Loss Of Mitochondrial Function Research Articles

Mitochondrial dynamics and quality control are altered in a hepatic cell culture model of cancer cachexia.

Hepatic mitochondrial function loss is associated with cancer cachexia pathology in vivo. Here, we examined if hepatic mitochondrial defects observed in vivo in the cachexic liver also recapitulate during the in vitro treatment of mouse hepatocytes with tumor conditioned media. In vitro experiments were combined with proteome-wide expression analysis of cachexic liver tissue curated for mitochondrial dynamics and quality control proteins, to determine the fidelity of hepatic mitochondrial maladaptation in cancer cachexia pathology. AML12 hepatocytes were exposed to colon-26 (C26) and Lewis lung carcinoma (LLC) conditioned media for 6-72h and assayed for cell viability, membrane potential, respiratory function, H2O2 production, total ROS/RNS, and mitochondrial dynamics and quality control proteins by immunoblotting. Liver tissue from cachexic C26 mice was analyzed by TMT-based quantitative proteomics for in vivo comparison. Cell viability, membrane potential, H2O2 production, total ROS/RNS, and respiration were decreased 48-72h after exposure to C26 and/or LLC. Protein expression of treated hepatocytes and cachexic liver tissue showed altered mitochondrial dynamics and quality control, in a manner that suggests limited fusion and content mixing, but also impaired ability to fragment and clear damaged mitochondria. Two strategies to maintain mitochondrial health, therefore, may not be functioning sufficiently in the cachexic liver. Together these findings imply adverse effects of C26 and LLC exposure on hepatocyte health, due to impaired mitochondrial function and remodeling. Exposure of mouse hepatocytes to tumor conditioned media models aspects of cachexic liver mitochondria dysfunction in vivo and validates the importance of hepatic mitochondrial maladaptation in cancer cachexia pathology.

Role of Oxidative Stress and Metal Toxicity in the Progression of Alzheimer's Disease.

Alzheimer’s disease (AD) is one of the life-threatening neurodegenerative disorders in the elderly (>60 years) and incurable across the globe to date. AD is caused by the involvement of various genetic, environmental and lifestyle factors that affect neuronal cells to degenerate over the period of time. The oxidative stress is engaged in the pathogenesis of various disorders and its key role is also linked to the etiology of AD. AD is attributed by neuronal loss, abnormal accumulation of Amyloid-β (Aβ) and neurofibrillary tangles (NFTs) with severe memory impairments and other cognitive dysfunctions which lead to the loss of synapses and neuronal death and eventual demise of the individual. Increased production of reactive oxygen species (ROS), loss of mitochondrial function, altered metal homeostasis, aberrant accumulation of senile plaque and mitigated antioxidant defense mechanism all are indulged in the progression of AD. In spite of recent advances in biomedical research, the underlying mechanism of disruption of redox balance and the actual source of oxidative stress is still obscure. This review highlights the generation of ROS through different mechanisms, the role of some important metals in the progression of AD and free radical scavenging by endogenous molecule and supplementation of nutrients in AD.

Human apolipoprotein L1 interferes with mitochondrial function in Saccharomycescerevisiae.

To the best of our knowledge, the vertebrate apolipoprotein L (APOL) family has not previously been ascribed to any definite pathophysiological function, although the conserved BH3 protein domain suggests a role in programmed cell death or an interference with mitochondrial processes. In the present study, the human APOL1 was expressed in the yeast Saccharomyces cerevisiae in order to determine the molecular action of APOL1. APOL1 inhibited cell proliferation in a non-fermentable carbon source, such as glycerol, while it had no effect on proliferation in fermentable carbon sources, such as galactose. APOL1, expressed in yeast, is localized in the mitochondrial fraction, as determined via western blotting. APOL1 induced a loss of mitochondrial function, demonstrated by a loss of respiratory index, and mitochondrial membrane potential. Green fluorescent protein tagging of mitochondrial protein revealed that APOL1 was associated with abnormal mitochondrial and lysosomal morphologies, observed by a loss of the normal mitochondrial tubular network. Thus, the results of the present study suggest that APOL1 could be a physiological regulator of mitochondrial function.

TGF-β1 attenuates mitochondrial bioenergetics in pulmonary arterial endothelial cells via the disruption of carnitine homeostasis

Transforming growth factor beta-1 (TGF-β1) signaling is increased and mitochondrial function is decreased in multiple models of pulmonary hypertension (PH) including lambs with increased pulmonary blood flow (PBF) and pressure (Shunt). However, the potential link between TGF-β1 and the loss of mitochondrial function has not been investigated and was the focus of our investigations. Our data indicate that exposure of pulmonary arterial endothelial cells (PAEC) to TGF-β1 disrupted mitochondrial function as determined by enhanced mitochondrial ROS generation, decreased mitochondrial membrane potential, and disrupted mitochondrial bioenergetics. These events resulted in a decrease in cellular ATP levels, decreased hsp90/eNOS interactions and attenuated shear-mediated NO release. TGF-β1 induced mitochondrial dysfunction was linked to a nitration-mediated activation of Akt1 and the subsequent mitochondrial translocation of endothelial NO synthase (eNOS) resulting in the nitration of carnitine acetyl transferase (CrAT) and the disruption of carnitine homeostasis. The increase in Akt1 nitration correlated with increased NADPH oxidase activity associated with increased levels of p47phox, p67phox, and Rac1. The increase in NADPH oxidase was associated with a decrease in peroxisome proliferator-activated receptor type gamma (PPARγ) and the PPARγ antagonist, GW9662, was able to mimic the disruptive effect of TGF-β1 on mitochondrial bioenergetics. Together, our studies reveal for the first time, that TGF-β1 can disrupt mitochondrial function through the disruption of cellular carnitine homeostasis and suggest that stimulating carinitine homeostasis may be an avenue to treat pulmonary vascular disease.

