membrane and deliver them to a precise sub-mitochondrial compartment. Because these machines are so sophisticated, it has been a major challenge to conceptualize the first phase of their evolution. Here we review recent studies on the protein import pathway in parasitic species that have mitosomes: in the course of their evolution for highly specialized niches these parasites, particularly Cryptosporidia and Microsporidia, have secondarily lost numerous protein functions, in accordance with the evolution of their genomes towards a minimal size. Microsporidia are related to fungi, Cryptosporidia are apicomplexans and kin to the malaria parasite Plasmodium; and this great phylogenetic distance makes it remarkable that Microsporidia and Cryptosporidia have independently evolved skeletal protein import pathways that are almost identical. We suggest that the skeletal pathway reflects the protein import machinery of the first eukaryotes, and defines the essential roles of the core elements of the mitochondrial protein import machinery. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► All mitosomes contain a highly reduced protein import machinery. ► The TOM, SAM, and TIM22/23 complexes are reduced to only one or two proteins. ► One TIM complex can carry out import through and insertion into the inner membrane. ► Different parasites retained similar protein components of the import machinery. ► This suggests a model for the nascent import machinery in the first eukaryotes.
Keywords: Mitosome; Microsporidia; Parasite; Protein import; Reductive evolution;
Unique components of the plant mitochondrial protein import apparatus by Owen Duncan; Monika W. Murcha; James Whelan (304-313).
The basic mitochondrial protein import apparatus was established in the earliest eukaryotes. Over the subsequent course of evolution and the divergence of the plant, animal and fungal lineages, this basic import apparatus has been modified and expanded in order to meet the specific needs of protein import in each kingdom. In the plant kingdom, the arrival of the plastid complicated the process of protein trafficking and is thought to have given rise to the evolution of a number of unique components that allow specific and efficient targeting of mitochondrial proteins from their site of synthesis in the cytosol, to their final location in the organelle. This includes the evolution of two unique outer membrane import receptors, plant Translocase of outer membrane 20 kDa subunit (TOM20) and Outer membrane protein of 64 kDa (OM64), the loss of a receptor domain from an ancestral import component, Translocase of outer membrane 22 kDa subunit (TOM22), evolution of unique features in the disulfide relay system of the inter membrane space, and the addition of an extra membrane spanning domain to another ancestral component of the inner membrane, Translocase of inner membrane 17 kDa subunit (TIM17). Notably, many of these components are encoded by multi-gene families and exhibit differential sub-cellular localisation and functional specialisation. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.
Keywords: Protein import; Mitochondrial biogenesis; TOM; TIM; Plant mitochondrion; Plant specific;
The chloroplast protein import system: From algae to trees by Lan-Xin Shi; Steven M. Theg (314-331).
Chloroplasts are essential organelles in the cells of plants and algae. The functions of these specialized plastids are largely dependent on the ~ 3000 proteins residing in the organelle. Although chloroplasts are capable of a limited amount of semiautonomous protein synthesis – their genomes encode ~ 100 proteins – they must import more than 95% of their proteins after synthesis in the cytosol. Imported proteins generally possess an N-terminal extension termed a transit peptide. The importing translocons are made up of two complexes in the outer and inner envelope membranes, the so-called Toc and Tic machineries, respectively. The Toc complex contains two precursor receptors, Toc159 and Toc34, a protein channel, Toc75, and a peripheral component, Toc64/OEP64. The Tic complex consists of as many as eight components, namely Tic22, Tic110, Tic40, Tic20, Tic21 Tic62, Tic55 and Tic32. This general Toc/Tic import pathway, worked out largely in pea chloroplasts, appears to operate in chloroplasts in all green plants, albeit with significant modifications. Sub-complexes of the Toc and Tic machineries are proposed to exist to satisfy different substrate-, tissue-, cell- and developmental requirements. In this review, we summarize our understanding of the functions of Toc and Tic components, comparing these components of the import machinery in green algae through trees. We emphasize recent findings that point to growing complexities of chloroplast protein import process, and use the evolutionary relationships between proteins of different species in an attempt to define the essential core translocon components and those more likely to be responsible for regulation. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► Summarizing the functions of Toc and Tic components ► Updating the findings on chloroplast protein translocation ► Comparing Toc and Tic components from five genomes, including those of algae and trees ► Identifying two new isoforms of Toc159
Keywords: Toc/Tic complex; Chloroplast; Protein import; Protein conducting channel; Precursor receptor; Evolution;
Molecular chaperone involvement in chloroplast protein import by Úrsula Flores-Pérez; Paul Jarvis (332-340).
