The full text of this article hosted at iucr. E-mail address: ihhwang postech. Use the link below to share a full-text version of this article with your friends and colleagues. Learn more. In eukaryotic cells consisting of many different types of organelles, targeting of organellar proteins is one of the most fundamental cellular processes. Proteins belonging to the endoplasmic reticulum ER , chloroplasts and mitochondria are targeted individually from the cytosol to their cognate organelles.
As the targeting to these organelles occurs in the cytosol during or after translation, the most crucial aspect is how specific targeting to these three organelles can be achieved without interfering with other targeting pathways. For these organelles, multiple mechanisms are used for targeting proteins, but the exact mechanism used depends on the type of protein and organelle, the location of targeting signals in the protein and the location of the protein in the organelle. In this review, we discuss the various mechanisms involved in protein targeting to the ER, chloroplasts and mitochondria, and how the targeting specificity is determined for these organelles in plant cells.
The organelles present in eukaryotic cells do not have or have only a limited ability to synthesize their proteins. Therefore, they have to import proteins from other compartments. Among these organelles, proteins destined to the endoplasmic reticulum ER , peroxisomes, chloroplasts and mitochondria are targeted directly from the cytosol to these organelles during or after translation 1 - 3.
Thus, the most crucial question in organellar protein biogenesis is how proteins are specifically sorted during or after translation and delivered from the cytosol to the target organelles. In animal cells, the targeting mechanisms concern only three organelles: the ER, peroxisomes and mitochondria. In contrast, plant cells have to sort proteins between four organelles: the ER, peroxisomes, chloroplasts and mitochondria. Thus, the targeting process in the cytosol is much more complex in plant cells than in animal cells. Among the four organelles, the ER, an endomembrane compartment, is thought to be the first organelle, which in the course of evolution was derived from the plasma membrane of the host cell 4.
In the case of peroxisomes, a favorite hypothesis is that it was originated from the ER 5 , 6. For this organellogenesis to be successful, the establishment of protein targeting mechanisms to these new organelles must have been pivotal. Moreover, the origin and the exact timing of organellogenesis of these organelles must have been important factors affecting the details of the individual targeting mechanisms.
However, in the case of chloroplasts and mitochondria, the protein targeting mechanisms must have been invented in completely new ways during organellogenesis. In addition, it is likely that the current protein targeting mechanisms operating in plant cells should have been optimized during evolution since their initial establishment during organellogenesis. In this review, we compare the mechanisms of protein sorting and targeting between an endomembrane compartment, the ER, and endosymbiotic compartments, chloroplast and mitochondrion, in plant cells.
The mechanism of protein targeting to the peroxisomes is referred to the recent reviews in Refs 6 and 8. The ER has a simple structure with only a single envelope membrane and the lumen therein, whereas endosymbiotic organelles such as chloroplasts and mitochondria have a more complex structure with various suborganellar compartments such as inner envelope membrane, intermembrane space, thylakoid membrane, lumen, stroma and matrix. The central hydrophobic core of the leader sequence must possess a certain level of hydrophobicity Little restriction is placed on either the length or the primary sequence of a functional signal sequence.
Thus, the exact amino acid sequence varies greatly depending on individual proteins However, the transit peptide and presequence show little conservation in their amino acid sequence, length and secondary structure. The length of transit peptides and presequences ranges from 13 to and 18 to amino acids, respectively. They show similar amino acid compositions and moreover exhibit common characteristic features such as a high content of hydroxylated serine and threonine and hydrophobic alanine, leucine, valine or phenylalanine amino acids, together with positively charged residues arginine and lysine , and a few acidic residues In contrast, the transit peptides do not possess this property.
A recent study provided an explanation for the lack of consensus sequence of the transit peptides. The hierarchical clustering of Arabidopsis authentic chloroplast proteins using the critical sequence motifs in transit peptides showed that these transit peptides can be divided into at least seven subgroups with distinctive sequence motifs, raising the possibility that the transit peptides were derived from multiple independent sequences Thus, an emerging concept is that transit peptides contain multiple sequence motifs that are distinct or have overlapping functions including interactions with cytosolic factors, envelope lipids or the SPP.
