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Stefano G.B.,MitoGenetics | Kream R.M.,MitoGenetics
Medical Science Monitor | Year: 2015

The primacy of glucose derived from photosynthesis as an existential source of chemical energy across plant and animal phyla is universally accepted as a core principle in the biological sciences. In mammalian cells, initial processing of glucose to triose phosphate intermediates takes place within the cytosolic glycolytic pathway and terminates with temporal transport of reducing equivalents derived from pyruvate metabolism by membrane-associated respiratory complexes in the mitochondrial matrix. The intra-mitochondrial availability of molecular oxygen as the ultimate electron acceptor drives the evolutionary fashioned chemiosmotic production of ATP as a high-efficiency biological process. The mechanistic bases of carcinogenesis have demonstrated profound alteration of normative mitochondrial function, notably dysregulated respiratory processes. Accordingly, the classic Warburg effect functionally links aerobic glycolysis, aberrant production and release of lactate, and metabolic down-regulation of mitochondrial oxidative processes with the carcinogenetic phenotype. We surmise, however, that aerobic fermentation by cancer cells may also represent a developmental reemergence of an evolutionarily conserved early phenotype, which was “sidelined” with the emergence of mitochondrial oxidative phosphorylation as a primary mechanism for ATP production in normal cells. Regardless of state-dependent physiological status in mixed populations of cancer cells, it has been established that mitochondria are functionally linked to the initiation of cancer and its progression. Biochemical, molecular, and physiological differences in cancer cell mitochondria, notably mtDNA heteroplasmy and allele-specific expression of selected nuclear genes, may represent major focal points for novel targeting and elimination of cancer cells in metastatic disease afflicting human populations. To date, and despite considerable research efforts, the practical realization of advanced mitochondrial targeted therapies has not been forthcoming. © Med Sci Monit, 2015.


Stefano G.B.,MitoGenetics | Kream R.M.,MitoGenetics
Medical Science Monitor | Year: 2015

In mammals and invertebrates, the activities of neuro- and immuno-competent cells, e.g., glia, which are present in nervous tissues, are deemed of critical importance to normative neuronal function. The responsiveness of invertebrate and vertebrate immuno-competent glia to a common set of signal molecules, such as nitric oxide and endogenous morphine, is functionally linked to physiologically driven innate immunological and neuronal activities. Importantly, the presence of a common, evolutionarily conserved, set of signal molecules in comparative animal groups strongly suggests an expansive intermediate metabolic profile dependent on high output mitochondrial ATP production and utilization. Normative bidirectional neural-immune communication across invertebrate and vertebrate species requires common anatomical and biochemical substrates and pathways involved in energy production and mitochondrial integrity. Within this closed-loop system, abnormal perturbation of the respective tissue functions will have profound ramifications in functionally altering associated nervous and vascular systems and it is highly likely that the initial trigger to the induction of a physiologically debilitating pro-inflammatory state is a micro-environmental hypoxic event. This is surmised by the need for an unwavering constant oxygen supply. In this case, temporal perturbations of normative oxygen tension may be tolerated for short, but not extended, periods and ischemic/hypoxic perturbations in oxygen delivery represent significant physiological challenges to overall cellular and multiple organ system viability. Hence, hypoxic triggering of multiple pro-inflammatory events, if not corrected, will promote pathophysiological amplification leading to a deleterious cascade of bio-senescent cellular and molecular signaling pathways, which converge to markedly impair mitochondrial energy utilization and ATP production. © Med Sci Monit.