Chloroplasts are organelles of endosymbiotic origin that perform essential functions in plants. They contain about 3000 different proteins, the vast majority of which are nucleus-encoded, synthesized in precursor form in the cytosol, and transported into the chloroplasts post-translationally. These preproteins are generally imported via envelope complexes termed TOC and TIC (Translocon at the Outer/Inner envelope membrane of Chloroplasts). They must navigate different cellular and organellar compartments (e.g., the cytosol, the outer and inner envelope membranes, the intermembrane space, and the stroma) before arriving at their final destination. It is generally considered that preproteins are imported in a largely unfolded state, and the whole process is energy-dependent. Several chaperones and cochaperones have been found to mediate different stages of chloroplast import, in similar fashion to chaperone involvement in mitochondrial import. Cytosolic factors such as Hsp90, Hsp70 and 14-3-3 may assist preproteins to reach the TOC complex at the chloroplast surface, preventing their aggregation or degradation. Chaperone involvement in the intermembrane space has also been proposed, but remains uncertain. Preprotein translocation is completed at the trans side of the inner membrane by ATP-driven motor complexes. A stromal Hsp100-type chaperone, Hsp93, cooperates with Tic110 and Tic40 in one such motor complex, while stromal Hsp70 is proposed to act in a second, parallel complex. Upon arrival in the stroma, chaperones (e.g., Hsp70, Cpn60, cpSRP43) also contribute to the folding, assembly or onward intraorganellar guidance of the proteins. In this review, we focus on chaperone involvement during preprotein translocation at the chloroplast envelope. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► Chaperones participate at various stages throughout chloroplast protein import. ► Cytosolic chaperones may aid preprotein docking at different chloroplast receptors. ► Hsp70 involvement in the chloroplast envelope intermembrane space is uncertain. ► Stromal chaperones play major roles in chloroplast protein import in motor complexes. ► Hsp93 and Hsp70 may act in parallel in two different stromal motor complexes.
Keywords: Chaperone; Chloroplast; Hsp70; Hsp93; Protein transport; TOC/TIC machinery;
Intra-plastid protein trafficking: How plant cells adapted prokaryotic mechanisms to the eukaryotic condition by Jose M. Celedon; Kenneth Cline (341-351).
Protein trafficking and localization in plastids involve a complex interplay between ancient (prokaryotic) and novel (eukaryotic) translocases and targeting machineries. During evolution, ancient systems acquired new functions and novel translocation machineries were developed to facilitate the correct localization of nuclear encoded proteins targeted to the chloroplast. Because of its post-translational nature, targeting and integration of membrane proteins posed the biggest challenge to the organelle to avoid aggregation in the aqueous compartments. Soluble proteins faced a different kind of problem since some had to be transported across three membranes to reach their destination. Early studies suggested that chloroplasts addressed these issues by adapting ancient-prokaryotic machineries and integrating them with novel-eukaryotic systems, a process called ‘conservative sorting’. In the last decade, detailed biochemical, genetic, and structural studies have unraveled the mechanisms of protein targeting and localization in chloroplasts, suggesting a highly integrated scheme where ancient and novel systems collaborate at different stages of the process. In this review we focus on the differences and similarities between chloroplast ancestral translocases and their prokaryotic relatives to highlight known modifications that adapted them to the eukaryotic situation. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► Protein routing pathways and machineries in the interior of the chloroplast. ► Novel adaptation of the SRP system for post-translational integration. ► Current description of folded protein transport by Tat. ► Speculative model for co-import membrane protein integration by Sec2.
Keywords: Chloroplast; Protein transport; Sec; Twin arginine; SecY2; SRP;
Protein sorting in complex plastids by Lilach Sheiner; Boris Striepen (352-359).
Taming a cyanobacterium in a pivitol event of endosymbiosis brought photosynthesis to eukaryotes, and gave rise to the plastids found in glaucophytes, red and green algae, and the descendants of the latter, the plants. Ultrastructural as well as molecular research over the last two decades has demonstrated that plastids have enjoyed surprising lateral mobility across the tree of life. Numerous independent secondary and tertiary endosymbiosis have led to a spread of plastids into a variety of, up to that point, non-photosynthetic lineages. Happily eating and subsequently domesticating one another protists conquered a wide variety of ecological niches. The elaborate evolution of secondary, or complex, plastids is reflected in the numerous membranes that bound them (three or four compared to the two membranes of the primary plastids). Gene transfer to the host nucleus is a hallmark of endosymbiosis and provides centralized cellular control. Here we review how these proteins find their way back into the stroma of the organelle and describe the advances in the understanding of the molecular mechanisms that allow protein translocation across four membranes. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► The evolutionary history of complex plastid includes at least three separate events of secondary endosymbiosis. ► Complex plastids have numerous compartments that are derived from cellular components of host and symbiont. ► A series of translocons enable the import of nuclear encoded proteins into the organelle. ► Molecular details of this import process is rapidly accumulating and a more and more detailed mechanistic model is emerging.
