Targeting of mitochondria by 10-N-alkyl acridine orange analogues: Role of alkyl chain length in determining cellular uptake and localization

Rodriguez, Myriam E.; Azizuddin, Kashif; Zhang, Ping; Chiu, Song Mao; Lam, Minh; Kenney, Malcolm E.; Burda, Clemens; Oleinick, Nancy L.

doi:10.1016/j.mito.2008.04.003

Cited by 46 publications

(45 citation statements)

References 25 publications

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“…Whatever the mechanism(s) involved, these results demonstrate strong alterations of mitochondrial biogenesis and activity in cls1 mutant plants. However, the presence of at least partially functional mitochondria, in particular giant mitochondria, is indicated by the accumulation of membrane potential-sensitive dyes and NAO (Figure 4), showing that this dye is definitely not specific for CL, as demonstrated previously in yeast (Gohil et al, 2005a;Rodriguez et al, 2008;Mileykovskaya and Dowhan, 2009).…”

Section: Discussionsupporting

confidence: 61%

The Importance of Cardiolipin Synthase for Mitochondrial Ultrastructure, Respiratory Function, Plant Development, and Stress Responses in Arabidopsis

Pineau

Bourge²,

Marion

et al. 2013

Plant Cell

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Cardiolipin (CL) is the signature phospholipid of the mitochondrial inner membrane. In animals and yeast (Saccharomyces cerevisiae), CL depletion affects the stability of respiratory supercomplexes and is thus crucial to the energy metabolism of obligate aerobes. In eukaryotes, the last step of CL synthesis is catalyzed by CARDIOLIPIN SYNTHASE (CLS), encoded by a single-copy gene. Here, we characterize a cls mutant in Arabidopsis thaliana, which is devoid of CL. In contrast to yeast cls, where development is little affected, Arabidopsis cls seedlings are slow developing under short-day conditions in vitro and die if they are transferred to long-day (LD) conditions. However, when transferred to soil under LD conditions under low light, cls plants can reach the flowering stage, but they are not fertile. The cls mitochondria display abnormal ultrastructure and reduced content of respiratory complex I/complex III supercomplexes. The marked accumulation of tricarboxylic acid cycle derivatives and amino acids demonstrates mitochondrial dysfunction. Mitochondrial and chloroplastic antioxidant transcripts are overexpressed in cls leaves, and cls protoplasts are more sensitive to programmed cell death effectors, UV light, and heat shock. Our results show that CLS is crucial for correct mitochondrial function and development in Arabidopsis under both optimal and stress conditions.

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Section: Discussionsupporting

confidence: 61%

The Importance of Cardiolipin Synthase for Mitochondrial Ultrastructure, Respiratory Function, Plant Development, and Stress Responses in Arabidopsis

Pineau

Bourge²,

Marion

et al. 2013

Plant Cell

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“…The calorimetry and fluorimetry data for NAO and PL mixtures described in this paper highlight the limitations of using NAO to make quantitative statements regarding CL in membranes (41,43,44). We found that NAO binds to anionic PLs promiscuously and displays spectroscopic changes that are inconsistent with a unique interaction between NAO and CL.…”

mentioning

confidence: 72%

“…Studies of the interaction of NAO with CL in mitochondrial membranes have not been particularly relevant to E. coli, since CL is the major anionic PL in mitochondria, whereas PG is the most abundant anionic PL in E. coli; the interaction of PG with NAO under physiological conditions remains unstudied. Several research groups have noted discrepancies with the use of NAO, primarily in its lack of specificity in both mitochondria (39,(41)(42)(43) and archaea (44). Here, we quantitatively study the organization of anionic PLs in E. coli cells using a combination of biophysical, microscopic, and mass spectrometric techniques.…”

Section: G Enome-wide Studies Of Bacillus Subtilis Escherichia Colimentioning

confidence: 99%

Localization of Anionic Phospholipids in Escherichia coli Cells

et al. 2014

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d Cardiolipin (CL) is an anionic phospholipid with a characteristically large curvature and is of growing interest for two primary reasons: (i) it binds to and regulates many peripheral membrane proteins in bacteria and mitochondria, and (ii) it is distributed asymmetrically in rod-shaped cells and is concentrated at the poles and division septum. Despite the growing number of studies of CL, its function in bacteria remains unknown. 10-N-Nonyl acridine orange (NAO) is widely used to image CL in bacteria and mitochondria, as its interaction with CL is reported to produce a characteristic red-shifted fluorescence emission. Using a suite of biophysical techniques, we quantitatively studied the interaction of NAO with anionic phospholipids under physiologically relevant conditions. We found that NAO is promiscuous in its binding and has photophysical properties that are largely insensitive to the structure of diverse anionic phospholipids to which it binds. Being unable to rely solely on NAO to characterize the localization of CL in Escherichia coli cells, we instead used quantitative fluorescence microscopy, mass spectrometry, and mutants deficient in specific classes of anionic phospholipids. We found CL and phosphatidylglycerol (PG) concentrated in the polar regions of E. coli cell membranes; depletion of CL by genetic approaches increased the concentration of PG at the poles. Previous studies suggested that some CL-binding proteins also have a high affinity for PG and display a pattern of cellular localization that is not influenced by depletion of CL. Framed within the context of these previous experiments, our results suggest that PG may play an essential role in bacterial physiology by maintaining the anionic character of polar membranes.

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“…191–193 Different alkyl chain lengths were tested for such purpose, and the conclusion is that the efficiency of cellular staining is increased with a longer alkyl chain but the target selectivity is compromised. 194,195 Because the probe is cationic, its cellular accumulation was demonstrated to be a function not only of mitochondrial mass and cardiolipin content but also of the mitochondrial membrane potential. 172,196 …”

Section: Transport Of Small Cationic Compounds and Biomolecules Tomentioning

confidence: 99%

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Zielonka¹,

Joseph²,

et al. 2017

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Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the potentials of cell and mitochondrial membranes, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

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Targeting of mitochondria by 10-N-alkyl acridine orange analogues: Role of alkyl chain length in determining cellular uptake and localization

Cited by 46 publications

References 25 publications

The Importance of Cardiolipin Synthase for Mitochondrial Ultrastructure, Respiratory Function, Plant Development, and Stress Responses in Arabidopsis

The Importance of Cardiolipin Synthase for Mitochondrial Ultrastructure, Respiratory Function, Plant Development, and Stress Responses in Arabidopsis

Localization of Anionic Phospholipids in Escherichia coli Cells

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

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