Age-dependent H3K9 trimethylation by dSetdb1 impairs mitochondrial UPR leading to degeneration of olfactory neurons and loss of olfactory function in

Aging is associated with a time-dependent organ dysfunction that increases the vulnerability of an organism to various forms of stress, ultimately leading to organism death ( Olofsson et al., 2021 ; Kondo et al., 2020 ; Fatuzzo et al., 2023 ; Lucke et al., 2020 ; Hussain et al., 2018 ; Pellegrino et al., 2013 ; Kim and Sieburth, 2018 ). Aging induces alterations across various physiological systems, with the olfactory system being particularly affected ( Olofsson et al., 2021 ). Olfaction, the sense of smell, is essential for detecting environmental odors crucial for feeding, reproductive and survival behaviors ( Kondo et al., 2020 ; Fatuzzo et al., 2023 ). Importantly, dysfunction in olfaction is emerging as one of the early signs of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease ( Jenkins et al., 2021 ; Couvillion et al., 2016 ; Nargund et al., 2012 ). Research on Drosophila melanogaster has shown that the age-related decline in odor response is influenced by the functional state of mitochondria in olfactory projection neurons (OPNs) ( Lucke et al., 2020 ). This decline is accompanied by defects in neuronal integrity and a decrease in synaptic proteins ( Hussain et al., 2018 ), which correlates with a reduction in mitochondria and an increase in ROS ( Hussain et al., 2018 ), but the underlying mechanisms has not been defined.

Under compromised mitochondrial integrity or function, cells engage in a transcriptional response known as the mitochondrial unfolded protein response (UPR ^MT ) ( Tian et al., 2016 ). This mitochondrial program can be activated by the impairment of the electron transport chain (ETC), alteration of mitochondrial dynamics, accumulation of unfolded proteins, reduction of mitochondrial DNA, or reduction of mitochondrial chaperones or protease ( Pellegrino et al., 2013 ; Kim and Sieburth, 2018 ; Jenkins et al., 2021 ; Couvillion et al., 2016 ). Upon UPR ^MT pathway engagement, the transcription factor ATFS-1 ( C. elegans ortholog of mammalian ATF5 and Drosophila crc) translocates from the mitochondria to the nucleus ( Fiorese et al., 2016 ; Nargund et al., 2012 ). In the nucleus, ATFS-1, DVE-1, and UBL-5 interact to reorganize the chromatin structure, enabling activation of the nuclear transcription of mitochondrial chaperones, including hsp-60 and hsp-6, and the protease clpp-1 and lonp. This coordinated transcriptional response restores mitochondrial function under stress conditions by metabolic adaptations and enhancing mitochondrial biogenesis ( Haynes et al., 2007 ; Benedetti et al., 2006 ; Tian et al., 2016 ). In mammals, the functional homolog of ATFS-1 is activating transcription factor 5 (ATF5). ATF5, like its C. elegans counterpart, contains both nuclear and mitochondrial localization signals, allowing it to shuttle between compartments depending on mitochondrial stress levels ( Fiorese et al., 2016 ), and when expressed in worms without ATFS-1, it induced hsp-60 during mitochondrial stress but not during endoplasmic reticulum (ER) stress ( Fiorese et al., 2016 ). Upon mitochondrial dysfunction, ATF5 accumulates in the nucleus. and induces the expression of HSP60, mtHSP70, LONP1 ( Fiorese et al., 2016 ) and numerous genes involved in mitochondrial biogenesis, metabolism, protein folding, and ROS detoxification ( Nargund et al., 2012 ; Wu et al., 2014 ). Notably, the Drosophila gene crc, which shares homology with both ATF5 and ATF4, is a key regulator of the UPR ^MT . While crc has been primarily characterized in the context of the ER unfolded protein response (UPR ^ER ), recent evidence suggests a broader role in cellular stress responses, including the UPR ^MT . For instance, the mammalian homolog ATF4 has been shown to regulate the UPR ^{MT 16} , suggesting a potential crosstalk between these stress pathways. Furthermore, studies have implicated crc in mitochondrial function and maintenance ( Celardo et al., 2017 ; Hunt et al., 2019 ). Although the precise mechanisms by which crc regulates the UPR ^MT in Drosophila remain to be fully elucidated, its homology to ATF5 and its involvement in mitochondrial processes strongly suggest a conserved role in mitochondrial stress response.

