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European Journal of Pharmacology Jun 2024Fenofibrate, a PPAR-α agonist clinically used to lower serum lipid levels, reduces cardiac remodeling and improves cardiac function. However, its mechanism of action is...
Fenofibrate, a PPAR-α agonist clinically used to lower serum lipid levels, reduces cardiac remodeling and improves cardiac function. However, its mechanism of action is not completely elucidated. In this study we examined the effect of fenofibrate on mitochondria in a rat model of renovascular hypertension, focusing on mediators controlling mitochondrial dynamics and autophagy. Rats with two-kidney one-clip (2K1C) hypertension were treated with fenofibrate 150 mg/kg/day (2K1C-FFB) or vehicle (2K1C-VEH) for 8 weeks. Systolic blood pressure and cardiac functional were in-vivo assessed, while cardiomyocyte size and protein expression of mediators of cardiac hypertrophy and mitochondrial dynamics were ex-vivo examined by histological and Western blot analyses. Fenofibrate treatment counteracted the development of hypertension and the increase of left ventricular mass, relative wall thickness and cross-sectional area of cardiomyocytes. Furthermore, fenofibrate re-balanced the expression Mfn2, Drp1 and Parkin, regulators of fusion, fission, mitophagy respectively. Regarding autophagy, the LC3-II/LC3-I ratio was increased in 2K1C-VEH and 2K1C-FFB, whereas the autophagy was increased only in 2K1C-FFB. In cultured H9C2 cardiomyoblasts, fenofibrate reversed the Ang II-induced mRNA up-regulation of hypertrophy markers Nppa and Myh7, accumulation of reactive oxygen species and depolarization of the mitochondrial membrane exerting protection mediated by up-regulation of the Uncoupling protein 2. Our results indicate that fenofibrate acts directly on cardiomyocytes and counteracts the pressure overload-induced cardiac maladaptive remodeling. This study reveals a so far hidden mechanism involving mitochondrial dynamics in the beneficial effects of fenofibrate, support its repurposing for the treatment of cardiac hypertrophy and provide new potential targets for its pharmacological function.
PubMed: 38909934
DOI: 10.1016/j.ejphar.2024.176767 -
Pharmacological Research Jun 2024Several cardiovascular illnesses are associated with aberrant activation of cellular pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis, and macrophage... (Review)
Review
Several cardiovascular illnesses are associated with aberrant activation of cellular pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis, and macrophage polarisation as hallmarks contributing to vascular damage and abnormal cardiac function. Meanwhile, these three novel forms of cellular dysfunction are closely related to mitochondrial homeostasis. Mitochondria are the main organelles that supply energy and maintain cellular homeostasis. Mitochondrial stability is maintained through a series of regulatory pathways, such as mitochondrial fission, mitochondrial fusion and mitophagy. Studies have shown that mitochondrial dysfunction (e.g., impaired mitochondrial dynamics and mitophagy) promotes ROS production, leading to oxidative stress, which induces cellular pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis and macrophage M1 phenotypic polarisation. Therefore, an in-depth knowledge of the dynamic regulation of mitochondria during cellular pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis and macrophage polarisation is necessary to understand cardiovascular disease development. This paper systematically summarises the impact of changes in mitochondrial dynamics and mitophagy on regulating novel cellular dysfunctions and macrophage polarisation to promote an in-depth understanding of the pathogenesis of cardiovascular diseases and provide corresponding theoretical references for treating cardiovascular diseases.
PubMed: 38909638
DOI: 10.1016/j.phrs.2024.107258 -
Redox Biology Jun 2024Sphingosine 1-phosphate (S1P), a bioactive lipid molecule, exerts multifaceted effects on cardiovascular functions via S1P receptors, but its effects on cardiac I/R...
Sphingosine 1-phosphate (S1P), a bioactive lipid molecule, exerts multifaceted effects on cardiovascular functions via S1P receptors, but its effects on cardiac I/R injury are not fully understood. Plasma lipidomics analysis by mass spectrometry revealed that sphingosine lipids, including sphingosine 1-phosphate (S1P), were significantly down-regulated following cardiac I/R injury in mice. The reduced S1P levels were also observed in the plasma of coronary heart disease (CHD) patients after percutaneous coronary intervention (PCI) compared with those without PCI. We found that S1P exerted a cardioprotective effect via endothelial cell (EC)-S1PR1, whereas EC-S1PR2 displayed a detrimental effect on cardiac I/R. Our data showed that EC-specific S1pr2 loss-of-function significantly lessened inflammatory responses and diminished cardiac I/R injury, while EC-specific S1pr2 gain-of-function aggravated cardiac I/R injury. Mechanistically, EC-S1PR2 initiated excessive mitochondrial fission and elevated ROS production via RHO/ROCK1/DRP1 pathway, leading to NLRP3 inflammasome activation and subsequent cell pyroptosis, thereby exacerbating inflammation and I/R injuries. Furthermore, RGD-peptide magnetic nanoparticles packaging S1pr2-siRNA to specifically knockdown S1PR2 in endothelial cells significantly ameliorated cardiac I/R injury. Taken together, our investigations demonstrate that EC-S1PR2 induces excessive mitochondrial fission, which results in NLRP3 inflammasome activation and subsequently triggers cell pyroptosis, ultimately exacerbating inflammatory responses and aggravating heart injuries following I/R.
