Schwann cells (SCs) are the main glial cell type of the peripheral nerves, where they closely associate with axons (for review, see Wilson et al., 2021). Many axons extend very far from neuronal cell bodies, preventing fast delivery of essential cellular substrates. Therefore, SCs are believed to provide essential trophic and metabolic support to nearby axons (Nave, 2010). In addition, SCs identify axons larger than 1 μm in diameter and wrap them in multiple layers of a specialized membrane extension known as myelin. The myelin sheath reduces the capacitance of the axonal membrane, and its discontinuous structure enables ‘saltatory conduction’, whereby ionic exchanges are concentrated in small myelin-free regions called nodes of Ranvier. The importance of SCs is evident from the great variety of inherited and acquired peripheral neuropathies that arises when these cells are impaired (England and Asbury, 2004).

Myelin is intuitively perceived as a stable structure, which can be exemplified by the remarkable discovery of preserved myelin ultrastructure in a 5000-year-old ice man (Hess et al., 1998). This notion of stability was initially confirmed by studies investigating the turnover of myelin components in brain, with many myelin proteins and lipids showing half-lives of months (Smith and Eng, 1965; Fischer and Morell, 1974). Nevertheless, even early studies were quick to point out that some of the myelin components had much faster turnover rates (Singh and Jungalwala, 1979; Sabri et al., 1974; Hayes and Jungalwala, 1976), suggesting that portions of the myelin (especially its non-compact regions) could be more dynamic. Furthermore, we now know that maintenance of the myelin structure is not passive, requiring sustained expression of the transcription factors EGR2 (also known as Krox20) (Decker et al., 2006) and SOX10 (Bremer et al., 2011) in SCs, as well as continuous synthesis of myelin proteins (Meschkat et al., 2020) and lipids (Zhou et al., 2020) in brain.

Recently, mitochondria and cell metabolism were also implicated in myelin formation and maintenance in SCs. We reported that ablation of the primarily mitochondrial protein prohibitin 1 (Phb1) in SCs greatly impairs myelin maintenance in the PNS (Della-Flora Nunes et al., 2021). In addition, SC-specific deletion of the mitochondrial transcription factor Tfam (Viader et al., 2011), the respiratory chain component Cox10 (Fünfschilling et al., 2012), the metabolic regulator Lkb1 (Beirowski et al., 2014; Pooya et al., 2014; Shen et al., 2014), the nicotinamide mononucleotide synthetizing enzyme Nampt (Sasaki et al., 2018), or the nutrient-sensing O-linked N-acetylglucosamine transferase Ogt (Kim et al., 2016), all lead to peripheral neuropathy phenotypes in mice. Nonetheless, the mechanisms linking mitochondrial dysfunction to impaired myelin maintenance in SCs remain poorly understood.

Two interesting candidate pathways that may be activated in the context of mitochondrial dysfunction in SCs are mTORC1 and c-Jun. The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates cellular growth and catabolism/anabolism rate according to the availability of nutrients and other cellular resources (Saxton and Sabatini, 2017). Functionally, mTOR exerts its activity in protein complexes known as mTOR complex 1 (mTORC1) and mTORC2, with mTORC1 being more widely studied. In SCs, mTORC1 plays a dual role: its high activity during development regulates SC proliferation and prevents premature differentiation, while its low but continuous activity in myelinating SCs drives myelin sheath growth (Beirowski et al., 2017; Figlia et al., 2017; Jiang et al., 2018). mTORC1 phosphorylates several substrates, among which are the extensively studied 4E-BP1 and ribosomal protein S6 kinase (S6K). S6K, in turn phosphorylates many other proteins, the first identified being the 40S ribosomal protein S6. Through phosphorylation of its targets, mTORC1 exerts many functions (for review, see Saxton and Sabatini, 2017), including: 1. Regulation of global translation levels; 2. Modulation of the metabolism of glucose, glutamine and lipids; 3. Suppression of autophagy; 4. Control of cell size. In SCs, the specific downstream targets of mTORC1 have seldomly been explored, but S6K seems to mediate the developmental suppression of EGR2, preventing precocious SC differentiation (Figlia et al., 2017). mTORC1 is also temporarily activated after nerve injury to induce expression of c-Jun (an AP-1 transcription factor) (Norrmén et al., 2018). c-Jun is the master transcription factor orchestrating the transdifferentiation of SCs to a repair phenotype that mounts a response favoring axon regrowth, tissue reinnervation and clearance of myelin debris (Jessen and Mirsky, 2019). In the case of myelinating SCs, this transdifferentiation process involves myelin removal followed by its autophagic degradation (myelinophagy) (Gomez-Sanchez et al., 2015). This, associated to the fact that enforced Jun expression is sufficient to trigger demyelination (Fazal et al., 2017), raises the possibility that c-Jun and mTORC1 may play a role in the dismantling of myelin in the context of peripheral neuropathies.