Chromatin remodeling is crucial for UPR ^MT regulation, with the epigenetic state of lysine 9 on histone 3 (H3K9) serving as a critical regulator of the response ( Tian et al., 2016 ; Merkwirth et al., 2016 ; Ono et al., 2017 ; Sobue et al., 2017 ). Changes in H3K9 methylation by the methyltransferase MET-2, the C. elegans ortholog of human SETDB1, modify UPR ^MT -related loci exposure, modulating binding of UPR ^MT regulators DVE-1 and ATFS-1 ( Sobue et al., 2017 ). In addition, enzymes that remove methyl groups from H3K9 significantly influence UPR ^MT activation. For example, demethylases JMJD-3.1 and JMJD-1.2 remove trimethylation from H3K9me3 and H3K27me3, enabling UPR ^MT activation ( Merkwirth et al., 2016 ; Sobue et al., 2017 ). Recent studies revealed the effects of H3K9me3 methylation on UPR ^MT activation and mitochondrial function across species. In C. elegans, the epigenetic factors BAZ-2 and SET-6, which regulate H3K9me3 levels, have conserved roles in impacting aging processes through mitochondrial function ( Yuan et al., 2020 ). In mice, deletion of Baz2b, a homologue of BAZ-2, shows beneficial effects on mitochondrial function and cognitive abilities, indicating a conserved mechanism across species that influences aging and healthspan through mitochondrial function and epigenetic regulation ( Hunt et al., 2019 ). Accordingly, in the hippocampus of aged mice, H3K9me3 levels rise with age, a change associated with age-related cognitive decline ( Snigdha et al., 2016 ). Age-related increases in H3K9me3 have also been observed in the brains of aged Drosophila and muscle stem cells of aged mice ( Wood et al., 2010 ; Schwörer et al., 2016 ). While previous research has linked changes in methylation levels to age-related functional decline, the specific role of these epigenetic alterations in the context of neuronal degeneration through reduced UPR ^MT activation capacity remains to be fully elucidated. This study aims to bridge this gap by providing detailed insights into how epigenetic mechanisms, particularly methylation changes, directly contribute to the aging-associated loss of olfactory function and neuronal degeneration by impacting the UPR ^MT pathway and mitochondrial function.

Here, we employed behavioral, molecular, and morphological methodologies to investigate whether epigenetic regulation of UPR ^MT is linked to neurodegeneration in the aging brain and its involvement in age-associated olfactory decline. To this end, we utilized the OPNs in the adult Drosophila antennal lobe (AL), which exhibit age-related neurodegeneration correlating with functional neuronal decline ( Hussain et al., 2018 ). Our results demonstrate that with aging, there is a decline in the response capacity of the UPR ^MT in OPNs, functionally associated with a dSetdb1-dependent increase in H3K9me3 levels. Genetic inhibition of dSetdb1 reduces H3K9me3 levels, enabling the activation of UPR ^MT , restoring mitochondrial oxidation to youthful levels, and preventing age-associated degeneration of OPNs. This effect is particularly evident in the somas located in the AL and the presynaptic connections of the lateral horn (LH) in the Drosophila brain. Importantly, maintaining UPR ^MT activation during aging preserved olfactory function. These findings underscore the critical role of epigenetic regulation, specifically through dSetdb1 and H3K9me3, in modulating neuronal integrity and sensory function during aging.

The UPR ^MT plays a critical role in preserving mitochondrial homeostasis ( Muñoz-Carvajal and Sanhueza, 2020 ). Therefore, any change in its activation potential, whether caused by physiological or pathological factors, could impact mitochondrial function ( Zhou et al., 2022 ; Merkwirth et al., 2016 ; Yuan et al., 2020 ; Ng et al., 2021 ). Although it is widely accepted that olfactory function declines with age, diverse factors have been associated with this age-related impairment ( Stevens et al., 1989 ; Wang et al., 2017 ; Xu et al., 2020 ; Dweck et al., 2018 ; Cerf-Ducastel and Murphy, 2003 ). Our findings indicate that the age-dependent decline of olfactory function in Drosophila is associated with a decrease in the activation capacity of the UPR ^MT in olfactory neurons. Crucially, the reduction in UPR ^MT activation is linked to an increase in H3K9me3, which is dependent on the methylation activity of dSetdb1. Importantly, targeting this methylation process can effectively prevent age-related neuronal degeneration and restore the loss of olfactory function associated with aging.