The signal sequences of luminal proteins show a clear difference in their biochemical and biophysical properties from those of the transit peptides or presequences of proteins imported into mitochondria, which is sufficient for determining the targeting specificity between the ER and chloroplasts or mitochondria, respectively. However, transit peptides and presequences show similar characteristic features in their amino acid composition.
In fact, it has been shown that chloroplast proteins can be imported into mitochondria or vice versa in vitro Despite such similarities, transit peptides or presequences are sufficient to deliver proteins correctly into either chloroplasts or mitochondria in plant cells. Currently, it is not fully understood how the protein import specificity is determined between chloroplasts and mitochondria in plant cells at the molecular level. Most of the functional studies on the SRP system have been performed on the mammalian and yeast cells. As the system is highly conserved in all eukaryotic cells, the SRP system in plant cells is likely to be similar to that in animal cells and yeast.
It recognizes the leader sequence of ER luminal proteins during translation. It has been reported that increased abundance and activity of the respiratory complex IV are part of a mitochondrial-specific signature of epithelial cancers, which mainly rely on oxidative phosphorylation for ATP production Whitaker-Menezes et al. A Top Western blot of total lysates of HEK cells transfected as indicated and bottom corresponding quantification of the relative abundances of the indicated oxidative phosphorylation complexes subunits, representing the abundance of the five oxidative phosphorylation complexes.
D Proteasomal activity in MCF7 cells transfected as indicated and analysed by flow cytometry. RFU: relative fluorescence units. F Red fluorescence of the mitochondrial potentiometric probe JC-1 in MCF7 cells transfected as indicated and analysed by flow cytometry. I Percentage of live, apoptotic and dead MCF7 cells analysed by flow cytometry and identified by the incorporation of Annexin V. Green arrows: upregulation; red arrows: downregulation.
All comparisons in L were not significant. We then analysed mitochondria-related stress levels in the presence and absence of AURKA by flow cytometry. On the contrary, the downregulation of AURKA increased the activity of the ubiquitin-proteasome system Figure 5D , which has been proposed to be a complementary system of autophagy for the degradation of selective mitochondrial proteins Zhu et al. The increased red mitoTimer was specifically due to mitochondrial turnover, as we did not detect significant reactive oxygen species variations when downregulating or over-expressing AURKA Data not shown.
Although mitochondria are depolarised after AURKA knockdown, no global effect on the mitochondrial oxygen consumption rate was observed under these conditions Figure 5H , despite both AURKA knockdown and over-expression have an impact on cell viability as previously published Figure 5I Zhang et al. In conclusion, our results indicate that AURKA maintains mitochondrial fission when expressed at physiological levels and that mitochondrial interconnectivity in the absence of AURKA is a consequence of a lack of fission.
This results in the mere accumulation of elongated mitochondria without any increase in the energetic capabilities of the mitochondrial network. These data reveal a novel role of AURKA in the control of mitochondrial bioenergetics, by acting on the mitochondrial respiratory chain and on mitochondrial functionality Figure 5M. Increased copy number of the AURKA gene region is generally associated with an aggressive disease and poor patient survival. The AURKA gene region is located on chromosome 20, and its amplification includes the enhanced expression of additional genes e.
These events are common in different cancer types as in ovarian, pancreatic, lung and colon cancers and lead to bad prognosis. For instance, the increased copy number of AURKA is associated with the evolution of colorectal polyp into carcinoma Carvalho et al. In breast cancer, the overexpression of AURKA is also linked to poor survival and it is associated with the overexpression of the human growth factor receptor 2 HER2 and progesterone receptor Nadler et al.
Our study is thus pioneer in correlating for the first time this multifaceted kinase and mitochondrial physiology. In addition to its well-characterised roles in mitosis, new functions of AURKA during interphase are regularly discovered Mori et al. Once it enters mitochondria, AURKA is cleaved in a two-step process to become a fully mature mitochondrial protein, potentially capable of interacting with multiple mitochondrial partners as the mitochondrial respiratory chain subunits. We discovered that the signal required for the import of AURKA into mitochondria is located within the first 36 amino acids of the kinase.