PubMed: 38909407
DOI: 10.1016/j.redox.2024.103244 -
Free Radical Biology & Medicine Jun 2024Oxygen is essential for aerobic life on earth but it is also the origin of harmful reactive oxygen species (ROS). Ubiquinone is par excellence the endogenous cellular...
Oxygen is essential for aerobic life on earth but it is also the origin of harmful reactive oxygen species (ROS). Ubiquinone is par excellence the endogenous cellular antioxidant, but a very hydrophobic one. Because of that, other molecules have been envisaged, such as idebenone (IDE) and mitoquinone (MTQ), molecules having the same redox active benzoquinone moiety but higher solubility. We have used molecular dynamics to determine the location and interaction of these molecules, both in their oxidized and reduced forms, with membrane lipids in a membrane similar to that of the mitochondria. Both IDE and reduced IDE (IDOL) are situated near the membrane interface, whereas both MTQ and reduced MTQ (MTQOL) locate in a position adjacent to the phospholipid hydrocarbon chains. The quinone moieties of both ubiquinone 10 (UQ10) and reduced UQ10 (UQOL10) in contraposition to the same moieties of IDE, IDOL, MTQ and MTQOL, located near the membrane interphase, whereas the isoprenoid chains remained at the middle of the hydrocarbon chains. These molecules do not aggregate and their functional quinone moieties are located in the membrane at different depths but near the hydrophobic phospholipid chains whereby protecting them from ROS harmful effects.
PubMed: 38908803
DOI: 10.1016/j.freeradbiomed.2024.06.017 -
Current Opinion in Cell Biology Jun 2024Dysfunction in mitochondrial maintenance and trafficking is commonly correlated with the development of neurodegenerative disorders such as Parkinson's disease and... (Review)
Review
Dysfunction in mitochondrial maintenance and trafficking is commonly correlated with the development of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Thus, biomedical research has been dedicated to understanding how architecturally complex neurons maintain and transport their mitochondria. However, the systems that coordinate mitochondrial QC (quality control) dynamics and trafficking in response to neuronal activity and stress are less understood. Additionally, the degree of integration between the processes of mitochondrial trafficking and QC is unclear. Recent work indicates that mitochondrial motility modulators (i.e., anchors and tethers) help coordinate mitochondrial health by mediating distinct, stress-level-appropriate QC pathways following mitochondrial damage. This review summarizes current evidence supporting the role of two mitochondrial motility modulators, Syntaphilin and Mitofusin 2, in coordinating mitochondrial QC to promote neuronal health. Exploring motility modulators' intricate regulatory molecular landscape may reveal new therapeutic targets for delaying disease progression and enhancing neuronal survival post-insult.
PubMed: 38908094
DOI: 10.1016/j.ceb.2024.102383 -
NPJ Parkinson's Disease Jun 2024Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing...
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing protein aggregates known as Lewy bodies (LB). Here, we investigated the entry of α-Syn into mitochondria to cause mitochondrial dysfunction and loss of cellular fitness in vivo. We show that α-Syn expressed in yeast and human cells is constitutively imported into mitochondria. In a transgenic mouse model, the level of endogenous α-Syn accumulation in mitochondria of dopaminergic neurons and microglia increases with age. The imported α-Syn is degraded by conserved mitochondrial proteases, most notably NLN and PITRM1 (Prd1 and Cym1 in yeast, respectively). α-Syn in the mitochondrial matrix that is not degraded interacts with respiratory chain complexes, leading to loss of mitochondrial DNA (mtDNA), mitochondrial membrane potential and cellular fitness decline. Importantly, enhancing mitochondrial proteolysis by increasing levels of specific proteases alleviated these defects in yeast, human cells, and a PD model of mouse primary neurons. Together, our results provide a direct link between α-synuclein-mediated cellular toxicity and its import into mitochondria and reveal potential therapeutic targets for the treatment of α-synucleinopathies.
PubMed: 38906862
DOI: 10.1038/s41531-024-00733-y -
Science Advances Jun 2024The central nervous system coordinates peripheral cellular stress responses, including the unfolded protein response of the mitochondria (UPR); however, the contexts for...
