Vascular mitohormesis couples Mfn2 with improved systemic metabolism and healthspan
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE174547 | GEO | 2026/02/17
REPOSITORIES: GEO
Similar Datasets
Project description:Vascular mitohormesis couples Mfn2 with improved systemic metabolism and healthspan
| PRJNA730519 | ENA
Project description:Mitohormesis, whereby transient mitochondrial stress induces adaptive signaling, promotes organismal resilience and longevity in invertebrates, but how this operates in mammals and the underlying metabolic signals involved remain unclear. Using a mouse model of mitohormesis, we show that transient mitochondrial superoxide stress during embryogenesis reprograms the adult heart to enhance mitochondrial biogenesis and antioxidant capacity. These adaptations confer protection against mitochondrial and oxidative injury in models of doxorubicin-induced cardiotoxicity, preserving mitochondrial content and preventing cardiac dysfunction and remodeling. Using a cell model of superoxide-mediated mitohormesis, we find that inhibition of mitochondrial aconitase promotes citrate export to the cytosol, where its conversion to acetyl-CoA drives histone acetylation and mitohormetic protection from oxidative stress. Preventing mitochondrial citrate export abolishes these adaptations, while Aco2 silencing or citrate supplementation recapitulates the response. Together, our findings identify mitochondrial citrate as a redox-sensitive second messenger linking mitochondrial superoxide stress to durable epigenetic and mitohormetic remodeling.
2026-09-10 | GSE337993 | GEO
Project description:Transient mitochondrial stress, even if only experienced in early development, paradoxically increases lifespan and confers future stress protection in a process termed mitohormesis. However, whether mitohormesis functions in the heart to prevent pathology driven by mitochondrial and oxidative injury has not been tested. While mitohormesis requires coordinated transcriptional and chromatin-level remodeling, the mitochondrial signals initiating these responses in mammals have not been fully defined. Using the iSOD2 mouse model of mitohormesis we previously developed, we show that SOD2 knockdown and accumulation of mitochondrial superoxide during embryogenesis results in adult hearts with enhanced mitochondrial biogenesis and antioxidant enzyme expression. Furthermore, these mitohormetic adaptations prevented cardiac dysfunction and remodeling in acute and chronic models of doxorubicin-induced cardiotoxicity (DIC) by preserving mitochondrial integrity and mitigating oxidative damage. In a mouse embryonic fibroblast model of mitohormesis, we found transient SOD2-knockdown resulted in similar mitohormetic outcomes to those in heart, including increased mitochondrial biogenesis and antioxidant responses, histone acetylation, and resistance to doxorubicin-induced cell death. In this model, mitochondrial matrix superoxide inhibited the tricarboxylic acid cycle enzyme aconitase (ACO2), thereby redirecting its substrate citrate into the cytosol where it is converted by ACLY to acetyl-CoA for histone acetylation. Thus, we conclude that citrate is a redox-sensitive second messenger of mitochondrial superoxide stress that initiates this form of mitohormesis. Supporting this conclusion, genetic loss of the mitochondrial citrate transporter, SLC25A1, prevented the mitohormetic response, while knockdown of ACO2 or addition of exogenous citrate recapitulated the superoxide- mediated adaptations. We speculate this redox-sensitive mitohormetic signaling pathway might illuminate new therapeutic approaches for DIC and possibly other pathology involving mitochondrial defects and oxidative stress.