Conventionally, MTS are incapable of shuttling to mitochondria when fused at the C-terminus of a fluorophore Chacinska et al. The hypothesis that centrosomal proteins play additional roles at mitochondria has already been raised Moore and Golden, It has been shown that the mitochondrial protein SUCLA2, which catalyses the conversion of succinyl CoA into succinate inside mitochondria, has a mitochondrial and centrosomal double localisation in Drosophila Hughes et al. It was shown that centrosomal SUCLA2 regulates the number and the stability of centrosomes, and this raises the fascinating hypothesis that mitochondrial proteins could in turn play roles at the centrosome under certain conditions e.
Given that AURKA is preferentially a centrosomal protein now shown to directly regulate mitochondrial functions, it is tempting to speculate that this mitochondria-to-centrosome crosstalk could also work in a retrograde manner from the centrosome to mitochondria, with centrosomal proteins as AURKA also regulating mitochondrial functions. In this light, it will be interesting to explore whether the centrosomal and mitochondrial pools of AURKA are spatiotemporally connected.
To this end, further studies are required to establish the exact molecular mechanisms that allow the first 36 amino acids of AURKA to act as a MTS only when bound to the rest of the protein. Proteins regulating energy metabolism in the cell, including multiple subunits of the mitochondrial respiratory chain, were found to significantly interact with AURKA at interphase Supplementary file 2 , Figure 5—figure supplement 1. This strongly supports a role of AURKA in the control of the mitochondrial respiratory chain functionality.
It is known that an interconnected mitochondrial network favours ATP production through mixing of the intramitochondrial content, which also counteracts the effects of deleterious mtDNA mutations in vivo Nakada et al. Interconnected mitochondrial networks have been proposed to act as energy-transmitting cables, delivering energy to parts of the cell in which oxygen for mitochondrial respiration is low Westermann, Mitochondrial fusion is also stimulated in selected stress conditions as starvation, helping the cell to cope with increasing energy demands Tondera et al.
The over-expression of AURKA represents a mitotic stress paradigm with centrosome abnormalities, chromosome misalignment, aberrant DNA inheritance at cell division and apoptosis Zhang et al. Therefore, it is not surprising that mitochondria under these conditions modify their functionality beyond mitosis as well, adapting to stress by increasing their connectivity and the production of ATP during interphase. On the contrary, the increased mitochondrial connectivity observed in the absence of AURKA or when the kinase is pharmacologically inhibited does not lead to an increased ATP production.
However, the connectivity of the mitochondrial network under these conditions resembles the one observed when AURKA is overexpressed. As AURKA drives mitochondrial fission when expressed at physiological levels, the absence of AURKA or the inhibition of its catalytic activity lead to the appearance of interconnected mitochondrial networks.
In the absence of an active AURKA, the paradigms regulating mitochondrial fission are therefore limited and fusion remains the only mechanism left to regulate mitochondrial morphology, as previously proposed in conditions of fission inhibition Hoitzing et al. In this light, we indeed demonstrate that the molecular mechanisms used by AURKA to regulate mitochondrial dynamics are distinct according to the expression levels of the kinase. In conclusion, the modifications induced by AURKA to mitochondrial morphology are multifaceted and, in this context, the simple interconnectivity of the mitochondrial network is not a direct readout of the energetic capabilities of mitochondria.
Nevertheless, the physical interaction of the kinase with multiple components of the mitochondrial respiratory chain, located on the Inner Mitochondrial Membrane, would require the kinase to be imported into mitochondria to ultimately promote ATP production.
Of note, increased S-OPA1 is a previously characterised hallmark of augmented mitochondrial respiratory chain activity Mishra et al. However, further studies are required to understand how AURKA spatiotemporally interacts with its multiple partners and if different sub-mitochondrial pools of AURKA are capable of driving changes in mitochondrial morphology and in energy production.
Through this modification, RALA can shuttle to mitochondria to ensure the correct segregation of these organelles to daughter cells.
First, the kinase is imported into mitochondria regardless of RALA. Although we demonstrated the existence of two different pathways taken by AURKA, further studies are necessary to better characterise their molecular players and their potential interplay.
Mitochondria with high metabolic capacity might escape turnover through fusion mechanisms and thus sustain the high metabolic needs of cancer cells, potentially representing a selective advantage for epithelial cancer progression. Targeting mitochondrial hyperfunctionality together with AURKA inhibition might therefore represent an innovative approach in the development of anti-cancer treatments.
