Cytosolic Proteostasis Through Importing of Misfolded Proteins Into Mitochondria Review
Introduction
While unique protein quality controls exist for individual organelles, disruption of the homeostasis of i organelle can affect the function of the others (Veatch et al., 2009; Hughes and Gottschling, 2012). Therefore, advice between cellular compartments is critical for the maintenance of cellular integrity.
In contempo years, the advice between the mitochondria and the nucleus has gained much attention and is referred as the mitochondrial unfolded poly peptide response (UPRmt). In addition, stress in both the endoplasmic reticulum and the mitochondria have been found to converge on the regulation of translation through phosphorylation and attenuation of the translation elongation gene eIF2a. This response is referred as the integrated stress response (ISR). Subsequently, a articulate interconnection betwixt the UPRmt and the ISR was described. Since both of these pathways have been the topic of splendid recent reviews (Pakos-Zebrucka et al., 2016; Costa-Mattioli and Walter, 2020), they will be simply discussed briefly in the electric current review.
The UPRmt has as well been linked to the regulation of cytosolic proteostasis and in addition new pathways such equally the UPRam and mitochondria-to-cytosol stress response (MCSR) take been reported to regulate cytosolic proteostasis, but their relation to the ISR and the UPRmt remains unclear.
Proteostasis is divers as the process by which a functional and balanced proteome is maintained. In order to be accomplished, a counterbalanced proteome requires the coordination betwixt mRNA translation, protein folding and regulated proteasome degradation also every bit autophagy (Figure i). The flick that emerges from the studies described in this review is that in terms of proteostasis, mitochondrial stress simultaneously impacts translation, folding, proteasome-mediated degradation of proteins, and autophagy. Therefore, the ISR may in fact be even more integrated and extend well beyond the regulation of translation and the UPRmt to include a well-orchestrated coordination of all steps leading to counterbalanced and functional proteome.
Figure i. Schematic representation of the interactions between integrated stress response, the mitochondrial UPR and cytosolic proteostasis. Of note, while autophagy represents an important aspect of cytosolic proteostasis, to our noesis mitochondrial stress and the UPRmt activates mitophagy specifically just non the elimination of poly peptide aggregates by autophagy.
The Cross Talk Betwixt Mitochondrial Stress and Attenuation of Cytosolic Protein Translation
The ISR refers a network of stress-activated kinases that phosphorylates the eukaryotic translation initiation gene 2 (eIF2a) leading to its inactivation and attenuation of general translation. These kinases are protein kinase R (PKR), PKR-similar endoplasmic reticulum kinase (PERK), heme-regulated eIF2a kinase (HRI), and general control non-repressed kinase ii (GCN2). An array of unlike stresses activates these kinases including amino acid starvation, heme deficiencies, viral infection, and stress in the endoplasmic reticulum (Wek et al., 2006; Wek and Cavener, 2007). The attenuation of translation results in a reduction in the production of newly synthesized proteins and therefore contributes to the reestablishment of proteostasis.
However, while general translation is attenuated, selected mRNAs that comprise upstream open reading frames (uORFs) are selectively translated during ISR (Andreev et al., 2015). The transcription factors CCAAT/enhancer-bounden protein homology protein (CHOP), the original transcription factor implicated in the mitochondrial UPR (Zhao et al., 2002), activating transcription factor 4 (ATF4) and ATF5 all contain uORF in their mRNA (Jousse et al., 2001; Vattem and Wek, 2004; Watatani et al., 2008; Palam et al., 2011). Collectively, the activation of ATF4, ATF5, and CHOP leads to increased mitochondrial proteases and chaperones, increment metabolic adaptation, and reduced oxidative phosphorylation. The roles of these transcription factors in mitochondrial biology have been extensively reviewed recently (Pakos-Zebrucka et al., 2016; McConkey, 2017; Melber and Haynes, 2018; Anderson and Haynes, 2020). However, prior to the discovery of their touch on on the mitochondria, each of these transcription factors were reported to be implicated in ER stress (Zhou et al., 2008; Teske et al., 2013; Juliana et al., 2017; Yang et al., 2017). Therefore, by having distinct roles in both the mitochondria and the endoplasmic reticulum, ATF4, ATF5, and CHOP permit the reduction of stress in both organelles simultaneously (Figure 1).
