Mitochondrial dysfunction, either inherited or acquired, is associated with several diseases in humans. Depending on the cell type and location, cells are prone to multiple types of insults that may compromise their proper function. Generally, these insults are overcome by defensive mechanisms but sometimes they lead to sustained damage, requiring the action of scavenging and repair machineries to retain the viability of the cells. As a final measure, severely damaged cells are targeted to a controlled cell death pathway in order to not to compromise the well-being of the whole tissue. The
polyamines,
spermine and
spermidine are essential cellular constituents, participating in many vital functions such as proliferation and differentiation, immune response and scavenging of
reactive oxygen species. Therefore, dysregulation of
polyamine metabolism is often associated with different pathological states.
Polyamine acetylating
enzyme spermidine/
spermine-N(1)-
acetyltransferase is induced by
inflammation, drugs and by several other environmental insults. Resulting accelerated
polyamine acetylation with accompanying
polyamine biosynthesis induction i.e. activation of
polyamine futile cycle generates excessive amount of
hydrogen peroxide, hampers cell energy metabolism and induces
mitochondrial dysfunction and biogenesis. Therefore, the drugs inhibiting
polyamine metabolism are valuable in protecting mitochondria and cell energy metabolism. Here we review the current literature focusing on the applicability of chargedeficient
polyamine analogs as drugs to modulate
polyamine metabolism. Alteration of pK(a) of amino group(s) in a respective analog is achieved by
fluorine substitution of
hydrogen atom,
hydroxylamine substitution of
methylamine or by reducing the numbers of
carbon atoms between
amine groups to two instead of three or four.