Subsequent mechanisms leading to the export of AURKA in the cytosol after mitochondrial cleavage remain to be elucidated. All restriction enzymes were purchased from Thermo Fisher Scientific. All cloning reactions were verified on a XL sequencer Applied Biosystems. All site-directed mutagenesis reactions were performed by QuickChange site-directed mutagenesis Stratagene.
The complete list of plasmid used in the study is reported in Supplementary file 3. Cells were harvested, fixed or imaged 48 hr after transfection unless otherwise indicated. Following molecular validation by sequencing, the pBFv-U6. AurA 3A is a 7 bp deletion encoding a aa protein containing the first aa of AurA.
The remaining strains used in this study are listed in Supplementary file 4. All crossings and the corresponding Fig. All images collected in this study were acquired from epithelial cells of the dorsal thorax notum at room temperature. Isolated mitochondrial fractions were obtained by differential centrifugation as previously described Bertolin et al.
Protein purification and in vitro kinase assays were performed as described in Bertolin et al. Dot-blot filter retardation assays were performed in a well BioDot microfiltration unit Bio-Rad using a 0. The list of primary antibodies is in Supplementary file 6. Secondary horseradish-peroxidase-conjugated antibodies anti-mouse and anti-rabbit were purchased from Jackson ImmunoResearch Laboratories; anti-rat antibodies were purchased from Bethyl Laboratories.
The membranes were incubated with commercially available Pierce or homemade enhanced chemiluminescence substrate as described in Bertolin et al. The relative abundance of specific bands of interest was calculated by normalising it towards the abundance of loading controls and indicated in each graph. Cells were trypsinised, resuspended in growth medium, and placed in the respiratory chamber of an Oroboros Oxygraph-2k WGT. The respiration reserve capacity was calculated by subtracting the basal respiration from the maximal respiration.
Precursor mass tolerance was set to 2 ppm and the fragment mass tolerance was set to 0. A semi-specific trypsin digestion setting allowing for N- or C-ragged peptides was specified. All peptide spectrum matches corresponding to AURKA peptides identified by Byonic were extracted from the peptide dataset for the identification of putative mitochondrial processing peptidases cleavage sites into AURKA. The number of occurrences of each non-tryptic cleavage sites was calculated and plotted relative to AURKA amino acid sequence.
Multicolour images of cultured cells were acquired with a Leica SP8 inverted confocal microscope Leica and a 63X oil-immersion objective NA 1. MitoDendra2 photoconversion was performed on a region of interest ROI with a nm laser at 0. The total number of red objects present s after photoconversion was normalised to the number of red objects in the ROI in the first image obtained after the photoconversion procedure 5 s. Mitochondrial aspect ratio and form factor were calculated from confocal images as in Koopman et al. For conventional electron microscopy, the cells were rinsed with 0.
After fixation, the cells were rinsed several times with 0. Ultra-thin sections of 80 nm were then cut from the blocks using a UCT ultramicrotome Leica , placed on grids, and post-stained with uranyl acetate for 30 min and with lead citrate for 20 min. After solidification on ice, the cell blocks were cut and immersed in 2. The blocks were then mounted on a pin holder and placed in a UC7 cryo-ultramicrotome Leica.
The grids were subjected to standard immunolabelling procedures Slot and Geuze, ; Griffiths et al. The combinations of primary and secondary antibodies used are listed in Supplementary file 7. Mitochondrial length, lysosomal abundance and number of gold beads were scored using the ImageJ software. Analyses of autophagy, apoptosis, mitochondrial membrane potential and proteasome peptidase activity were performed on a BD Accuri C6 flow cytometer BD Biosciences. Mitochondrial inner membrane potential was measured with the JC-1 probe Thermo Fisher Scientific as previously described Agier et al.
Statistical tests were performed after testing data for normality. Two-way ANOVA and the Holm-Sidak method were used to compare the the effect of siRNAs and AURKA isoforms on the relative mitochondrial abundance of AURKA Figure 1C , Figure 1—figure supplement 3E , the effect of the pharmacological treatment and the mitochondrial respiratory parameter on mitochondrial respiration Figure 5L the effect of pharmacological treatment and the fluorescence protein on lifetime Figure 2D , the effect of pharmacological treatment and transfection conditions on TMRM fluorescence Figure 5G , the effect of time and transfection conditions or Drosophila genotypes on the number of mitoDendra2 red objects Figure 3B , Figure 3—figure supplements 4B—D and 5 and the effect of the pharmacological treatment and the cell line on mitochondrial aspect ratio and form factor Figure 4B.
