Adhesion-mediated mechanosignaling forces mitohormesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA718277 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14094964.fastq.gz | Fastqsanger.gz | |||
| SRR14094965.fastq.gz | Fastqsanger.gz | |||
| SRR14094966.fastq.gz | Fastqsanger.gz | |||
| SRR14094967.fastq.gz | Fastqsanger.gz | |||
| SRR14094968.fastq.gz | Fastqsanger.gz |
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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.
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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.
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