Here we report that mice lacking Phb1 in SCs (Phb1-SCKO) activate a response involving c-Jun and the mTORC1 pathway, possibly directly downstream of the mitochondrial damage. In addition, both c-Jun and mTORC1 seem to participate in the demyelination process in Phb1-SCKO animals. Moreover, inhibition of mTORC1 using rapamycin is able to partially rescue morphological and functional aspects of the phenotype of Phb1-SCKO mice. These results reveal a previously unknown mechanism that contributes to myelin loss secondary to SC mitochondrial damage. Furthermore, our findings implicate c-Jun and mTORC1 in the SC adaptation to mitochondrial dysfunction, raising the possibility that c-Jun and mTORC1 may also be involved in the response to mitochondrial damage in other cell types.

About a third of all patients with mitochondrial genetic disorders develop peripheral neuropathies (Pareyson et al., 2013). Most commonly, these patients show axonal degeneration, but, when demyelination is present, the alterations in mitochondrial morphology concentrate in SCs rather than axons (Ino and Iino, 2017). Moreover, many recent reports demonstrate the importance of SC mitochondria in myelin homeostasis in the PNS (Viader et al., 2011; Fünfschilling et al., 2012; Niemann et al., 2014; Wang et al., 2016; Della-Flora Nunes et al., 2021). Nevertheless, the SC adaptations to mitochondrial dysfunction and the connection to demyelination remain incompletely understood.

Here, we report on a new mechanism involving mTORC1 and c-Jun that could provide a link between mitochondrial dysfunction in SCs and demyelination. Ablation of the mitochondrial protein PHB1 in SCs in mice results in continuous upregulation of c-Jun and downstream targets of mTORC1. Moreover, we demonstrate that mTORC1 can be activated in vitro by direct inhibition of mitochondrial function with oligomycin or antimycin, while c-Jun is associated with mitochondrial loss in SCs in vivo. This supports the hypothesis that c-Jun and mTORC1 are involved in the SC adaptation to mitochondrial damage. The c-Jun N-terminal Kinase (JNK) signaling pathway has been reported to modulate mitochondrial respiration and production of reactive oxygen species (ROS) (Win et al., 2014; Chambers and LoGrasso, 2011), while mTORC1 is a well-known regulator of metabolism and mitochondrial function (Ramanathan and Schreiber, 2009; de la Cruz López et al., 2019). Therefore, it is possible that mTORC1 and c-Jun also participate in the response to mitochondrial damage in other cells types. In fact, c-Jun was suggested to be involved in the activation of the mtUPR in COS-7 cells (Horibe and Hoogenraad, 2007), while mTORC1 was shown to participate in the response to mitochondrial dysfunction in muscle (Khan et al., 2017) and mouse embryonic fibroblasts (Hardy and Pryde, 2020).

Interestingly, we identified a consistent upregulation of 4E-BP1 and S6 (two downstream effectors of the mTORC1 pathway) during situations of mitochondrial dysfunction. To our knowledge, the consequences of overexpression of these proteins in SCs has not been explored. However, overexpression of 4E-BP1 is neuroprotective in neuronal cultures treated with brefeldin A, rotenone, maneb, or paraquat (Dastidar et al., 2020), compounds known to affect mitochondrial function (Drechsel and Patel, 2008). Importantly, these neuroprotective effects are believed to be mediated by activation of the mtUPR downstream of 4E-BP1 (Dastidar et al., 2020). Moreover, upregulation of 4E-BP1 is protective in pancreatic islet cells in a context of ER stress in different models of diabetes (Yamaguchi et al., 2008). 4E-BP1 is also overexpressed in a multitude of cancer types, inhibiting the pro-oncogene eIF4E, but also favoring tumorigenesis, especially in the context of cellular stress (Musa et al., 2016). Similarly, S6 is commonly upregulated in tumors, which can be important for tumor progression (Hagner et al., 2011; Chen et al., 2015). Therefore, it is possible that 4E-BP1 and S6 levels play a role in the adaptation of cells to stress.