Alpha for statistical tests used in this study was equal to 0. In the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included. The first decision letter after peer review is shown below. Thank you for submitting your work entitled "Aurora kinase A localises to mitochondria and modifies mitophagy and energy production when over-expressed" for consideration by eLife.
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As you will see, while the reviewers found the subject interesting, they found the study to be preliminary, making its interpretation confusing. The main problem we had was there was a lack of mechanistic insight about what substrate Aurora kinase A AURKA would phosphorylate to alter mitochondria function and turnover. Moreover, there was concern about the AurA localization at mitochondria, which changes in different pictures in the manuscript and is not supported in other studies cited below and in a recent BioRxiv pre-print, which we do not use to compare but mention here for your interest , something that live imaging may better address.
Without a clear understanding of where AurA dynamically localizes and what it signals to in mitochondria, it is hard to clearly determine whether it has a primary role in mitochondria fission or secondary function from its role in mitosis. Unfortunately, at present, the model proposed is speculative and not sufficiently supported by the data. The manuscript by Bertolin et al. While previous roles for AURKA have focused predominantly on its role in mitosis regulation, this paper represents an important departure indicating its role in controlling mitochondrial form and function.
They show that AURKA gets imported and cleaved at mitochondria and its loss through knockdown disrupted mitochondrial turnover and function, leading to longer mitochondria. Because increased AURKA and an activating mutation are frequent in cancer, they next examined how overexpression or expression of the mutant affects mitochondria and found that it promotes increased respiration, and fusion, while reducing the overall total mass of cellular mitochondria. This study is very interesting suggesting a new role for AURKA on mitochondrial function and turnover, which may have important implications for its overactivation in cancer cells.
This may go beyond the depth of this study, however, it makes the findings that both overexpression and loss of AURKA lead to longer mitochondria somewhat confusing. It would be useful at least in the Discussion to address how both loss and gain of function could lead to similar phenotypes.
Does this mean that normally, AURKA is controlling mitochondrial quality by degrading non-functional mitochondria but when overexpressed it increases fusion of functional mitochondria. This point is interesting but confusing. How common is it? Is it an indicator of poor prognosis or restricted to certain types of cancers? Do you see similar mitochondrial hallmarks in these cancers or do other mutations alter the phenotypes?
This paper reports the association of AURKA, which is often amplified in particular types of cancer, with mitochondrial. The authors claim that AURKA is active in the mitochondrial matrix and alters a host of mitochondrial parameters with either depleted or overexpressed. The author's data is interpreted to indicate "functional", physical and direct interactions with a variety of diverse proteins involved in mitochondrial dynamics and electron transport chain function.
AURKA within the mitochondria is also associated with alterations in rates of mitophagy. In my opinion, the data described here is not really believable nor is its physiological significance clearly demonstrated. Even this conclusion seems dubious. Although there could of course be proteins that are mitochondrial that have been missed as being mitochondrial, the absence of AURKA in combination with the absence of a clear mitochondrial targeting sequence in its N-terminus raises questions.
One possibility for the processing seen in extracts is that cell lysis results in release of the protease from the mitochondria that has the ability to cleave AURKA, a possibility that wasn't tested. It is hard to see, given how the translocon and mitochondrial target sequences work, that this construct would be successfully imported into mitochondria and cleaved by PMPCB.
Many of these assays end up being descriptive, and they paint a bewilderingly complex interplay between AURKA and mitochondria, which makes it hard to put any specific finding into a logical biological process. They apparently have no negative controls and try to make the conclusion that because certain mitochondrial proteins are detected, that they are likely real and direct. It is well known that the vast majority of proteins present on anti-GFP resin are non-specific binders, but they haven't tried to control for this. So ultimately, they do not rigorously demonstrate that the proposed interactions with proteins that are both in the inner membrane and function at the outer membrane during fission are specific or not.