Keywords: Complex plastid; Import; TIC; TOC; ERAD; Chromalveolates;
Processing peptidases in mitochondria and chloroplasts by Pedro Filipe Teixeira; Elzbieta Glaser (360-370).
Most of the mitochondrial and chloroplastic proteins are nuclear encoded and synthesized in the cytosol as precursor proteins with N-terminal extensions called targeting peptides. Targeting peptides function as organellar import signals, they are recognized by the import receptors and route precursors through the protein translocons across the organellar membranes. After the fulfilled function, targeting peptides are proteolytically cleaved off inside the organelles by different processing peptidases. The processing of mitochondrial precursors is catalyzed in the matrix by the Mitochondrial Processing Peptidase, MPP, the Mitochondrial Intermediate Peptidase, MIP (recently called Octapeptidyl aminopeptidase 1, Oct1) and the Intermediate cleaving peptidase of 55 kDa, Icp55. Furthermore, different inner membrane peptidases (Inner Membrane Proteases, IMPs, Atp23, rhomboids and AAA proteases) catalyze additional processing functions, resulting in intra-mitochondrial sorting of proteins, the targeting to the intermembrane space or in the assembly of proteins into inner membrane complexes. Chloroplast targeting peptides are cleaved off in the stroma by the Stromal Processing Peptidase, SPP. If the protein is further translocated to the thylakoid lumen, an additional thylakoid-transfer sequence is removed by the Thylakoidal Processing Peptidase, TPP. Proper function of the D1 protein of Photosystem II reaction center requires its C-terminal processing by Carboxy-terminal processing protease, CtpA. Both in mitochondria and in chloroplasts, the cleaved targeting peptides are finally degraded by the Presequence Protease, PreP. The organellar proteases involved in precursor processing and targeting peptide degradation constitute themselves a quality control system ensuring the correct maturation and localization of proteins as well as assembly of protein complexes, contributing to sustenance of organelle functions. Dysfunctions of several mitochondrial processing proteases have been shown to be associated with human diseases. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► Most of the organellar proteins are synthesized with N-terminal targeting peptides. ► Targeting peptides are cleaved off inside the organelles by processing peptidases. ► Precursors can be trimmed to increase stability or for intraorganellar routing. ► The cleaved targeting peptides are degraded by the organellar peptidasome, PreP. ► Dysfunctions of processing proteases are associated with human diseases.
Keywords: Mitochondria; Chloroplast; Processing peptidase; Presequence protease; Mitochondrial disease; Targeting peptide;
Rhomboid proteases in mitochondria and plastids: Keeping organelles in shape by Danny V. Jeyaraju; Aditi Sood; Audrey Laforce-Lavoie; Luca Pellegrini (371-380).
Rhomboids constitute the most widespread and conserved family of intramembrane cleaving proteases. They are key regulators of critical cellular processes in bacteria and animals, and are poised to play an equally important role also in plants. Among eukaryotes, a distinct subfamily of rhomboids, prototyped by the mammalian mitochondrial protein Parl, ensures the maintenance of the structural and functional integrity of mitochondria and plastids. Here, we discuss the studies that in the past decade have unveiled the role, regulation, and structure of this unique group of rhomboid proteases. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► Rhomboids are the most ancient family of intramembrane-cleaving proteases. ► The rhomboid domain of mammalian mitochondrial rhomboids is structurally similar to that of bacterial rhomboids. ► Whereas bacterial rhomboids use a dyad-based mechanism of catalysis, mitochondrial rhomboids might use a triad. ► Mitochondrial rhomboids regulate mitochondrial dynamics. ► Parl is emerging as a key regulator of mitochondrial quality control and seems implicated in Parkinson’s disease.
Keywords: Rhomboid protease; Parl; PINK1; Opa1; Hax1; Mitophagy;
Protein quality control in organelles — AAA/FtsH story by Hanna Janska; Malgorzata Kwasniak; Joanna Szczepanowska (381-387).