Our study uncovers a novel aspect of epigenetic regulation in the aging process, emphasizing the specific role of dSetdb1 in modulating H3K9me3 levels and suppressing the UPR ^MT . While previous research has established the impact of H3K9 methylation on the UPR ^MT , primarily through the actions of the demethylases JMJD 3.1 and JMJD 1.3, as well as methyltransferases, such as MET-2 (dSetdb1 orthologue), SET6, BAZ2 in worms and mice, respectively ( Tian et al., 2016 ; Merkwirth et al., 2016 ; Yuan et al., 2020 ), the specific function of Setdb1 in this context remained unclear. Our analysis indicates that in the AL of Drosophila brain, the absence of dSetdb1, also known as eggless , leads to a reduction in H3K9me3 in aged flies, suggesting its role as a tri-methyltransferase that acts as an epigenetic modulator of UPR ^MT during aging. The specificity of this effect was rigorously confirmed, as two independent RNAi lines and a classic loss-of-function allele for dSetdb1 (egg²³⁵) all consistently rescued the age-related decline in olfactory behavior ( Figure 4—figure supplement 1 ). This finding aligns with evolutionary conservation in epigenetic regulation across species. Supporting this, research shows that in C. elegans , knocking out met-2 also reduces H3K9me3, suggesting a conserved mechanism ( Delaney et al., 2022 ). However, previous research on the role of met-2 in UPR ^MT regulation only focused on H3K9Me2 and did not extend their examination to H3K9me3 ( Tian et al., 2016 ). Additionally, the role of SET6 in tri-methylating H3K9 and reducing UPR ^MT in mice further highlights a possible conserved epigenetic pathway influencing aging across distinct species ( Yuan et al., 2020 ).

Existing research underscores the beneficial role of UPR ^MT in maintaining cellular integrity, primarily through maintaining mitochondrial function, a critical factor for healthy aging ( Durieux et al., 2011 ; Mouchiroud et al., 2013 ; Dillin et al., 2002 ). Indeed, the overexpression of the histone demethylases JMJD-1.2 and JMJD-3.1 extends lifespan in C. elegans ( Merkwirth et al., 2016 ). Conversely, reduced expression of UPR ^MT nuclear effectors ATFS-1, UBL-5, and DVE-1, as well as demethylases JMJD-1.2 and JMJD-3.1, compromises lifespan and cellular viability ( Merkwirth et al., 2016 ; Durieux et al., 2011 ; Houtkooper et al., 2013 ; Cooper et al., 2017 ; Lan et al., 2019 ). Recent work reveals the fine-tuned regulation of UPR ^MT along aging, particularly through the H3K9 methyltransferase SET-6 and the epigenetic reader BAZ-2, which modulate gene expression related to mitochondrial health and stress responses, essential for neuronal viability ( Yuan et al., 2020 ). Importantly, beyond the impact on lifespan, UPR ^MT regulation has profound implications for neuronal function. In C. elegans , mitochondrial function was found to influence pharyngeal pumping (eating) and defecation rates, crucial for lifespan ( Dillin et al., 2002 ). Additionally, deficits in dopamine-dependent behaviors were observed in pdr-1 and pink-1 mutants, indicative of neuronal dysfunction without neuronal loss. This dysfunction is exacerbated by the downregulation of atfs-1, which is critical for UPR ^MT ( Cooper et al., 2017 ). In a mammalian context, Baz2b ablation enhanced mitochondrial function in the hippocampus and cerebellum in older mice, suggesting its role in modulating age-related cognitive decline ( Yuan et al., 2020 ). This was accompanied by improved performance in locomotion, reflecting preserved motor functions in aged mice. Beyond these, UPR ^MT regulates hippocampal neural stem cell aging, with implications for cognitive functions ( Wang et al., 2023b ) and affects skeletal muscle aging, as exercise improves coordination of UPR ^MT and mitophagy in aging skeletal ( Wang et al., 2023a ). Moreover, it plays a critical role in fertility and reproductive aging ( Seli et al., 2019 ), suggesting that UPR ^MT disruption can pivot healthy aging towards pathological states. Our data indicate that reducing H3K9me3 levels during aging to enhance UPR ^MT activation is beneficial for olfactory function and supports the prevailing hypothesis that modulation of epigenetic regulators, which suppress UPR ^MT transcriptional activation, constitutes a viable therapeutic approach for ameliorating mitochondrial dysfunction associated with aging.