Thus, there are no experiments to demonstrate the absence of off target effects for any individual RNAi reagent. Given that many of the effects are small, it is conceivable that some of the conclusions drawn are based on off-target effects. Additionally, in Figure 3 the authors conclude that high levels of AURKA lead to increases in Complex IV, but no substantial changes in other electron transport chain complexes. One would think there would be opposite activities. The physiological significance of most of the measurements in this figure isn't clear. Many of the conclusions just don't make sense and could result from overexpression effects.
Does this suggest that there are no lysosomes, for example? The authors do not look any further than this but make the conclusion that AURKA regulates autophagy — a complete non-sequiter. They claim they use accepted assays but this really isn't the case. The TEM assay is very difficult to quantify, and overall they are looking at very small numbers of cells and trying to make conclusions. Both of these assays are highly used in the field. Based on these and many other issues with the paper, I cannot support publication in eLife.
I think a much more rigorous analysis would need to be done. The structure of those small noncoding RNA are close to the microRNA so that the researchers wonder that if the putative small noncoding RNA serve as a potential regulator of the nuclear functionthrough a microRNA-like mechanism [ , ] Fig.
The theory of noncoding RNA as a new regulator in nuclear and mitochondria communication is beginning to emerge; most studies have focused on long noncoding RNA lncRNA. LncRNA regulates nuclear and mitochondria communication. Nuclear-encoded lncRNA are transmitted into the mitochondria and coordinate mitochondria-induced apoptosis [ , ], mitochondria metabolism, and mitochondria biogenesis. In contrast, lncRNA encoded by the mitochondria modulate nuclear genome reprogramming.
Mitochondrial DNA. Mitochondrial gene expression [ ]. Unknown [ ]. Bending nuclear DNA? Nuclear DNA. EMT [ ]. Modulate mitochondria complex I [ ]. The functions of noncoding RNAs in nuclear and mitochondria communication in tumorigenesis are unclear. Based on their specific mechanisms of action, further studies should focus on identifying the targets of certain noncoding RNAs to determine their roles in tumorigenesis. However, there are still numerous mystery of the role that mitochondria might play in tumorigenesis to be solved, for example, the specific mechanism of mtDNA mutation and defects in tumorigenesis.
Despite the metabolism angle that we used to visualize the mitochondria in cancer, the organelle interplay may offer a new clue for further exploration in clinical drug design and development. Currently, we study the cell as a whole and not as a mix of different organelles.
Researchers are realizing that organelles are communicating and maintaining the cell homeostasis through their tight connection. It is universally acknowledged that the mitochondrion is the major source of energy, and its importance cannot be disputed. Therefore, it is indispensable for us to explore the interplay between the mitochondria and other organelles.
As elaborated above in this review, understanding the communication between mitochondria and the ER, peroxisome and nucleus is necessary in terms of understanding the role that mitochondria play in tumorigenesis. We regard the mitochondria a decent target in cancer treatment for the reason that the mitochondria is pivotal in the cell cycle.
Ongoing clinical trials and drug development are mainly focusing on the metabolism mechanism such as electron transport chain, TCA cycle and the Oxidative phosphorylation. Other drugs also target at the calcium buffering the signaling pathways involved in this communication. The mitochondria are a rather multifunctional organelle; hence, considering a single mechanism or focusing on a single target can be counterproductive.
For example, the use of pro-oxidants to destroy the redox balance in tumor cells promotes cell death, but it also increases the risk of normal cell canceration. The use of antioxidants reduces intracellular ROS in tumor cells, thereby weakening their mutation and invasive ability, but it also attenuates the ability of ROS to induce cell injury and apoptosis, which promotes tumor development to a certain degree.
However, studies on organelle communication are limited. Moreover, recent studies have focused on the molecular level, and thus, further investigations are needed using animal models, which would be more significant for clinical application and drug development. Therefore, considering the complexity of organelle interaction, there are still unknown molecular mechanisms that warrant further exploration. Bcllike protein IP3Rs binding protein released with IP3.
For instance, the increased copy number of AURKA is associated with the evolution of colorectal polyp into carcinoma Carvalho et al. Lysosomes are abundant in animal cells that ingest food through food vacuoles. For example, chloroplasts contain a high density of thylakoid discs and numerous grana to allow for increased surface area for the absorption of sunlight, thus producing a high quantity of food for the plant. However, we made an exception for gamma- and beta-proteobacterial proteins. Conversely, increasing oxidative damage can shorten the lifespan of mice and worms.
