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-N1-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 pKa 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.