This review focuses on organellar AAA/FtsH proteases, whose proteolytic and chaperone-like activity is a crucial component of the protein quality control systems of mitochondrial and chloroplast membranes. We compare the AAA/FtsH proteases from yeast, mammals and plants. The nature of the complexes formed by AAA/FtsH proteases and the current view on their involvement in degradation of non-native organellar proteins or assembly of membrane complexes are discussed. Additional functions of AAA proteases not directly connected with protein quality control found in yeast and mammals but not yet in plants are also described shortly. Following an overview of the molecular functions of the AAA/FtsH proteases we discuss physiological consequences of their inactivation in yeast, mammals and plants. The molecular basis of phenotypes associated with inactivation of the AAA/FtsH proteases is not fully understood yet, with the notable exception of those observed in m-AAA protease-deficient yeast cells, which are caused by impaired maturation of mitochondrial ribosomal protein. Finally, examples of cytosolic events affecting protein quality control in mitochondria and chloroplasts are given. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► AAA proteases are key elements of the organellar protein quality control systems. ► AAA are involved in processing, dislocation and degradation of regulatory proteins. ► Inactivation of AAA results in phenotypic alterations in yeast, mammals and plants.
Keywords: AAA protease; FtsH; Mitochondrion; Chloroplast; Protein quality control;
Chaperone–protease networks in mitochondrial protein homeostasis by Wolfgang Voos (388-399).
As essential organelles, mitochondria are intimately integrated into the metabolism of a eukaryotic cell. The maintenance of the functional integrity of the mitochondrial proteome, also termed protein homeostasis, is facing many challenges both under normal and pathological conditions. First, since mitochondria are derived from bacterial ancestor cells, the proteins in this endosymbiotic organelle have a mixed origin. Only a few proteins are encoded on the mitochondrial genome, most genes for mitochondrial proteins reside in the nuclear genome of the host cell. This distribution requires a complex biogenesis of mitochondrial proteins, which are mostly synthesized in the cytosol and need to be imported into the organelle. Mitochondrial protein biogenesis usually therefore comprises complex folding and assembly processes to reach an enzymatically active state. In addition, specific protein quality control (PQC) processes avoid an accumulation of damaged or surplus polypeptides. Mitochondrial protein homeostasis is based on endogenous enzymatic components comprising a diverse set of chaperones and proteases that form an interconnected functional network. This review describes the different types of mitochondrial proteins with chaperone functions and covers the current knowledge of their roles in protein biogenesis, folding, proteolytic removal and prevention of aggregation, the principal reactions of protein homeostasis. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► Description of the relevance and principles of mitochondrial protein homeostasis. ► Mitochondrial chaperones are required for protein import and folding reactions of precursor proteins. ► Stabilization and refolding of damaged polypeptides by chaperones maintain mitochondrial functions under stress conditions. ► Degradation of damaged polypeptides by ATP-dependent proteases avoids the accumulation of protein aggregates.
Keywords: Mitochondrion; Protein homeostasis; Quality control; Chaperone; Protease;
The retrograde response: When mitochondrial quality control is not enough by S. Michal Jazwinski (400-409).
Mitochondria are responsible for generating adenosine triphosphate (ATP) and metabolic intermediates for biosynthesis. These dual functions require the activity of the electron transport chain in the mitochondrial inner membrane. The performance of these electron carriers is imperfect, resulting in release of damaging reactive oxygen species. Thus, continued mitochondrial activity requires maintenance. There are numerous means by which this quality control is ensured. Autophagy and selective mitophagy are among them. However, the cell inevitably must compensate for declining quality control by activating a variety of adaptations that entail the signaling of the presence of mitochondrial dysfunction to the nucleus. The best known of these is the retrograde response. This signaling pathway is triggered by the loss of mitochondrial membrane potential, which engages a series of signal transduction proteins, and it culminates in the induction of a broad array of nuclear target genes. One of the hallmarks of the retrograde response is its capacity to extend the replicative life span of the cell. The retrograde signaling pathway interacts with several other signaling pathways, such as target of rapamycin (TOR) and ceramide signaling. All of these pathways respond to stress, including metabolic stress. The retrograde response is also linked to both autophagy and mitophagy at the gene and protein activation levels. Another quality control mechanism involves age-asymmetry in the segregation of dysfunctional mitochondria. One of the processes that impinge on this age-asymmetry is related to biogenesis of the organelle. Altogether, it is apparent that mitochondrial quality control constitutes a complex network of processes, whose full understanding will require a systems approach. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► The retrograde response compensates for mitochondrial dysfunction accumulating over a cell's lifetime. ► Autophagy and mitophagy provide mitochondrial quality control. ► Age-asymmetry in segregation of dysfunctional mitochondria is another quality control mechanism. ► Mitochondrial quality control constitutes a complex network of processes that requires a systems approach to understand fully.