Stefano G.B.,MitoGenetics | Kream R.M.,MitoGenetics
African Journal of Psychiatry (South Africa) | Year: 2015

Microglia have selectively evolved as a morphologically and chemically distinct class of immuno-competent CNS resident cells with potent bidirectional signaling capabilities linked to induction of a macrophage-like phenotype following metabolic, microbiological, or viral insults. It has been empirically determined that a conserved set of shared chemical messengers connects a communication network mediating reciprocal exchange of regulatory information between immune, central nervous, and neuroendocrine systems. From an evolutionary perspective, the pluripotent neuro-protective capabilities of invertebrate microglia have been extended and amplified in classes of mammalian microglia. The state-dependent plasticity of microglia has provoked considerable empirical investigation into their functional/regulatory roles in mediating innate immune surveillance and neural protection within the CNS. Upon pathophysiological dysregulation, aberrant microglial activities may provide significant contributory factors in the etiology and persistence of major neurological, degenerative, and psychiatric disorders. Within this context, invertebrate microglia appear to represent highly appropriate model systems to investigate underlying cellular and molecular mechanisms involved in higher order neuroimmune regulation of multiple CNS activities by mammalian microglia. © 2015 Stefano GB, et al.


Stefano G.B.,MitoGenetics | Kream R.M.,MitoGenetics
International Journal of Molecular Medicine | Year: 2016

Mitochondria and chloroplasts represent endosymbiotic models of complex organelle development, driven by intense evolutionary pressure to provide exponentially enhanced ATP-dependent energy production functionally linked to cellular respiration and photosynthesis. Within the realm of translational medicine, it has become compellingly evident that mitochondrial dysfunction, resulting in compromised cellular bioenergetics, represents a key causative factor in the etiology and persistence of major diseases afflicting human populations. As a pathophysiological consequence of enhanced oxygen utilization that is functionally uncoupled from the oxidative phosphorylation of ADP, significant levels of reactive oxygen species (ROS) may be generated within mitochondria and chloroplasts, which may effectively compromise cellular energy production following prolonged stress/inflammatory conditions. Empirically determined homologies in biochemical pathways, and their respective encoDing gene sequences between chloroplasts and mitochondria, suggest common origins via entrapped primordial bacterial ancestors. From evolutionary and developmental perspectives, the elucidation of multiple biochemical and molecular relationships responsible for errorless bioenergetics within mitochondrial and plastid complexes will most certainly enhance the depth of translational approaches to ameliorate or even prevent the destructive effects of multiple disease states. The selective choice of discussion points contained within the present review is designed to provide theoretical bases and translational insights into the pathophysiology of human diseases from a perspective of dysregulated mitochondrial bioenergetics with special reference to chloroplast biology.


Stefano G.B.,MitoGenetics | Kream R.M.,MitoGenetics
Annals of Transplantation | Year: 2015

The vital status of diverse classes of eukaryotic mitochondria is reflected by the high degree of evolutionary modification functionally linked to ongoing multifaceted organelle development. From this teleological perspective, a logistical enhancement of eukaryotic cellular energy requirements indicates a convergence of metabolic processes within the mitochondrial matrix for optimal synthesis of ATP from ADP and inorganic phosphate and necessitates an evolutionarily driven retrofit of the primordial endosymbiont bacterial plasma membrane into the inner mitochondrial membrane. The biochemical complexity of eukaryotic inner membrane electron transport complexes linked to temporally- defined, state-dependent, fluctuations in mitochondrial oxygen utilization is capable of generating deleterious reactive oxygen species. Within this functional context, an extensive neurochemical literature supports the role of the free radical gas nitric oxide (NO) as a key signaling molecule involved in the regulation of multiple aspects of mitochondrial respiration/oxidative phosphorylation. Importantly, the unique chemical properties of NO underlie its rapid metabolism in vivo within a mechanistic spectrum of small oxidative molecules, free and protein-bound thiol adducts, and reversible binding to ferrous heme iron centers. Recent compelling work has identified a medically relevant dual regulation pathway for mitochondrial NO expression mediated by traditionally characterized NO synthases (NOS) and by enzymatic reduction of available cellular nitrite pools by a diverse class of cytosolic and mitochondrial nitrite reductases. Accordingly, our short review presents selected medically-based discussion topics relating to multi-faceted NO regulation of mitochondrial functions in human health and disease states. © Ann Transplant, 2015.

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