In addition to CHOP, ATF4 is also straight implicated in the regulation of mitochondria proteostasis (Harding et al., 2003). Farther, the Haynes lab reported that, while reactive oxygen species (ROS) are non required for the activation of ATFS-ane (the homolog of ATF5 in C. elegans), ROS are necessary for the GCN-ii dependent phosphorylation of eIF2a. GCN-ii is a food sensor and is mainly known to be activated by starvation or amino acid depletion via deacylated tRNA (Dong et al., 2000; Zaborske et al., 2009; Perez and Kinzy, 2014). However, ROS can also stimulate GCN-ii activity past a mechanism involving the tRNA synthetase domain (Mascarenhas et al., 2008; Berlanga et al., 2010).
This suggests that these two pathways represent singled-out axes of mitochondrial unfolded poly peptide response (UPRmt). In agreement with this possibility, they constitute that deletion of GCN-2 in C. elegans increases the dependency on ATFS-1 for survival (Baker et al., 2012). Since the vast majority of mitochondrial proteins are translated in the cytosol, the regulation of mitochondrial chaperones and proteases by ATFS-1 and cytosolic protein synthesis by GCN-ii announced to complement each other in reducing mitochondrial proteotoxic stress.
The coordination of the ISR to mitochondrial proteostasis was further demonstrated past the finding that Tim17A, a subunit of the mitochondrial import translocase complex TIM23, which is required for the import of 99% of mitochondrial proteins, is degraded in a Yme1L dependent mode upon activation of the ISR (Chacinska et al., 2009; Schmidt et al., 2010; Rainbolt et al., 2013). The resulting subtract in protein import in the mitochondria activates the UPRmt and genes implicated in mitochondrial proteostasis (Figure 1; Rainbolt et al., 2013). The stress-induced degradation of Tim17A increased stress resistance in C. elegans but was found to be independent of ATFS-1, indicating that additional transcription factors induce mitochondrial proteostasis genes in C. elegans in add-on to ATFS-1 (Rainbolt et al., 2013).
Proteostatic Stress in the Intermembrane Space of the Mitochondria Promotes the Activeness of the Proteasome
While the latter study demonstrated that defect in mitochondrial proteins import due to inactivation of the Tim23 translocase complex promotes mitochondrial proteostasis, defect in mitochondrial import specifically in the inter-membrane space (IMS) of the mitochondria was shown to affect cytosolic proteostasis. Having 2 sub-compartments, the IMS and the matrix, importing proteins into the mitochondria requires a precise sorting of proteins destined to these corresponding sub-compartments. The MIA machinery is responsible for the import of proteins specifically in the IMS (Neupert and Herrmann, 2007; Chacinska et al., 2009; van der Laan et al., 2010; Endo et al., 2011). The Chacinska group performed an RNA seq assay of a yeast strain (Mia40-1int) that is defective for import of proteins in the IMS at restrictive temperature. First, they found that inhibition of IMS proteins import leads to inhibition of protein synthesis but, unlike the ISR pathway, the reduction in proteins synthesis was due to a subtract in expression of cytosolic ribosomal proteins and proteins involved in translation (Wrobel et al., 2015). This finding indicates that diverse mitochondrial stresses result in decreased cytosolic translation, although through distinct mechanisms. Second, they found that inhibition of IMS proteins import leads to activation of the proteasome (Wrobel et al., 2015). In yeast, the coordinated expression of proteasome genes is mediated by the transcription gene Rpn4 (Kruegel et al., 2011). While, the specific role of Rpn4 was not investigated in the this written report, the authors reported that the increase in proteasome activity did not correlate with an increase in the abundance of proteasome subunits. Rather, the increased activity of the proteasome was associated with increased proteasome associates (Effigy 1; Wrobel et al., 2015). The response was named the unfolded poly peptide response activated past protein mistargeting (UPRam) and is considered to be a distinct response to the UPRmt, since the UPRmt is all-time known to regulate mitochondrial proteases and chaperones.
