Mitochondrial Respiratory Chain Research Papers (original) (raw)

Treating Pain and Inflammation Naturally – Part 9 [Abstract]: Building upon previous reviews in this Journal, this new review discusses advances in our understanding of natural/nonpharmacologic treatments for disorders of pain and... more

Treating Pain and Inflammation Naturally – Part 9 [Abstract]: Building upon previous reviews in this Journal, this new review discusses advances in our understanding of natural/nonpharmacologic treatments for disorders of pain and inflammation by extending the information detailed in Part 6, discussing the role of the microbiome and dysbiosis in musculoskeletal disorders of persistent pain and inflammation. Following the introduction, a survey of the history of and recent developments in the study of the microbiome and dysbiosis will be provided; thereafter, fibromyalgia will be used as an example of dysbiosis-induced disease, exemplifying dysbiotic mitochondriopathy along with microbe-induced microglial activation as the cause of central sensitization and pain amplification. [This document was relocated July 2019 because a hyperlink in the document needed to be updated and multiple attempts to upload to the original location (various attempts, with different browsers, etc). Previous version had 1,832 Views as of July 2019.]

The mitochondria of the oocyte are a prominent source of energy metabolism as well as mitochondrial DNA that will later populate the cells of the offspring. Recent discoveries provided new insight into the physiology of the mitochondria... more

The mitochondria of the oocyte are a prominent source of energy metabolism as well as mitochondrial DNA that will later populate the cells of the offspring. Recent discoveries provided new insight into the physiology of the mitochondria and its unique genetics. The concept of heteroplasmy defined as the presence of more than one type of mitochondrial genome, is gaining increasing recognition as an important contributor to several complex morbidities, age-related reproductive dysfunction and aging. Understanding the changes caused by pathogenic mutations as well as identifying defects occurring during reproductive aging will enhance our knowledge of the role of mitochondria as organelles in germ cell biology. In this review, we summarize the current state of knowledge about the role of mitochondria in embryo and fetal development.

Recent evidence highlights that energy requirements of cancer cells vary greatly from normal cells and they exhibit different metabolic phenotypes with variable participation of both glycolysis and oxidative phosphorylation (OXPHOS).... more

Recent evidence highlights that energy requirements of cancer cells vary greatly from normal cells and they exhibit different metabolic phenotypes with variable participation of both glycolysis and oxidative phosphorylation (OXPHOS). Interestingly, mitochondrial electron transport chain (ETC) has been identified as an essential component in bioenerget-ics, biosynthesis and redox control during proliferation and metastasis of cancer cells. This dependence converts ETC of cancer cells in a promising target to design small molecules with anti-cancer actions. Several small molecules have been described as ETC inhibitors with different consequences on mitochondrial bioenergetics, viability and proliferation of cancer cells, when the substrate availability is controlled to favor either the glycolytic or OXPHOS pathway. These ETC inhibitors can be grouped as 1) inhibitors of a respiratory complex (e.g. rotenoids, vanilloids, alkaloids, biguanides and polyphenols), 2) inhibitors of several respiratory complexes (e.g. capsaicin, ME-344 and epigallocatechin-3 gallate) and 3) inhibitors of ETC activity (e.g. elesclomol and VLX600). Although pharmacological ETC inhibition may produce cell death and a decrease of proliferation of cancer cells, factors such as degree of inhibition of ETC activity by small molecules, bioenergetic profile and metabolic flexibility of different cancer types or subpopulations of cells in a particular cancer type, can affect the impact of the anti-cancer actions. Particularly interesting are the adap-tive mechanisms induced by ETC inhibition, such as induction of glutamine-dependent reductive carboxylation, which may offer a strategy to sensitize cancer cells to inhibitors of glutamine metabolism.

