Targeting Mitochondria with Organelle‐Specific Compounds: Strategies and Applications

Yousif, Lema F.; Stewart, Kelly M.; Kelley, Shana O.

doi:10.1002/cbic.200900185

Cited by 306 publications

(222 citation statements)

References 103 publications

(105 reference statements)

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“…Modulation of PDEs by using small molecules is even better established and PDEs are widely used as drug targets (27,31). Our findings that PDE2A2 localizes to the mitochondrial matrix and that its inhibition stimulates oxidative phosphorylation suggest an exciting inroad for generating specific drugs modulating mitochondrial functions by targeting existing PDE inhibitors, through appropriate modifications (68), to mitochondria. Such compounds would help in the exciting challenge to further characterize the mitochondrial cNMP signaling system, its connection to other systems, and its potential therapeutic use.…”

Section: Discussionmentioning

confidence: 84%

A Phosphodiesterase 2A Isoform Localized to Mitochondria Regulates Respiration

Acı́n-Pérez

Russwurm

Günnewig

et al. 2011

Journal of Biological Chemistry

120

133

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Mitochondria are central organelles in cellular energy metabolism, apoptosis, and aging processes. A signaling network regulating these functions was recently shown to include soluble adenylyl cyclase as a local source of the second messenger cAMP in the mitochondrial matrix. However, a mitochondrial cAMPdegrading phosphodiesterase (PDE) necessary for switching off this cAMP signal has not yet been identified. Here, we describe the identification and characterization of a PDE2A isoform in mitochondria from rodent liver and brain. We find that mitochondrial PDE2A is located in the matrix and that the unique N terminus of PDE2A isoform 2 specifically leads to mitochondrial localization of this isoform. Functional assays show that mitochondrial PDE2A forms a local signaling system with soluble adenylyl cyclase in the matrix, which regulates the activity of the respiratory chain. Our findings complete a cAMP signaling cascade in mitochondria and have implications for understanding the regulation of mitochondrial processes and for their pharmacological modulation.Mitochondria play central roles in cellular energy metabolism, as well as in the regulation of cell cycle progression, apoptosis, and aging processes (1, 2). Despite their importance, signaling into, from, and within mitochondria is still not well understood. Emerging signaling mechanisms in mitochondria and between the organelle and its environment include reversible protein deacetylation (3, 4), redox regulation and reactive oxygen species formation (5-7), and cyclic adenosine monophosphate (cAMP) signaling (8, 9).cAMP-dependent effects and proteins of cAMP signaling systems, such as cAMP-responsive element-binding protein (CREB), protein kinase A (PKA), and A-kinase anchoring proteins (AKAPs), 3 have been described in mitochondria (10 -12). In addition to these effector proteins, a complete cAMP signaling microdomain requires enzymes for synthesis and degradation of the second messenger. Although an intramitochondrial cAMP source has been identified recently (8), there is no known cAMP-degrading enzyme in this organelle. Cyclic AMP is formed inside mitochondria by soluble adenylyl cyclase (sAC) (8), a member of Class III of the nucleotidyl cyclase family, which also comprises the G-protein-regulated transmembrane adenylyl cyclases (13). Unique from transmembrane adenylyl cyclases, sAC is activated by bicarbonate (14), and it appears to act as a metabolic sensor (15), whose mitochondrial form(s) seems to modulate PKA-mediated regulation of respiration (8) and apoptosis (16).The opponents of the cyclic nucleotide-forming cyclases are cyclic nucleotide monophosphate (cNMP)-degrading phosphodiesterases (PDEs). Mammalian cells contain a varying subset of members of the classical PDE family, which comprises 11 PDE gene families (PDE1-11) (17, 18) and non-generic PDEs such as the protein human Prune (19,20). The isoforms of the generic PDEs comprise homologous catalytic domains, fused to varying regulatory domains, making them sensitive to a variety of signals s...

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Section: Discussionmentioning

confidence: 84%

A Phosphodiesterase 2A Isoform Localized to Mitochondria Regulates Respiration

Acı́n-Pérez

Russwurm

Günnewig

et al. 2011

Journal of Biological Chemistry

120

133

View full text Add to dashboard Cite

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“…It has been proposed that delocalized lipophilic cations, such as the triphenylphosphonium group, can specifically and efficiently drive their cargo to active mitochondria, which maintain a negative-inside transmembrane gradient (46,47). Such a delivery strategy has led to the development of MitoQ, a ubiquinone-triphenylphosphonium conjugate that has entered clinical trials against neurodegenerative diseases (48,49).…”

Section: Discussionmentioning

confidence: 99%

Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

Morrisey

et al. 2017

Antimicrob Agents Chemother

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Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia. CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ϳ10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents.

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“…We reasoned that the sulfonamide group in 3 can act as the electron acceptor group, making it a donor-acceptor type dye and thus can generate intramolecular charge transfer excited states [35]. To demonstrate usefulness of probe 1, we also synthesized probe 2 that contains a cationic triphenylphosphonium group which moiety is known to target analytes in mitochondria (Scheme 1) [36,37].…”

Section: Introductionmentioning

confidence: 99%