While transcription of proteasomes subunits and assembly factors are regulated by Rpn4 in yeast, in mammals this task is mediated by Nuclear gene erythroid derived 2-related frole player i, Nrf1 also named NFE2L1 (Radhakrishnan et al., 2010; Steffen et al., 2010), which resides at the endoplasmic reticulum. Importantly Nrf1/NFE2L1 is not to exist confused with the Nuclear Respiratory Cistron-1, NRF-1, a transcription factor implicated in the UPRmt and involved in mitochondrial biogenesis but does not regulate the proteasome. When the proteasome activity is diminished, Nrf1/NFE2L1 translocates to the nucleus due to its processing by NGLY1 and DDI2 (Radhakrishnan et al., 2010; Steffen et al., 2010; Koizumi et al., 2018) to promote the transcription of proteasome genes (for a recent review Northrop et al., 2020). Interestingly, disruption of NGLY1 affects mitochondrial part (Kong et al., 2018; Yang et al., 2018) further indicating the importance of the proteasome on mitochondrial function.
The activation of the proteasome by proteostatic stress in the IMS was also reported in a mammalian cancer cell model (Papa and Germain, 2011). The Germain group conducted this report to interrogate whether the original CHOP axis of the UPRmt described by the Hoogenraad group, where overexpression of the misfolded matrix poly peptide OTCdelta was used as a model, is also activated when misfolded proteins are in the IMS rather than the matrix. They found that proteostatic stress in the IMS does not actuate CHOP and the matrix proteases and chaperones. Rather they found that stress in the IMS leads to a distinct axis of the UPRmt regulated past the estrogen receptor blastoff (ERα), a stiff transcription factor and leads to the up-regulation of proteasome activity (Figure one; Papa and Germain, 2011). Therefore, while stress in the endoplasmic reticulum activates the activeness of the proteasome via Nrf1/NFE2L1, stress in the mitochondria activates the proteasome via the ERα. While the precise mechanism by which the ERα affects the proteasome remains to be determined, inhibition of the ERα by shRNA abolishes this effect of IMS stress on the proteasome (Papa and Germain, 2011). Because that the ERα regulates the transcription of hundreds of genes, including transcription factors, but that the vast bulk of ERα binding sites are located at a great distance from its target genes (Carroll et al., 2006), the impact of the ERα on the transcription of proteasome genes may be straight or indirect. In add-on, they reported that the ERα is also necessary for the transcription of the mitochondrial biogenesis transcription factor, nuclear respiratory factor 1, NRF-1 (Papa and Germain, 2011), confirming a previous report of an estrogen receptor responsive element in the promoter of NRF-i (Ivanova et al., 2013). Importantly and as mention higher up Nrf1/NFE2L1 is a transcription factor straight regulating the proteasome but not NRF-ane. Mechanistically, they testify that mitochondrial ROS is elevated upon aggregating of misfolded proteins in the IMS and leads to the activation of the kinase Akt, which then phosphorylates and activates the ERα (Papa and Germain, 2011). The Germain group has also shown that inhibition of the ERα does non cancel the activation of CHOP past matrix stress and conversely that inhibition of CHOP does not inhibit the activation of the ERα. Based on these findings, they concluded that the UPRmt has multiple axes that regulate different cytoprotective and mito-protective outcomes (Papa and Germain, 2011).
