Mitochondrial dysfunction has been implicated in the development of a wide spectrum of major human diseases, including
diabetes mellitus, heart disorders, neurodegeneration and cancer. Several therapeutic approaches targeting mitochondrial function have
been applied in most cases without however the desired outcome. The limited effectiveness of these therapeutic schemes is due to the fact
that several important aspects of mitochondrial function have not been elucidated as yet, including the detailed mechanism of ATP production.
Although it is known that electron transport chain (ETC) is the central machinery responsible for mitochondrial oxidative ATP
production, major important functions attributed to ETC are still unresolved while other activities which are in fact carried out by the
ETC have been overlooked. This review revisits ATP synthesis providing a detailed account of the experimentally-verified ETC functions
focused on the ability of ETC to act as an electro-electric converter, able to accept different electrons from any given energy source
(light, food or metals) in order to produce the correct voltage and store it in the form of electrostatic potentials (mitochondrial membrane
potential). This stored electric energy, in the order of 3x107 V/m, can then be used by F1F0 ATP synthase for ATP production. The present
review provides supportive evidence that this ETC function suffices to fully explain the missing parts of ATP production, thus redirecting
the current therapeutic schemes for the management of mitochondrial diseases to a more complete and effective avenue.