Keywords: Yeast; Autophagy; Mitophagy; Age-asymmetry; Ceramide signaling; Replicative life span;
Signaling the mitochondrial unfolded protein response by Mark W. Pellegrino; Amrita M. Nargund; Cole M. Haynes (410-416).
Mitochondria are compartmentalized organelles essential for numerous cellular functions including ATP generation, iron-sulfur cluster biogenesis, nucleotide and amino acid metabolism as well as apoptosis. To promote biogenesis and proper function, mitochondria have a dedicated repertoire of molecular chaperones to facilitate protein folding and quality control proteases to degrade those proteins that fail to fold correctly. Mitochondrial protein folding is challenged by the complex organelle architecture, the deleterious effects of electron transport chain-generated reactive oxygen species and the mitochondrial genome's susceptibility to acquiring mutations. In response to the accumulation of unfolded or misfolded proteins beyond the organelle's chaperone capacity, cells mount a mitochondrial unfolded protein response (UPRmt). The UPRmt is a mitochondria-to-nuclear signal transduction pathway resulting in the induction of mitochondrial protective genes including mitochondrial molecular chaperones and proteases to re-establish protein homeostasis within the mitochondrial protein-folding environment. Here, we review the current understanding of UPRmt signal transduction and the impact of the UPRmt on diseased cells. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► Mitochondrial protein homeostasis is maintained by localized chaperones and proteases. ► Mitochondrial protein folding capacity can be adjusted by the mitochondrial UPRs. ► Mitochondrial UPRs are mitochondrial-to-nuclear stress signaling pathways. ► Mitochondrial dysfunction and stress responses are linked to aging and cancer.
Keywords: Mitochondria; UPR; Molecular chaperones; Proteases; Signaling; Protein homeostasis;
Staying cool in difficult times: Mitochondrial dynamics, quality control and the stress response by Timothy E. Shutt; Heidi M. McBride (417-424).
One of the critical problems with the combustion of sugar and fat is the generation of cellular oxidation. The ongoing consumption of oxygen results in damage to lipids, protein and mtDNA, which must be repaired through essential pathways in mitochondrial quality control. It has long been established that intrinsic protease pathways within the matrix and intermembrane space actively degrade unfolded and oxidized mitochondrial proteins. However, more recent work into the field of quality control has established distinct roles for both mitochondrial fragmentation and hyperfusion in different aspects of quality control and survival. In addition, mitochondrial derived vesicles have recently been shown to carry cargo directly to the lysosome, adding further insight into the integration of mitochondrial dynamics in cellular homeostasis. This review will focus on the mechanisms and emerging questions concerning the links between mitochondrial dynamics and quality control. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► Mitochondrial dynamics are essential for quality control. ► Hyperfusion protects cells transiently against stress and cell death. ► MDVs transit to the lysosome for degradation during cellular stress.
Keywords: Mitochondrial dynamics; Fusion; Fission; Mitophagy; Vesicle; Quality control;
Plastid-to-nucleus communication, signals controlling the running of the plant cell by Juan de Dios Barajas-López; Nicolás E. Blanco; Åsa Strand (425-437).
The presence of genes encoding organellar proteins in both the nucleus and the organelle necessitates tight coordination of expression by the different genomes, and this has led to the evolution of sophisticated intracellular signaling networks. Organelle-to-nucleus signaling, or retrograde control, coordinates the expression of nuclear genes encoding organellar proteins with the metabolic and developmental state of the organelle. Complex networks of retrograde signals orchestrate major changes in nuclear gene expression and coordinate cellular activities and assist the cell during plant development and stress responses. It has become clear that, even though the chloroplast depends on the nucleus for its function, plastid signals play important roles in an array of different cellular processes vital to the plant. Hence, the chloroplast exerts significant control over the running of the cell. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.► Plastids emit signals that regulate nuclear gene expression. ► Tetrapyrroles, phosphonucleotides and peptides are potential plastid signals. ► Changes of the redox state of PET and accumulation of ROS trigger plastid signaling. ► Plastid signals play important roles in a wide range of cellular processes. ► Chloroplasts play a critical role as sensors of changes in the growth environment.
Keywords: Signaling; Retrograde; Plastids; Stress; Redox; Photosynthesis;