RNA-dependent protein kinase-like kinase. PH and SEC7 domain-containing protein. ER-mitochondrial encounter structure. RNA polymerase. G-rich RNA sequence-binding factor 1. All authors read and approved the final manuscript. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Review Open Access. Communication between mitochondria and other organelles: a brand-new perspective on mitochondria in cancer. Abstract Mitochondria are energy factories of cells and are important pivots for intracellular interactions with other organelles. They interact with the endoplasmic reticulum, peroxisomes, and nucleus through signal transduction, vesicle transport, and membrane contact sites to regulate energy metabolism, biosynthesis, immune response, and cell turnover.
However, when the communication between organelles fails and the mitochondria are dysfunctional, it may induce tumorigenesis. In this review, we elaborate on how mitochondria interact with the endoplasmic reticulum, peroxisomes, and cell nuclei, as well as the relation between organelle communication and tumor development.
Relatively stable contacts provide the basis for the interaction between ER and mitochondria to coordinate cellular biological functions, such as calcium ion calcium signaling, apoptosis regulation, ER stress response, phospholipid synthesis, and translocation of the phospholipid from the ER membrane to the mitochondrial membrane. MAMs are rich in calcium transport channels, enzymes for lipid synthesis and transport and proteins encoded by oncogenes that regulate cellular signaling pathways, and tumor suppressors. Therefore, changes in the above mechanisms may be related to the occurrence and development of cancer.
The connections between the two organelles in biogenesis, degradation, and fission Mitochondria participate in the formation of peroxisomes. In mammals, peroxisomes can be produced by asymmetric growth and division from pre-existing organelles, as well as by the fusion of pre-peroxisomes from the ER and mitochondria [ 87 , 91 ], allowing the transport of functional proteins and other compounds from the mitochondria into peroxisomes, which may be one of the reasons why peroxisomes and mitochondria have many similar functions [ 91 ] Fig.
The function of mitochondrial and peroxisomal coordination cannot be separated from the transcriptional regulation mechanism, including peroxisome proliferator-activated receptors PPARs , whose different subtypes have different tissue expression patterns and substrate specificities as well as regulate different target genes [ 91 , 92 ]. PPARs form a sub-family of nuclear hormone receptors that function as ligand-activated transcription factors to regulate various biological processes [ 93 ]. The activity of PPARs is also regulated by many transcriptional coactivators and co-repressors [ 87 , 91 ].
Anterograde regulation The nucleus controls the proteins and information transmitted to the mitochondria by anterograde regulation. Anterograde regulation reflects different stressors through the nuclear genome reprograming which modulate mitochondria biogenesis. Transcriptional control in the mitochondria involves multiple transcription factors and co-activators.
By binding to the cytochrome C promoter, NRF1 directly or indirectly regulates mitochondria biogenesis by activating genes related to OXPHO or decreasing other transcription factors such as MEF2A which is related to mitochondria biogenesis. PGC functions as a co-activator by integrating all physiologic signals and enhancing the function of other transcription factors [ , ] Fig.
The mitochondrion OXPHOS and TCA cycle involves genes that easily get damaged in tumorigenesis; however, cancer cells still rely on energy supplied by the mitochondria, in which retrograde signaling plays an important role [ 1 ].
Defects in fumarate hydratase FH increase fumarate levels in mitochondria, which activates NRF2 signaling and increases the expression of heme oxygenase HMOX1 , which is beneficial for forming colonies [ 1 , , ]. MicroRNAs are also vital in the interplay between the two organelles. For example, miRc directly enters the mitochondria and affects the transcription of its target gene, while miR affects OXPHOS in the mitochondria and accelerates carcinoma by downregulating the expression of ubiquinol-cytochrome c reductase complex assembly factor 2 [ ].
Acknowledgements Not applicable. Competing interests The authors declare that they have no competing interests. Availability of data and materials Not applicable. Consent for publication Not applicable. Ethics approval and consent to participate Not applicable. References Wallace DC. Mitochondria and cancer. Nat Rev Cancer. Role of metabolism in cancer cell radioresistance and radiosensitization methods. J Exp Clin Cancer Res. Mitochondria in neurodegeneration. Adv Exp Med Biol. Mitochondria: in sickness and in health. Prog Neurobiol.
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