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

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

Jacek Zielonka; Joy Joseph; Adam Sikora; Micael Hardy; Olivier Ouari; Jeannette Vasquez-Vivar; Gang Cheng; Marcos Lopez; Balaraman Kalyanaraman

2017

Scholarcy highlights

  • Mitochondria, which are generally considered the cellular powerhouse, are small subcellular organelles that generate most cellular energy in the form of adenosine triphosphate. Over the last two decades, research focusing on mitochondria-dependent cellular signaling and cell death has flourished. Mitochondrial defects or dysfunctions are associated with the onset of several neurological and cardiovascular diseases. Development of therapeutic drugs capable of restoring mitochondrial function is highly significant and critically needed. specific mitochondrial targeting leads to more-precise and effective drugs
  • 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
  • Mito-CP inhibited the late/secondary expression of mRNA and protein levels of ROSgenerating enzymes, NOX2/4.490 These findings indicate a novel signaling role for mitochondria-targeted antioxidants, which downregulate the expression of proinflammatory processes induced by chemotherapeutics such as cisplatin in normal tissues
  • We discuss the potential applications of TPP+-based mitochondria-targeted probes for detecting, detoxifying, and releasing reactive oxygen, nitrogen, and sulfur species and electrophiles in mitochondria; the anticancer and antimetastatic properties of mitochondria-targeted, naturally occurring bioactive compounds and their effect on mitochondrial bioenergetics and the mitochondria-dependent signaling mechanism; the cardioprotective effects of mitochondria-targeted therapeutics in chemotherapy; the neuroprotective effects of TPP+-based mitochondria-targeted compounds; and the possibility of imaging mitochondrial metabolism and function using mitochondria-targeted paramagnetic agents and radiopharmaceuticals
  • This review reveals the therapeutic potency of several TPP+-modified bioactive compounds in preclinical models
  • While there was no significant difference in sensitivity to DOX versus TPPDOX in wild-type breast cancer cells, TPP-DOX was much more potent in DOX-resistant cells
  • MitoQ is currently available in health-food stores and is used to enhance mitochondrial function and energy, it has not undergone extensive clinical-trial analyses for this purpose

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