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Called “bioblasts” in 1890, named “mitochondria” in 1898, baptized in 1957 as the “powerhouse of the cell” and christened in 1999 as the “motor of cell death”, mitochondria have been anointed in 2017 as “powerhouses of immunity”. In 1962, for the first time a causal link between mitochondria and human diseases was described, the genetic basis for which was revealed in 1988. The term “mitochondrial medicine” was coined in 1994. Research into mitochondria has been conducted ever since light microscopic studies during the end of the 19th century revealed their existence. To this day, new discoveries around this organelle and above all new insights into their fundamental role for human health and disease continue to surprise. Nowadays hardly any disease is known for which either the etiology or pathogenesis is not associated with malfunctioning mitochondria. In this second part of our review about recent developments in mitochondrial medicine we continue tracking and highlighting selected lines of mitochondrial research from their beginnings up to the present time. Mainly written for readers not familiar with this cell organelle, we hope both parts of our review will substantiate what we articulated over a decade ago, namely that the future of medicine will come through better understanding of the mitochondrion.

Research into elucidating structure and function of mitochondria has been quite steady between the time of discovery during the end of the 19th century until towards the late 1980’s. During the 1990s there was talk about a “comeback” of this organelle reflecting a widely revitalized interest into mitochondrial research which was based on two major discoveries made during that time. The first was the etiological association between human diseases and mitochondrial DNA mutations, while the second revealed the crucial function of mitochondria during apoptosis. The March 5th, 1999 issue of Science even featured a textbook image of a mitochondrion on its front cover and was entirely dedicated to this organelle. Whilst the term “comeback” might have been appropriate to describe the general excitement surrounding the new mitochondrial discoveries made during the 1990s, a term for describing the progress made in mitochondrial research during the last two decades is difficult to find. Between 2000 and 2020 the number of publications on mitochondria has skyrocketed. It is now widely accepted that there hardly exists any human disease for which either the etiology or pathogenesis does not seem to be associated with mitochondrial malfunction. In this review we will discuss and follow several lines of mitochondrial research from their early beginnings up to the present. We hope to be able to convince the reader of what we expressed about a decade ago, that the future of medicine will come through mitochondria.

Previously, we demonstrated that ferulate ethyl and tocopherol reduced HIV replication. In this study, we investigate whether the conjugation of both compounds (O-tocopheryl succinyl O-ethyl ferulate) can increase HIV inhibition. We show here for the first time that O-tocopheryl succinyl O-ethyl ferulate inhibits 80% of HIV replication (HIV-1 acute infection and HIV transmission), inhibits cell lipoperoxidation and prevents cellular glutathione consumption. Compared to ferulate ethyl and tocopheryl succinyl, O-tocopheryl succinyl O-ethyl ferulate inhibits more HIV replication. This may be due in part to the great increase in the lipophilicity of this compound.

The frequent neoplastic disorders present in HIV-infected patients and the implication of oxidative stress in AIDS-Kaposi's sarcoma pathogenesis prompted us to study whether the mechanisms implicated in genotoxic effects of clastogenic factors (CFs) (i.e., chromosome damaging materials released by cells under conditions of oxidant stress) can play a role in HIV-1 expression and whether exogenous superoxide dismutase can inhibit the clastogenic and HIV-inducing effects of CFs. CFs were found in the plasma of all HIV-1 infected patients (n = 21) of this study group, in asymptomatic (CDC II) as well as in symptomatic patients (CDC IV). In addition to their chromosome damaging effect, CFs are able to upregulate HIV-1 expression in U1 cells and in PBMCs activated with PHA and IL2 at all time points (p < .05). Their formation, therefore, is an early event in the disease. It occured despite antiviral medication in these patients. Superoxide dismutase inhibited the clastogenic and the viral inducing effects (p < .05). On the basis of our findings, association of SOD mimetics or superoxide scavengers with antiviral drugs may be a new therapeutic approach. This polytherapy, if started early enough after infection, may prolong the latency period and limit the emergence of drug-resistant viral strains.

We recently demonstrated that exogenous copper-zinc superoxide dismutase (SOD) reduced HIV replication in tumor necrosis factor alpha activated chronically HIV-infected promonocytic U1 cell line and in peripheral blood mononuclear cells coculture. However, whether exogenous SOD penetrates the cellular membrane or acts extracellularly has been remained controversial. SOD has been considered as not to penetrate the cellular membrane because of its high molecular weight, thus the main site of action is presumed to be extracellular. In order to determine whether exogenous SOD penetrates inside the cell, we utilized a gentle immunocytochemical method to detect Mn and Cu,Zn SOD in peripheral blood lymphocytes incubated with various concentrations of exogenous carrier-free Cu,Zn SOD without prior permeabilization of cell membranes. After 24 hrs. the total SOD activity and immunocytochemical studies were performed. Here we demonstrate clearly that a large amount of carrier-free Cu,Zn SOD, added exogenously, penetrates the cellular membrane and increases total SOD activity.