The aforementioned group subsequently validated these findings in a disease relevant mouse model of familial ALS, where G93A-SOD1 mutant is known to accrue in the IMS (Riar et al., 2017). This study not only validated the activation of the estrogen receptor axis of the UPRmt in vivo and during disease progression, but besides revealed meaning differences in the activation of the proteasome between sexes (Riar et al., 2017). Consequent with the synergy between estrogen and Akt in the activation of the estrogen receptor, it was found that females show higher activity of proteasome than males (Riar et al., 2017).
Therefore, as with the apparent multiple mechanisms of attenuation of translation upon mitochondria stress, at least two mechanisms of proteasome activation upon mitochondria stress take been reported. However, whether these differences are conserved in divergent pathways across model systems such as yeast and C. elegans compared to mammalian cells remains to be clarified.
In addition to the findings that mitochondrial stress activates the proteasome, a written report also reported that mitochondrial stress promotes the disassembly of the 19S regulatory chapeau from the 20S catalytic core of the proteasome (Livnat-Levanon et al., 2014). The fully assembled 26S proteasome promotes the degradation of poly-ubiquitinated proteins past the recognition of ubiquitin chains, followed by deubiquitination and unfolding of proteins by the19S regulatory lid, which are then pushed into the catalytic cadre for degradation by the chymotrypsin, trypsin-like and caspase like catalytic subunits facing the catalytic sleeping room. The deposition results into pocket-size peptides that are expelled into the cytoplasm (Budenholzer et al., 2017; Collins and Goldberg, 2017, for recent reviews). In absence of the 19S regulatory lid, the 20S proteasome is unable to degrade poly-ubiquitinated proteins, nonetheless, the 20S proteasome was shown to promote the degradation of unstructured proteins and oxidized proteins (Demasi and da Cunha, 2018; Kumar Deshmukh et al., 2019, for recent reviews). Treatment with antimycin A led to increase in ROS was shown to promote the dissociation of the 19S from the 20S in yeast (Livnat-Levanon et al., 2014). Poly-ubiquitinated proteins accumulated and the action of the 20S proteasome increased following dissociation (Livnat-Levanon et al., 2014). However, this dissociation was institute to be transient and the reassembly into 26S proteasome chop-chop restored suggesting that proteasome dissociation represents a response to astute mitochondrial stress (Livnat-Levanon et al., 2014).
Collectively, these findings suggest a stiff cross-talk between mitochondrial stress and the activity of the proteasome. Based on the prove available and if these pathways are conserved in mammalian cells, the hypothesis that emerges is that the effect of mitochondrial stress on the proteasome may fluctuate and adjust with the level of stress. In presence of astute mitochondria stress, rapid and transient dissociation and aggregating of 20S proteasome is observed, which would permit for the elimination of unstructured and oxidized proteins. Under more moderate stress weather such as those observed by attenuation important in the IMS or aggregating of misfolded proteins in the IMS, proteasome assembly by the UPRam and transcription of proteasome subunits by the estrogen receptor axis of the UPRmt are observed. Increased 26S proteasome activity is expected to contribute to the emptying of accumulated mitochondrial precursors and accelerate the degradation of other poly-ubiquitinated proteins, therefore contributing to the rapid restoration of a balanced proteome. Clearly more than studies are required to examination this hypothesis as more than detailed understanding of the link between mitochondrial stress and increased proteasome activeness could pb to novel therapeutic intervention confronting proteopathies.
Mitochondrial Stress and Cytosolic Protein Folding
The Dillin group reported the results of a screen where 12 organelles specific variants of the chaperone hsp70 were inhibited genetically and the effect of their elimination of cellular proteostasis analyzed. They found that inhibition of mitochondrial hsp70 leads to the up-regulation of cytosolic hsp60 in absence of heat shock conditions and this effect was unique to mitochondrial hsp70 equally inhibition of all other xi organelle-specific variants did not induce the aforementioned result (Kim et al., 2016). Perhaps non surprisingly, inhibition of mitochondrial hsp70 induced the UPRmt and was dependent on the transcription factors atfs-ane and dve1, only more surprisingly it likewise activated the heat-daze factor ane (HSF-1), a cardinal transcription factor for the heat shock response in the cytosol (Figure i). This study also revealed a novel role of lipid biosynthesis in this response that was associated with decreased fatty acrid oxidation and increased lipid accumulation (Kim et al., 2016). Therefore, since this pathway presented unique features and embrace both the UPRmt and heat shock response (HSR), they named this response the mitochondria-to-cytosol response (MCSR) (Kim et al., 2016). Of note, the activity of the proteasome was not affected by inhibition of mitochondria hsp70 (Kim et al., 2016).