2026-05-31 | GSE313130 | GEO
Project description:Transient mitochondrial stress, even if only experienced in early development, paradoxically increases lifespan and confers future stress protection in a process termed mitohormesis. However, whether mitohormesis functions in the heart to prevent pathology driven by mitochondrial and oxidative injury has not been tested. While mitohormesis requires coordinated transcriptional and chromatin-level remodeling, the mitochondrial signals initiating these responses in mammals have not been fully defined. Using the iSOD2 mouse model of mitohormesis we previously developed, we show that SOD2 knockdown and accumulation of mitochondrial superoxide during embryogenesis results in adult hearts with enhanced mitochondrial biogenesis and antioxidant enzyme expression. Furthermore, these mitohormetic adaptations prevented cardiac dysfunction and remodeling in acute and chronic models of doxorubicin-induced cardiotoxicity (DIC) by preserving mitochondrial integrity and mitigating oxidative damage. In a mouse embryonic fibroblast model of mitohormesis, we found transient SOD2-knockdown resulted in similar mitohormetic outcomes to those in heart, including increased mitochondrial biogenesis and antioxidant responses, histone acetylation, and resistance to doxorubicin-induced cell death. In this model, mitochondrial matrix superoxide inhibited the tricarboxylic acid cycle enzyme aconitase (ACO2), thereby redirecting its substrate citrate into the cytosol where it is converted by ACLY to acetyl-CoA for histone acetylation. Thus, we conclude that citrate is a redox-sensitive second messenger of mitochondrial superoxide stress that initiates this form of mitohormesis. Supporting this conclusion, genetic loss of the mitochondrial citrate transporter, SLC25A1, prevented the mitohormetic response, while knockdown of ACO2 or addition of exogenous citrate recapitulated the superoxide- mediated adaptations. We speculate this redox-sensitive mitohormetic signaling pathway might illuminate new therapeutic approaches for DIC and possibly other pathology involving mitochondrial defects and oxidative stress.
2026-05-31 | GSE313129 | GEO
Project description:Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria.
2021-04-04 | GSE169728 | GEO
Project description:Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria.
2021-04-04 | GSE169727 | GEO
Project description:Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria.
2021-04-04 | GSE169730 | GEO
Project description:Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria.
2021-04-04 | GSE169729 | GEO
Project description:Mild mitochondrial stress can produce positive effects, a phenomenon referred to as \"mitohormesis.\" This process involves activation of signaling pathways such as the mitochondrial unfolded protein response (UPRmt), which helps restore mitochondrial function and has also been linked to improved health and extended lifespan across various model organisms. In C. elegans, mitohormesis can be triggered through several means—including inhibition of the electron transport chain (ETC), reduction in mitochondrial protein translation, or impaired mitochondrial import—all of which can lead to UPRmt-mediated lifespan extension. However, not all triggers of UPRmt result in increased longevity. For instance, while inhibiting ETC complex II strongly activates UPRmt, it has not been associated with lifespan extension. These findings raise the possibility that UPRmt activation alone may not directly promote longevity. In this study, we aim to investigate this complexity by examining how different mitochondrial stressors that induce UPRmt influence the lifespan of C. elegans. We use RNA-sequencing to profile genome-wide transcriptional responses, with the goal of identifying transcriptomic patterns that may clarify the relationship between UPRmt and longevity.
2025-08-31 | E-MTAB-15031 | biostudies-arrayexpress
Project description:Mitochondrial fusion and fission proteins regulate mitochondrial quality control and mitochondrial metabolism. In turn, mitochondrial dysfunction is associated with aging, although its causes are still under debate. Here, we show that aging is characterized by a progressive reduction of Mitofusin 2 (Mfn2) in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, muscle Mfn2-deficient mice show unhealthy aging characterized by altered metabolic homeostasis and sarcopenia. Mfn2 deficiency impairs mitochondrial quality control, which contributes to an exacerbated age-related mitochondrial dysfunction. Surprisingly, aging-induced Mfn2 deficiency triggers a ROS-dependent retrograde signaling pathway through induction of HIF1 transcription factor and BNIP3. This pathway ameliorates mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that repression of Mfn2 in skeletal muscle during aging is determinant for the loss of mitochondrial quality, contributing to age-associated metabolic alterations and loss of muscle fitness. Quadriceps muscle from four mice per genotype were used (Control young (6 month-old), Mfn2KO young (6-month-old), control old (22-month-old) and Mfn2KO old (22-month-old)
2016-08-08 | E-GEOD-71501 | biostudies-arrayexpress