Brain hexokinase is associated with the outer membrane of mitochondria, and its activity has been implicated in the regulation of ATP synthesis and apoptosis. Reactive oxygen species (ROS) are by-products of the electron transport chain... more

Brain hexokinase is associated with the outer membrane of mitochondria, and its activity has been implicated in the regulation of ATP synthesis and apoptosis. Reactive oxygen species (ROS) are by-products of the electron transport chain in mitochondria. Here we show that the ADP produced by hexokinase activity in rat brain mitochondria (mt-hexokinase) controls both membrane potential (m) and ROS generation. Exposing control mitochondria to glucose increased the rate of oxygen consumption and reduced the rate of hydrogen peroxide generation. Mitochondrial associated hexoki-nase activity also regulated m , because glucose stabilized low m values in state 3. Interestingly, the addition of glucose 6-phosphate significantly reduced the time of state 3 persistence, leading to an increase in the m and in H 2 O 2 generation. The glucose analogue 2-de-oxyglucose completely impaired H 2 O 2 formation in state 3-state 4 transition. In sharp contrast, the mt-hexoki-nase-depleted mitochondria were, in all the above mentioned experiments, insensitive to glucose addition, indicating that the mt-hexokinase activity is pivotal in the homeostasis of the physiological functions of mitochon-dria. When mt-hexokinase-depleted mitochondria were incubated with exogenous yeast hexokinase, which is not able to bind to mitochondria, the rate of H 2 O 2 generation reached levels similar to those exhibited by control mitochondria only when an excess of 10-fold more enzyme activity was supplemented. Hyperglycemia induced in embryonic rat brain cortical neurons increased ROS production due to a rise in the intracellu-lar glucose 6-phosphate levels, which were decreased by the inclusion of 2-deoxyglucose, N-acetyl cysteine, or carbonyl cyanide p-trifluoromethoxyphenylhydrazone. Taken together, the results presented here indicate for the first time that mt-hexokinase activity performed a key role as a preventive antioxidant against oxidative stress, reducing mitochondrial ROS generation through an ADP-recycling mechanism.

Retinal pigment epithelial cells exert an important supporting role in the eye and develop adaptiveresponses to oxidative stress or high glucose levels, as observed during diabetes. Endogenous antioxi-dant defences are mainly regulated by... more

Retinal pigment epithelial cells exert an important supporting role in the eye and develop adaptiveresponses to oxidative stress or high glucose levels, as observed during diabetes. Endogenous antioxi-dant defences are mainly regulated by Nrf2, a transcription factor that is activated by naturally-derivedand electrophilic compounds. Here we investigated the effect of the Nrf2 activators dimethylfumarate(DMF) and carnosol on antioxidant pathways, oxygen consumption rate and wound healing in humanretinal pigment epithelial cells (ARPE-19) cultured in medium containing normal (NG, 5 mM) or high(HG, 25 mM) glucose levels. We also assessed wound healing using an in vivo corneal epithelial injurymodel. We found that Nrf2 nuclear translocation and heme oxygenase activity increased in ARPE cellstreated with 10 M DMF or carnosol irrespective of glucose culture conditions. However, HG renderedretinal cells more sensitive to regulators of glutathione synthesis or inhibition and caused a decrease ofboth cellular and mitochondrial reactive oxygen species. Culture in HG also reduced ATP production andmitochondrial function as measured with the Seahorse XF analyzer and electron microscopy analysisrevealed morphologically damaged mitochondria. Acute treatment with DMF or carnosol did not restoremitochondrial function in HG cells; conversely, the compounds reduced cellular maximal respiratory andreserve capacity, which were completely prevented by N-acetylcysteine thus suggesting the involvementof thiols in this effect. Interestingly, the scratch assay showed that wound closure was faster in cells cul-tured in HG than NG and was accelerated by carnosol. This effect was reversed by an inhibitor of hemeoxygenase activity. Moreover, topical application of carnosol to the cornea of diabetic rats significantlyaccelerated wound healing. In summary, these data indicate that culture of retinal epithelial cells in HGdoes not affect the activation of the Nrf2/heme oxygenase axis but influences other crucial oxidativeand mitochondrial-dependent cellular functions. The additional effect on wound closure suggests thatresults obtained in in vitro experimental settings need to be carefully evaluated in the context of theglucose concentrations used in cell culture.

