Targeting Antioxidants to Mitochondria by Conjugation to Lipophilic Cations

Abstract

Mitochondrial oxidative damage contributes to a range of degenerative diseases. Consequently, the selective inhibition of mitochondrial oxidative damage is a promising therapeutic strategy. One way to do this is to invent antioxidants that are selectively accumulated into mitochondria within patients. Such mitochondria-targeted antioxidants have been developed by conjugating the lipophilic triphenylphosphonium cation to an antioxidant moiety, such as ubiquinol or alpha-tocopherol. These compounds pass easily through all biological membranes, including the blood-brain barrier, and into muscle cells and thus reach those tissues most affected by mitochondrial oxidative damage. Furthermore, because of their positive charge they are accumulated several-hundredfold within mitochondria driven by the membrane potential, enhancing the protection of mitochondria from oxidative damage. These compounds protect mitochondria from damage following oral delivery and may therefore form the basis for mitochondria-protective therapies. Here we review the background and work to date on this class of mitochondria-targeted antioxidants.

Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

“…Several cationic protonophores have been described, although their acting concentrations are in the submillimolar or even millimolar range (10 -13). Murphy and co-workers (14) were the first who used conjugation with penetrating cations for addressed delivery of substances into mitochondria having ⌬ negative inside (15,16). Among other compounds, Murphy and co-workers (4) designed a conjugate of triphenylphosphonium with DNP to increase the protono- 2 To whom correspondence may be addressed.…”

Synthetic Studies Toward a Novel Hydroxylamine of Potential Utility in the Preparation of Mitochondriotropic Nitrones

“…If mitochondrial function is impaired and ATP production is compromised, necrotic cell death can occur as a result of disruption of cell functions, tissues and organs 22 . Thus, it is reasonable to think that mitochondrial dysfunction resulting from oxidative damage is highly associated with the etiology of countless human pathologies.…”

“…Thus, it is reasonable to think that mitochondrial dysfunction resulting from oxidative damage is highly associated with the etiology of countless human pathologies. In fact, there is evidence that imbalanced metabolism and overproduction of ROS can cause oxidative damage to biomolecules (DNA, lipids, proteins) resulting in worsening a range of disorders such as cancer, stroke, chronic inflammation and neurodegenerative diseases 22,17,23 . Therefore, targeting antioxidants to mitochondria is a promising approach to prevent or delay progression of these conditions 24,25 .…”

“…One possible explanation for these poor outcomes is the lack of antioxidant accumulation inside the mitochondria. For example, Vitamin E and CoQ are highly lipophilic and failed to accumulate inside the mitochondria, which are the sites where most ROS are generated 5,6,22 .…”

“…These compounds will be discussed in detail in the following section: proportional to the radius of the cation. Thus, the large radius of the TPP cation results in a small enthalpy required to move the cation into the membrane 22,28 . The increase in hydrophobicity of these positively charged ions facilitates crossing of the phospholipid bilayer relative to other cations 22,29,30 .…”