While the precise molecular mechanisms of the UPR ^MT in Drosophila may differ from those in C. elegans , our findings demonstrate the critical role of this pathway in maintaining olfactory function during aging. The rescue of age-related olfactory decline by dSetdb1 knockdown, which is abolished by further knockdown of the UPR ^MT transcriptional activators dve and crc, highlights the importance of this pathway in neuronal maintenance. The Drosophila homolog of ATF5 and ATF4, crc, appears to play a key role in this process. Although its direct translocation from the mitochondria to the nucleus remains to be definitively shown, crc is known to be a target of mitochondrial stress and the UPR ^ER ( Ryoo, 2015 ; Vasudevan et al., 2022 ; Ryoo et al., 2007 ). Moreover, previous studies have demonstrated that mitochondrial dysfunction in Drosophila neurons can lead to the activation of crc via the UPR ^ER ( Hunt et al., 2019 ), suggesting potential crosstalk between these stress response pathways. This complex interplay between the UPR ^MT and other cellular stress responses, including the ISR, has also been observed in mammals ( Jenkins et al., 2021 ; Quirós et al., 2017 ; Anderson and Haynes, 2020 ). The involvement of ATF4, a key ISR effector, in the mammalian UPR ^MT further supports the idea of interconnected stress signaling networks ( Quirós et al., 2017 ; Jiang et al., 2020 ).

All together, these findings suggest that crc may function as a critical node integrating signals from both the ER and mitochondria to orchestrate a coordinated cellular response to stress. Further investigation is warranted to fully elucidate the molecular mechanisms by which crc regulates the UPR ^MT and its potential role in mediating crosstalk between different stress response pathways in Drosophila .

Brain aging exhibits distinct regional variations across multiple levels, including gene expression, organelle, and neuronal function ( Burtscher et al., 2015 ; Almanzar et al., 2020 ; Aibar et al., 2017 ). Our analysis of gene expression from single-cell studies reveals neuronal-specific transcriptional expression for H3K9-regulating enzymes, such as dSetdb1, utx, and kdm2 in aged vAChT, vGlut, and Gad1 neurons. It has been previously demonstrated that H3K9me3 levels are not uniform across the brain, varying based on brain regions or neuronal types ( Cao and Dang, 2018 ; Benayoun et al., 2015 ; Kane and Sinclair, 2019 ). Neurodegenerative conditions, characterized by the selective degeneration of specific neurons and their projections, exhibit differential neuronal vulnerability that is intricately linked to variations in neuronal morphology, activity patterns, and gene expression profiles within these affected structures ( Fu et al., 2018 ; Paß et al., 2021 ; Morrison et al., 1998 ). Our data suggest that the age-dependent reduction in H3K9 demethylation enzymes within specific neuronal populations may contribute to differential neuronal vulnerability along aging, which deserves further exploration.

The increase we had shown in the levels of H3K9me3 in the brains of aged fruit flies aligns with prior studies reporting a rise in H3K9me3 in aged Drosophila heads ( Herz et al., 2010 ). Studies performed in C. elegans have revealed that as age progresses, there is an increase in the expression of the H3K9me3 methyltransferase SET-6 and the epigenetic reader BAZ-2. Remarkably, inhibiting their expression has been linked to preservation of pharyngeal pumping in these organisms ( Yuan et al., 2020 ). In mice, administering an inhibitor for the histone methyltransferase SUV39H1, which is responsible for the trimethylation of H3K9, was found to mitigate age-associated cognitive decline and augment dendritic spines in the hippocampus ( Snigdha et al., 2016 ). Such findings support the notion that reducing H3K9me3 levels might enhance functionality of different brain modules during aging. While our findings suggest that reducing hypermethylation in aging could potentially enhance UPR ^MT response, it is critical to acknowledge that methylation processes also govern a vast of other cellular and neuronal functions ( Richard et al., 2010 ). For instance, histone methylation plays a crucial role in gene expression regulation, cellular differentiation, and even neuronal activity ( Park et al., 2022 ; Basavarajappa and Subbanna, 2021 ), all of which could be inadvertently impacted by broad-spectrum epigenetic interventions. This pleiotropic nature of methylation underscores the importance of a targeted approach.