Chiefly, they too tested the bear on of MCSR on the toxicity of protein aggregates using a model of YFP poly peptide fused with 35 poly-glutamine repeats and expressed in C. elegans. They found that activation of the MCSR reduced the aggregating and toxicity of polyQ protein aggregates in skeletal muscle and improved motility in C. elegans (Kim et al., 2016).
Further support to the link between heat shock response and mitochondrial stress arises from a report from the Morimoto group, who performed a screen for genes that can restore resistance to estrus shock in 24-hour interval 2 C. elegans adults. This screen identified F29C4.2, which is orthologous to COX6C in human, a gene implicated in the electron transport chain (Labbadia et al., 2017). Inhibition of F29C4.2 activated the UPRmt and promoted the maintenance of the oestrus shock response through increased binding of HSF-i to the promoters of its target genes (Labbadia et al., 2017). No activation of the endoplasmic reticulum UPR was observed. Of notation the inhibition of F29C4.2 was institute to cause only mild mitochondrial stress (non acute) and resulted in increased longevity (Labbadia et al., 2017). This finding is in agreement with the notion that mitohormesis is associated with longevity (Neafsey, 1990; Rattan, 2008; Santoro et al., 2020). Still, the increased longevity was non dependent on atfs-1 and the UPRmt (Labbadia et al., 2017).
Farther, in understanding with the Dillin group study, the toxicity of the expression of a protein containing 44 polyglutamine repeats in the intestine of C. elegans was reduced by inhibition of F29C4.2 (Labbadia et al., 2017).
Taken together, these studies indicate that mitochondrial stress also induce the heat shock response and cytosolic chaperones, which represents another critical layer of overall cytosolic proteostasis (Figure 1).
The Integrated Stress Response and the Mitochondrial Unfolded Protein Response Also Touch Autophagy, Mitophagy
In add-on to the chaperones and the proteasome, autophagy represents an of import additional layer to maintain the cytosolic proteome. Autophagy is a well-orchestrated pathway implicating more than than thirty autophagy-related (ATG) genes. Nutrient starvation was initially shown to be the mechanism of activation of autophagy (Mizushima and Komatsu, 2011). Later on, yet, aggregating in the lumen of the endoplasmic reticulum and the UPRER was too found to activate autophagy (Deegan et al., 2013). Importantly for this review, ATF4 and CHOP, which are both implicated in the ISR, were shown to promote the transcription of several ATG genes (B'chir et al., 2013). The link between autophagy and ER stress has been recently reviewed elsewhere (Senft and Ronai, 2015).
The SIRT3 axis of the UPRmt has also been reported to actuate the transcription of several autophagy genes (Papa and Germain, 2014). Therefore, autophagy appears to represent yet another layer of cytosolic proteostasis that is activated past both the IRS and the UPRmt.
Further, link between mitochondrial dysfunction, autophagy and proteasome activity was demonstrated by the Trougakos group, who showed that subtract in proteasomal office results in astringent defects in mitochondrial function (Tsakiri et al., 2019), a finding that has been reported by several independent groups using different model systems (Pellegrino and Haynes, 2015; Llanos-Gonzalez et al., 2019). The Trougakos group also reported that enhanced mitochondrial fusion and autophagy both improved the result of proteasome dysfunction (Tsakiri et al., 2019).