The mechanism activating mTORC1 and c-Jun downstream of mitochondrial damage is still unknown, but we demonstrated that it is not likely to involve the Akt/PI3K pathway (because phosphorylation of Akt and of mTOR are not altered in Phb1-SCKO mice) or the ISR (since treatment of Phb1-SCKO mice with ISRIB only led to minor changes in the mTORC1 and c-Jun pathways). Even though we favor an indirect role of PHBs on the activation of the mTORC1/c-Jun axis, we cannot rule out a direct interaction. Supporting this idea, PHB2 was found to be a putative mTORC1 interactor in human T lymphoblasts (CCRF-CEM) and human embryonic kidney (HEK293) cells (Rahman et al., 2014), while PHB1 was found to bind to the mTOR inhibitor FK506 binding protein 8 (FKBP8) in different cell lines (Zhang et al., 2021), to inhibit c-Jun N-terminal kinase (JNK) signaling in cancer cell lines (Yang et al., 2019) and to stimulate c-Jun expression in cells of the colon of a mouse model of colitis (Kathiria et al., 2013). It is worth noting that, although PHBs are mostly found in the mitochondria, they can be present in the cytosol and nucleus of some cells in specific conditions (Thuaud et al., 2013), which could allow them to directly interact with transcription factors and signaling cascades.

SCs present a remarkable plasticity that endows peripheral nerves with the capacity to recover from a variety of insults. After nerve injury, myelinating and non-myelinating SCs convert to a repair-promoting phenotype, allowing degradation of myelin and cell debris and stimulating axon survival and regrowth. Later, these SCs can also differentiate to form new myelin. This entire process is controlled by the transcriptional regulator c-Jun, whose upregulation requires activation of mTORC1 (for review, see Jessen and Mirsky, 2019). Given this particular biology of SCs, we hypothesized that activation of mTORC1 and c-Jun in the context of mitochondrial damage could inadvertently induce demyelination in Phb1-SCKO mice. In line with this hypothesis, we found a strong association between demyelination (identified by the presence of myelin ovoids) and overactivation of c-Jun or mTORC1 in these animals. Moreover, deletion of c-Jun in SCs reduced the demyelination in Phb1-SCKO mice, but also seemed to exacerbate the developmental defects observed in these animals. On the other hand, treatment of Phb1-SCKO mice with the mTORC1 inhibitor rapamycin resulted in an important rescue in nerve morphology, while also providing a significant functional benefit in nerve conduction velocity. Thus, both c-Jun and mTORC1 seem to participate in the demyelination process of Phb1-SCKO mice.

Interestingly, c-Jun and mTORC1 have also been implicated in other peripheral neuropathies. mTORC1 overactivation may be involved in the focal hypermyelination observed in Charcot–Marie–Tooth disease types 4B1 and 4B2 (CMT4B1 and CMT4B2) (Sawade et al., 2020), while rapamycin treatment is able to ameliorate myelination defects in a mouse model of CMT1A (Nicks et al., 2014). On the other hand, c-Jun was found to be upregulated in nerve biopsies from patients affected by a variety of peripheral neuropathies (Hutton et al., 2011). Hence, c-Jun and mTORC1 may underlie key aspects of nerve pathology. Although outside the scope of the current work, one important facet of the pathogenesis of peripheral neuropathies is the impaired trophic support from SCs to axons. c-Jun was shown to be required to prevent loss of sensory axons in a mouse model of CMT1A (Hantke et al., 2014), while mTORC1 is crucial to trigger a metabolic shift in SCs that supports axonal integrity in the context of acute and subacute nerve injury (Babetto et al., 2020). Therefore, mTORC1 and c-Jun may have opposite effects in the SC functions of myelin maintenance and axonal support, and it would be premature to conceive therapeutics targeting these pathways for peripheral neuropathies. From our results, it seems that the main beneficial effect of rapamycin on Phb1-SCKO mice is in preventing their demyelination, while deficits in axonal integrity are not altered (analysis from electron micrographs) or are only minimally improved (quantifications from semithin sections) by this treatment.

