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Cryptococcal Hsf3 controls intramitochondrial ROS homeostasis by regulating the respiratory process.

ABSTRACT: Mitochondrial quality control prevents accumulation of intramitochondrial-derived reactive oxygen species (mtROS), thereby protecting cells against DNA damage, genome instability, and programmed cell death. However, underlying mechanisms are incompletely understood, particularly in fungal species. Here, we show that Cryptococcus neoformans heat shock factor 3 (CnHsf3) exhibits an atypical function in regulating mtROS independent of the unfolded protein response. CnHsf3 acts in nuclei and mitochondria, and nuclear- and mitochondrial-targeting signals are required for its organelle-specific functions. It represses the expression of genes involved in the tricarboxylic acid cycle while promoting expression of genes involved in electron transfer chain. In addition, CnHsf3 responds to multiple intramitochondrial stresses; this response is mediated by oxidation of the cysteine residue on its DNA binding domain, which enhances DNA binding. Our results reveal a function of HSF proteins in regulating mtROS homeostasis that is independent of the unfolded protein response.

SUBMITTER: Gao X

PROVIDER: S-EPMC9477856 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Cryptococcal Hsf3 controls intramitochondrial ROS homeostasis by regulating the respiratory process.

Gao Xindi X Fu Yi Y Sun Shengyi S Gu Tingyi T Li Yanjian Y Sun Tianshu T Li Hailong H Du Wei W Suo Chenhao C Li Chao C Gao Yiru Y Meng Yang Y Ni Yue Y Yang Sheng S Lan Tian T Sai Sixiang S Li Jiayi J Yu Kun K Wang Ping P Ding Chen C

Nature communications 20220915 1

Mitochondrial quality control prevents accumulation of intramitochondrial-derived reactive oxygen species (mtROS), thereby protecting cells against DNA damage, genome instability, and programmed cell death. However, underlying mechanisms are incompletely understood, particularly in fungal species. Here, we show that Cryptococcus neoformans heat shock factor 3 (CnHsf3) exhibits an atypical function in regulating mtROS independent of the unfolded protein response. CnHsf3 acts in nuclei and mitocho ...[more]

PMID: 36109512

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Project description:Rationale: Internal modifications of mammalian RNA have been suggested to be essential for the maintenance of cardiac homeostasis. However, the role of RNA cytosine methylation (m5C) in the heart remains largely unknown. Methods: Bulk and single cell RNA sequencing data and tissues from the human hearts were exploited for analyzing the expression of RNA m5C modifying proteins. Neonatal rat and adult mouse cardiomyocytes were isolated to assess the impact of Nsun2 on cellular hypertrophic response. Cre/LoxP-mediated gene knockout and recombinant adeno-associated virus serotype 9 (rAAV9) were employed respectively to achieve cardiac-specific interference of the expression of related genes in mice that were subjected to heart stresses from aging, aortic constriction, and angiotensin II stimulation. RNA m5C immunoprecipitation sequencing (m5C-RIP-seq), RNA pull-down, polysome profiling, reporter gene analysis, and IonOptix measurement were conducted to elucidate the involved regulatory mechanisms. Results: Nsun2 expression was significantly elevated in human, rat, and mouse hypertrophic myocardial cells. Knockout of Nsun2 (αMHC-CreERT2, Nsun2 flox+/+) abolished the hypertrophic response of mice to diverse stresses, while accelerating the progression of heart failure. Mechanistically, Nsun2 specifically methylates PKA catalytic subunit alpha (PRKACA) mRNA, which substantially promotes PRKACA translation in a YBX1-dependent manner. Nsun2 ablation markedly attenuated the activation of PKA signaling, as evidenced by the reduced PKA activity and protein phosphorylation levels of PKA substrates, impaired myocyte contraction and relaxation, and disturbed calcium transients. Overexpressing Nsun2 and PRKACA-3'UTR transcripts in the myocardia sensitized and desensitized heart hypertrophic responses, respectively, whereas co-administration of the PKA inhibitor H-89 or overexpressing PRKACA-3'UTR transcript lacking Nsun2 methylating regions failed to produce corresponding responses, reiterating the significance of Nsun2-PRKACA regulation in the cardiac hypertrophic program. Conclusion: These observations reveal the importance of Nsun2-PRKACA regulation in cardiac homeostasis, which provides novel insights into heart function modulation and sheds light on future treatments for hypertrophic remodeling associated heart diseases.

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Cryptococcal Hsf3 controls intramitochondrial ROS homeostasis by regulating the respiratory process.

Publications

Cryptococcal Hsf3 controls intramitochondrial ROS homeostasis by regulating the respiratory process.

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