Xanthine oxidoreductase (XOR) is increased in the left ventricle (LV) of humans with volume overload (VO), and mitochondrial inhibition of the respiratory chain occurs in animal models of VO. Because mitochondria are both a source and a... more

Xanthine oxidoreductase (XOR) is increased in the left ventricle (LV) of humans with volume overload (VO), and mitochondrial inhibition of the respiratory chain occurs in animal models of VO. Because mitochondria are both a source and a target of reactive oxygen and nitrogen species, we hypothesized that activation of XOR and mitochondrial dysfunction are interdependent. To test this we used the aortocaval fistula (ACF) rat model of VO and a simulation of the stretch response in isolated adult cardiomyocytes with and without the inhibitor of XOR, allopurinol, or the mitochondrially targeted antioxidant MitoQ. Xanthine oxidase (XO) activity was increased in cardiomyocytes from ACF vs sham rats (24 h) without an increase in XO protein. A twofold increase in LV end-diastolic pressure/wall stress and a decrease in LV systolic elastance with ACF were improved when allopurinol treatment (100 mg/kg) was started at ACF induction. Subsarcolemmal State 3 mitochondrial respiration was significantly decreased in ACF and normalized by allopurinol. Cardiomyocytes subjected to 3 h cyclical stretch resulted in an increase in XO activity and mitochondrial swelling, which was prevented by allopurinol or MitoQ pretreatment. These studies establish an early interplay between cardiomyocyte XO activation and bioenergetic dysfunction that may provide a new target that prevents progression to heart failure in VO.► Acute cardiac volume overload results in contractile/bioenergetic dysfunction. ► Allopurinol protects cardiac/bioenergetic function in acute volume overload. ► Cardiomyocyte stretch damages myofibrils and mitochondria which is prevented by MitoQ or allopurinol. ► Mitochondrial ROS regulates activation of Xanthine Oxidase leading to cell damage in the heart.

Salinity exerts a severe detrimental effect on crop yields globally. Growth of plants in saline soils results in physiological stress, which disrupts the essential biochemical processes of respiration, photosynthesis, and transpiration.... more

Salinity exerts a severe detrimental effect on crop yields globally. Growth of plants in saline soils results in physiological stress, which disrupts the essential biochemical processes of respiration, photosynthesis, and transpiration. Understanding the molecular responses of plants exposed to salinity stress can inform future strategies to reduce agricultural losses due to salinity; however, it is imperative that signalling and functional response processes are connected to tailor these strategies. Previous research has revealed the important role that plant mitochondria play in the salinity response of plants. Review of this literature shows that 2 biochemical processes required for respiratory function are affected under salinity stress: the tricarboxylic acid cycle and the transport of metabolites across the inner mitochondrial membrane. However, the mechanisms by which components of these processes are affected or react to salinity stress are still far from understood. Here, we examine recent findings on the signal transduction pathways that lead to adaptive responses of plants to salinity and discuss how they can be involved in and be affected by modulation of the machinery of energy metabolism with attention to the role of the tricarboxylic acid cycle enzymes and mitochondrial membrane transporters in this process.

Many pathological conditions can be the cause or the consequence of mitochondrial dysfunction. For instance anoxia, which is initiated by a critical reduction of oxygen availability for mitochondrial oxidations, is followed by a wide... more

Many pathological conditions can be the cause or the consequence of mitochondrial dysfunction. For instance anoxia, which is initiated by a critical reduction of oxygen availability for mitochondrial oxidations, is followed by a wide variety of mitochondrial alterations. A crucial role in the evolution of cell injury is to be attributed to the direction of operation of the F0F1 ATPase, which may turn mitochondria into the major consumers of cellular ATP in the futile attempt to restore the proton electrochemical gradient. On the other hand, functional mitochondria can paradoxically accelerate or exacerbate cell damage. This concept is particularly relevant for the ischemic myocardium. Indeed, inhibition of the respiratory chain or addition of uncouplers of oxidative phosphorylation can both limit the extent of enzyme release in the intact heart and prevent the onset of irreversible morphological changes in isolated myocytes. From studies on different tissues in a variety of patholog...