Mitochondrial stress is a potent activator of mitophagy, the selective autophagy of the mitochondria. Still, since this topic has been extensively covered elsewhere, this aspect will not be further discussed in the current review.
Drugs Able to Stimulate Mitochondrial-Stress Mediated Cytosolic Proteostasis
The remarkable ability of balmy mitochondrial stress to simultaneously benumb translation, increment folding of existing proteins by consecration of the heat stupor response and simulate the 26S proteasome creates a unique therapeutic opportunity confronting proteopathies including neurodegeneration.
And so far a few drugs have been identified in this setting. While their full clinical potential and precise mechanism by which they led to activation of the UPRmt remains to be explored, they are nevertheless worth attending.
Inhibition of Mitochondrial Enzymes
Carnitine palmitoyltransferase (CPT) inhibitor perhexiline (PHX) leads to inhibition of fatty acid oxidation, CPT inhibitors are already used clinically to meliorate heart function. The Dillin lab showed that by inducing MCSR pathway, CPT inhibition by PHX reduces the accumulation of polyQ protein aggregates (Kim et al., 2016). Therefore, while these drugs stand for potential candidates for treatment of neurodegenerative diseases associated with toxic protein aggregates, considering that perhexiline inhibits Complex Iv and Complex V and moderately inhibited Complex Ii and Complex Ii and 3, which cause mitochondrial dysfunction, apoptosis and hepatoxicity (Ren et al., 2020, 2021), the toxicity of these drugs is a concern.
Doxycycline
Doxycycline promotes the inhibition of mitochondrial translation. Handling with doxycycline was constitute to actuate the UPRmt in C. elegans only not the HSR and was found to reduce amyloid beta deposits in the SH-SY5Y neuroblastoma cell line (Sorrentino et al., 2017).
Further, Doxycycline was recently shown to improve survival and reduce neuronal prison cell expiry in a mouse model of the mitochondrial disease Leigh syndrome (Perry et al., 2021). Considering that a recent clinical trial found that doxycycline did not cause major toxicity in patients (D'Souza et al., 2020), the use of doxycycline for treatment of neurodegenerative diseases appears to be feasible and rubber.
In agreement with the therapeutic potential of doxycycline, the Germain group also observed sexual activity and CNS specific regions furnishings of doxycycline on the proteasome and that doxycycline activates the ERα axis of UPRmt in the CNS (Jenkins et al., 2021, Scientific Reports, In Printing).
Raloxifene
In that location has been a long history of interest of the part of the estrogen receptor alpha (ERα) in neurodegenerative diseases peculiarly due to the observation of sex differences that characterize these diseases and because the basis of these differences are largely unknown (Zagni et al., 2016). Several drugs accept been developed to target the ERα in the context of breast cancer merely, while these drugs inhibit the ERα in the breast, they were institute to stimulate its action in the CNS (Halbreich and Kahn, 2000; Littleton-Kearney et al., 2002; Miller, 2002; Veenman, 2020). This observation raised the possibility to utilize selective estrogen receptor modulators (SERMs) equally potential therapeutic against neurodegenerative diseases. Nonetheless, the initial enthusiasm of using SERMs in this context was blunted due to their failure to improve clinical outcomes in several diseases (Rapp et al., 2003; Espeland et al., 2004; Gleason et al., 2015; Henderson et al., 2015).