Mitochondria play a central role as primary sensors for degenerative stimuli ( Court and Coleman, 2012 ). With aging, neurodegeneration is often preceded by mitochondrial dysfunction, which manifests as morphological changes, including swelling, fragmentation, reduced volume, and increased oxidative stress ( Stahon et al., 2016 ; Olesen et al., 2020 ; Venkateshappa et al., 2012 ; Wang et al., 2021 ; Rottenberg and Hoek, 2017 ; Rottenberg and Hoek, 2021 ; Salvadores et al., 2017 ; Kim et al., 2018 ; Arrázola et al., 2019 ). Consistent with prior studies in aged flies ( Hussain et al., 2018 ), we did not observe an increase in fragmentation within axons of the OPNs and lateral horn (LH), which could be attributed to the specific neuronal types under investigation ( Burman et al., 2012 ). Interestingly, our observations align with those from other studies ( Hussain et al., 2018 ), as we identified an age-related deterioration in Drosophila’s olfactory circuits, which coincides with a rise in oxidative mitochondria. Current research underscores the central role of UPR ^MT activation in orchestrating mitochondrial morphology and function ( Zhang et al., 2016 ; Liu et al., 2020 ; Chen et al., 2021 ; Yan et al., 2021 ; Wang et al., 2019 ). Importantly, our study demonstrated that genetic inhibition of dSetdb1 restored youthful levels of H3K9me3, enabling UPR ^MT activation to restore mitochondrial morphology and oxidative status. This maintenance of cellular viability through UPR ^MT activation parallels findings from a recent study, which revealed that mild mitochondrial dysfunction-dependent UPR ^MT activation protects cardiomyocytes against cardiac ischemia-reperfusion injury in mice ( Bomer et al., 2021 ). Also, NAD +activation of the UPR ^MT rejuvenated muscle stem cells in aged mice ( Zhang et al., 2016 ), highlighting the role of UPR ^MT in altering aging markers in stem cells and extending lifespan.

Our research highlights the crucial role of UPR ^MT regulation in the age-related decline of olfactory function. Focusing on the olfactory system in aged Drosophila , we have demonstrated detrimental effects of epigenetic changes on mitochondrial function, impacting neuronal survival. The importance of olfaction extends beyond sensory perception, with human olfactory processing is intricately linked to emotions and memories, mediated by the limbic system and cerebral cortex ( Churchwell and Yurgelun-Todd, 2013 ; Dan et al., 2021 ). A compromised sense of smell is not only associated with depression in a significant number of cases ( Croy et al., 2014 ) but also frequently precedes the onset of age-related neurodegenerative diseases, such as Alzheimer’s ( Vasavada et al., 2015 ; Zou et al., 2016 ) and Parkinson’s disease ( Leonhardt et al., 2019 ; Cecchini et al., 2019 ). Our findings underscore the need for further exploration of the UPR ^MT pathway and its epigenetic regulation as a potential target for developing interventions to mitigate the decline in neuronal function associated with the aging process.

All data generated or analysed during this study are included in the manuscript and supporting files, source data files have been provided.

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Author details

1. Francisco Muñoz-Carvajal

   1. Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile
   2. Center for Aging Research and Healthy Longevity, Faculty of Sciences, Universidad Mayor, Santiago, Chile
   3. Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile

   Contribution

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

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0009-0003-6650-0374

2. Nicole Sanhueza

   Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0009-0001-5173-0471

3. Mario Sanhueza

   1. Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile
   2. Center for Resilience, Adaptation and Mitigation, Universidad Mayor, Temuco, Chile

   Contribution

   Conceptualization, Resources, Supervision, Validation, Investigation, Methodology, Writing – original draft, Writing – review and editing

   For correspondence

   mario.sanhueza@umayor.cl

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0125-0154

4. Felipe A Court

   1. Center for Aging Research and Healthy Longevity, Faculty of Sciences, Universidad Mayor, Santiago, Chile
   2. Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile
   3. Buck Institute for Research on Aging, Novato, United States
   4. Centro Científico y Tecnológico de Excelencia Ciencia and Vida, Fundación Ciencia and Vida, Santiago, Chile

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Validation, Methodology, Project administration, Writing – review and editing

   For correspondence

   felipe.court@umayor.cl

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9394-7601

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