It is unlikely that c-Jun and mTORC1 are the only pathways involved in demyelination in response to mitochondrial damage in SCs, but we believe they may form an important hub controlling this process together with the ISR. Our pharmacological and genetic approaches revealed that c-Jun, mTORC1, and ISR are interconnected, with mTORC1 playing a central role and possibly modulating the other two pathways (Figure 8). An interesting hypothesis that we would like to explore in the future is that the global control of translation is a key response in SCs downstream of mitochondrial damage. ISR and mTORC1 (in particular its 4E-BP1 arm) are two of the most important pathways regulating cellular translation rates. Activation of the ISR through phosphorylation of eIF2α inhibits global translation and simultaneously promotes the expression of stress response genes in a response coordinated by ATF4. On the other hand, mTORC1 phosphorylates 4E-BP1 relieving its inhibition of eIF4E and promoting translation (Ryoo and Vasudevan, 2017). Therefore, it is interesting that treatment with rapamycin (an approach that should reduce global translation levels) was able to ameliorate the demyelination phenotype of Phb1-SCKO mice, while treatment with ISRIB (an ISR inhibitor that should increase global translation levels) was detrimental for the demyelinating pathology (Della-Flora Nunes et al., 2021). Moreover, it is intriguing that ISRIB was specifically able to modulate the phosphorylation levels of 4E-BP1 and had little effect on S6. This hypothesis is particularly compelling since, in a model of CMT1B, aberrant activation of translation has already been shown to underlie demyelination in the context of ISR (D’Antonio et al., 2013).

Figure 8

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In conclusion, this study reveals that mTORC1 and c-Jun may participate in the SC response to mitochondrial damage and that long-term activation of these pathways may be detrimental for myelin maintenance in the PNS. We propose this maladaptive response as a new mechanism by which perturbations in SC mitochondria trigger demyelination. This furthers our understating of how SCs respond to mitochondrial damage and could be relevant in the context of peripheral neuropathies. The link between c-Jun, mTORC1 and ISR evaluated in our study is also likely to be relevant to other cell types, and may help to advance the general understanding of cellular adaptations elicited in response to mitochondrial dysfunction.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Gustavo Della-Flora Nunes

   1. Hunter James Kelly Research Institute, University at Buffalo, Buffalo, United States
   2. Department of Biochemistry, University at Buffalo, Buffalo, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft

   For correspondence

   gnunes@buffalo.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9323-3556

2. Emma R Wilson

   1. Hunter James Kelly Research Institute, University at Buffalo, Buffalo, United States
   2. Department of Biochemistry, University at Buffalo, Buffalo, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Writing – review and editing

   For correspondence

   ewilson5@buffalo.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8069-0173

3. Edward Hurley

   Hunter James Kelly Research Institute, University at Buffalo, Buffalo, United States

   Contribution

   Investigation, Methodology

   For correspondence

   edwardhu@buffalo.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1967-8933

4. Bin He

   Immunobiology & Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Houston, United States

   Contribution

   Methodology, Resources

   Competing interests

   No competing interests declared

5. Bert W O'Malley

   Department of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States

   Contribution

   Funding acquisition, Resources

   For correspondence

   berto@bcm.edu

   Competing interests

   No competing interests declared

6. Yannick Poitelon

   Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, United States

   Contribution

   Conceptualization, Data curation, Investigation, Methodology, Writing – review and editing

   For correspondence

   poitely@amc.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9868-1569

7. Lawrence Wrabetz

   1. Hunter James Kelly Research Institute, University at Buffalo, Buffalo, United States
   2. Department of Biochemistry, University at Buffalo, Buffalo, United States
   3. Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, United States

   Contribution

   Conceptualization, Funding acquisition, Supervision, Writing – review and editing

   For correspondence

   lwrabetz@buffalo.edu

   Competing interests

   No competing interests declared

8. M Laura Feltri

   1. Hunter James Kelly Research Institute, University at Buffalo, Buffalo, United States
   2. Department of Biochemistry, University at Buffalo, Buffalo, United States
   3. Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, United States

   Contribution

   Conceptualization, Funding acquisition, Supervision, Validation, Writing – review and editing

   For correspondence

   mlfeltri@buffalo.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2276-9182

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