Withal, a meaning oversight in the use of SERMs in these diseases is the differential result of SERMs, including tamoxifen and raloxifene, on the transcriptional activeness of the ERα (Eeckhoute et al., 2006; Lupien et al., 2008; Martinkovich et al., 2014; Jeselsohn et al., 2018) as well as the tissue specific activeness of the ERα (Eeckhoute et al., 2006; Lupien et al., 2008; Martinkovich et al., 2014; Jeselsohn et al., 2018). A comparative study recently reported the effects of estrogen, raloxifene, and tamoxifen in the spinal cord, a tissue afflicted in ALS. This study found that raloxifene specifically stimulates the ability of the ERα to promote the activeness of the proteasome and delay disease progression in a mouse model of familial ALS (Jenkins et al., 2021). Chiefly, the beneficial effect of raloxifene was observed in female mice merely not in males (Jenkins et al., 2021). This observation indicates that mimicking the activation of the ER α centrality of the UPRmt leading to stimulation of proteasome activity is besides a promising artery to stimulate cytosolic proteostasis. Further, since raloxifene is widely used clinically (Maricic and Gluck, 2002; Simpson et al., 2020) and no significant toxicity is associated with this drug, the expansion of it used against neurodegeneration appears a realistic possibility.
Resveratrol
Resveratrol, a compound derived from ruddy wine was shown to reduce accumulation of b-amyloid poly peptide, an hallmark of Alzheimer's illness. In a recent study the Wenzel group investigated the mechanism by which resveratrol mediate this consequence. They plant that resveratrol activates both the UPRER and the UPRmt in C. elegans (Regitz et al., 2016). Further, inhibition of macro-autophagy and chaperone-mediated autophagy blocked the beneficial upshot of resveratrol. Similarly, inhibition of the proteasome also blocks the effect of resveratrol (Regitz et al., 2016). However, since the beneficial effects of resveratrol are dose dependent, its clinical utilize confronting neurodegeneration remain to be determined (Jardim et al., 2018).
Concluding Remarks
The history of the discovery of the UPRmt and the ISR has been fascinating and the complexity of these pathways and the respective roles of distinct axes remain to be clearly divers. In this review, we have attempted to argue that mitochondrial stress leads to the activation of a combination of axes of these pathways that ultimately leads to a comprehensive command of cytosolic proteostasis at all levels; translation, folding and degradation by the proteasome every bit well as autophagy (Effigy 1).
Of particular interest is the observation that proteins localized to the membrane of the endoplasmic reticulum notably PERK and NRF1/NFE2L1 contribute to the maintenance of mitochondrial role by regulating the ISR and activation of the UPRmt and the directly upregulation of the proteasome, respectively. The moving picture that emerges is that similar the UPRmt, the ISR may actually consists of several axes.
The fact that drugs currently used clinically begin to emerge equally potential therapeutics against proteopaties by exerting moderate mitochondrial stress and activating cytosolic proteostasis stand for an exciting avenue for time to come research. However, the success of these drugs is likely to be tissue specific. Notably, while the expression of the mitochondria import mechanism is ubiquitous (Bauer et al., 1999), it was noted that the sensitivities to stress-regulated translation attenuation is tissue specific, and also indicated that the regulation of TIM23 may vary betwixt tissues (Rainbolt et al., 2013). Similarly, the level of expression of chaperones and the overall proteome are also highly tissue specific and can affect each other through transcellular chaperone signaling (van Oosten-Hawle et al., 2013; van Oosten-Hawle and Morimoto, 2014). A recent written report indicated that the activity of the proteasome is tissue and sexual activity -specific (Jenkins et al., 2020) supporting the notion of a broad number of different species of proteasomes (Dahlmann, 2016). Combined with the fact that the number of individual mitochondrion, as well as the wide variation in the shape and distribution of the mitochondrial network between tissues, it appears very important to apply nuanced interpretation of the results obtained in time to come investigations of the cross talk between the mitochondria and cytosolic proteostasis, thus allowing for the complexity that results from differences between sexes and tissues.
Author Contributions
DG and EJ fabricated the figure. All authors have participated in the writing of this review.
Funding
This review was funded by RO1 AG059635, RO1 NS084486, and R21 NS109913 from the National Constitute of Aging to DG.
Disharmonize of Involvement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential disharmonize of interest.
Publisher's Note
All claims expressed in this commodity are solely those of the authors and do non necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Whatever production that may exist evaluated in this commodity, or claim that may be fabricated by its manufacturer, is non guaranteed or endorsed by the publisher.
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