The central nervous system coordinates peripheral cellular stress responses, including the unfolded protein response of the mitochondria (UPR); however, the contexts for which this regulatory capability evolved are unknown. UPR is up-regulated upon pathogenic infection and in metabolic flux, and the olfactory nervous system has been shown to regulate pathogen resistance and peripheral metabolic activity. Therefore, we asked whether the olfactory nervous system in controls the UPR cell nonautonomously. We found that silencing a single inhibitory olfactory neuron pair, AWC, led to robust induction of UPR and reduction of oxidative phosphorylation dependent on serotonin signaling and -mediated mitophagy. Further, AWC ablation confers resistance to the pathogenic bacteria partially dependent on the UPR transcription factor and fully dependent on mitophagy machinery. These data illustrate a role for the olfactory nervous system in regulating whole-organism mitochondrial dynamics, perhaps in preparation for postprandial metabolic stress or pathogenic infection.
Topics: Animals; Caenorhabditis elegans; Mitophagy; Mitochondria; Caenorhabditis elegans Proteins; Smell; Unfolded Protein Response; Pseudomonas aeruginosa; Ubiquitin-Protein Ligases; Oxidative Phosphorylation; Signal Transduction; Serotonin; Transcription Factors
PubMed: 38905346
DOI: 10.1126/sciadv.adn0014 -
International Journal of Biological... 2024The sirtuins constitute a group of histone deacetylases reliant on NAD for their activity that have gained recognition for their critical roles as regulators of numerous... (Review)
Review
The sirtuins constitute a group of histone deacetylases reliant on NAD for their activity that have gained recognition for their critical roles as regulators of numerous biological processes. These enzymes have various functions in skeletal muscle biology, including development, metabolism, and the body's response to disease. This comprehensive review seeks to clarify sirtuins' complex role in skeletal muscle metabolism, including glucose uptake, fatty acid oxidation, mitochondrial dynamics, autophagy regulation, and exercise adaptations. It also examines their critical roles in developing skeletal muscle, including myogenesis, the determination of muscle fiber type, regeneration, and hypertrophic responses. Moreover, it sheds light on the therapeutic potential of sirtuins by examining their impact on a range of skeletal muscle disorders. By integrating findings from various studies, this review outlines the context of sirtuin-mediated regulation in skeletal muscle, highlighting their importance and possible consequences for health and disease.
Topics: Muscle, Skeletal; Humans; Sirtuins; Animals; Muscle Development; Muscular Diseases
PubMed: 38904020
DOI: 10.7150/ijbs.96885 -
Frontiers in Genetics 2024Mitochondria are semi-autonomous organelles in eukaryotic cells with their own genome. Plant mitogenomes differ from animal mitogenomes in size, structure, and...
Mitochondria are semi-autonomous organelles in eukaryotic cells with their own genome. Plant mitogenomes differ from animal mitogenomes in size, structure, and repetitive DNA sequences. Despite larger sizes, plant mitogenomes do not have significantly more genes. They exhibit diverse structures due to variations in size, repetitive DNA, recombination frequencies, low gene densities, and reduced nucleotide substitution rates. In this study, we analyzed the mitochondrial genome of using Nanopore and Illumina sequencing. assembly and annotation were conducted using Unicycler, Geseq, tRNAscan-SE and BLASTN, followed by codon usage, repeat sequence, RNA-editing, synteny, and phylogenetic analyses. mitogenome consisted of one linear contig and six circular contigs totaling 724,751 bp. It had 39 protein-coding genes, 27 tRNA genes, and 3 rRNA genes. Transfer of chloroplast sequences accounted for 13.14% of the mitogenome. Various analyses provided insights into genetic characteristics, evolutionary dynamics, and phylogenetic placement. Further investigations can explore transferred genes' functions and RNA-editing's role in mitochondrial gene expression in .
PubMed: 38903753
DOI: 10.3389/fgene.2024.1395805 -
ELife Jun 2024Mitochondria are the cellular energy hub and central target of metabolic regulation. Mitochondria also facilitate proteostasis through pathways such as the 'mitochondria...
Mitochondria are the cellular energy hub and central target of metabolic regulation. Mitochondria also facilitate proteostasis through pathways such as the 'mitochondria as guardian in cytosol' (MAGIC) whereby cytosolic misfolded proteins (MPs) are imported into and degraded inside mitochondria. In this study, a genome-wide screen in uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of MPs into mitochondria while promoting mitochondrial biogenesis under glucose starvation. We show that this inhibition requires a downstream transcription factor regulating mitochondrial gene expression and is likely to be conferred through substrate competition and mitochondrial import channel selectivity. We further show that Snf1/AMPK activation protects mitochondrial fitness in yeast and human cells under stress induced by MPs such as those associated with neurodegenerative diseases.
Topics: Saccharomyces cerevisiae; Mitochondria; Humans; Protein Transport; Protein Folding; Protein Serine-Threonine Kinases; Saccharomyces cerevisiae Proteins; Glucose
PubMed: 38900507
DOI: 10.7554/eLife.87518