Changes in PGC-1α/SIRT1 Signaling Impact on Mitochondrial Homeostasis in Amyloid-Beta Peptide Toxicity Model.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment that increasingly afflicts the elderly population. Soluble oligomers (AβOs) has been implicated in AD pathogenesis: however, the molecular events underlying a role for Aβ are not well understood. We studied the effects of AβOs on mitochondrial function and on key proteins that regulate mitochondrial dynamics and biogenesis in hippocampal neurons and PC-12 cells. We find that AβOs treatment caused a reduction in total Mfn1 after a 2 h exposure (42 ± 11%); while DRP1 increased at 1 and 2 h (205 ± 22% and 198 ± 27%, respectively), correlating to changes in mitochondrial morphology. We also observed that SIRT1 levels were reduced after acute and chronic AβOs treatment (68 ± 7% and 77 ± 6%, respectively); while PGC-1α levels were reduced with the same time treatments (68 ± 8% and 67 ± 7%, respectively). Interestingly, we found that chronic treatment with AβOs increased the levels of pSIRT1 (24 h: 157 ± 18%), and we observed changes in the PGC-1α and p-SIRT1 nucleus/cytosol ratio and SIRT1-PGC-1α interaction pattern after chronic exposure to AβOs. Our data suggest that AβOs induce important changes in the level and localization of mitochondrial proteins related with the loss of mitochondrial function that are mediated by a fast and sustained SIRT1/PGC-1α complex disruption promoting a “non-return point” to an irreversible synaptic failure and neuronal network disconnection.

Mitochondrial Transplantation: A Critical Analysis.

"Mitochondrial transplantation" refers to a procedure for introducing isolated mitochondria into a damaged area of a heart or other organ. A considerable amount of data has been accumulated on the therapeutic effects of "mitochondrial transplantation" in animals with ischemic heart damage. In 2017, the first attempts were made to apply this procedure in a clinic. The authors of the method suggest that exogenous mitochondria penetrate into cardiomyocytes, retaining functional activity, and compensate for impaired energy output of endogenous mitochondria. This hypothesis contradicts the well-known fact of loss of mitochondrial functions in the presence of high concentrations of Ca2+, which are characteristic of the extracellular medium. This review critically considers the possible mechanisms of the therapeutic effect of "mitochondrial transplantation".

MCL-1Matrix maintains neuronal survival by enhancing mitochondrial integrity and bioenergetic capacity under stress conditions

Mitochondria play a crucial role in neuronal survival through efficient energy metabolism. In pathological conditions, mitochondrial stress leads to neuronal death, which is regulated by the anti-apoptotic BCL-2 family of proteins. MCL-1 is an anti-apoptotic BCL-2 protein localized to mitochondria either in the outer membrane (OM) or inner membrane (Matrix), which have distinct roles in inhibiting apoptosis and promoting bioenergetics, respectively. While the anti-apoptotic role for Mcl1 is well characterized, the protective function of MCL-1 Matrix remains poorly understood. Here, we show MCL-1OM and MCL-1Matrix prevent neuronal death through distinct mechanisms. We report that MCL-1Matrix functions to preserve mitochondrial energy transduction and improves respiratory chain capacity by modulating mitochondrial oxygen consumption in response to mitochondrial stress. We show that MCL-1Matrix protects neurons from stress by enhancing respiratory function, and by inhibiting mitochondrial permeability transition pore opening. Taken together, our results provide novel insight into how MCL-1Matrix may confer neuroprotection under stress conditions involving loss of mitochondrial function.

Genetic regulation of nitric oxide-dependent mitochondrial metabolism and immune function in dendritic cells

Abstract Dendritic cell (DC) activation is characterized by a rapid “metabolic switch” towards increased glycolysis that supports maturation. Sustained glycolysis post-activation is a requirement for survival in DC subsets that express inducible nitric oxide synthase (iNOS), due to the production of nitric oxide (NO) which acts as an inhibitor of mitochondrial respiration. Long-term metabolic reprogramming in activated DCs has almost exclusively been studied in the strain C57BL/6, which experience loss of mitochondrial function due to NO accumulation. To assess the conservation of NO-driven metabolic regulation in DCs, we generated and compared cells from C57BL/6 mice to the wild-derived genetically diverse PWD/PhJ (PWD) strain. We show attenuated iNOS induction and significantly lower NO production in PWD DCs. Decreased NO production allows PWD DCs to maintain mitochondrial respiration following activation, and significantly alters their glucose-dependent carbon flux through the TCA cycle compared to C57BL/6 DCs. We utilize a consomic strain which includes the PWD chromosome segment containing the iNOS locus on an otherwise C57BL/6 genetic background to demonstrate that intrinsic differences in the iNOS locus drive differential iNOS regulation. We demonstrate that differential iNOS regulation amongst these strains impacts DC post-activation survival and immune effector functions. These studies provide a more comprehensive understanding of NO-driven metabolic reprogramming in the murine myeloid lineage and establish a natural genetic model for investigating the contribution of NO in regulating the interplay between DC metabolism and immune function.

Synthetic antiprotozoal thiazolide drug induced apoptosis in colorectal cancer cells: implications of IL-6/JAK2/STAT3 and p53/caspases-dependent signaling pathways based on molecular docking and in vitro study.

Colorectal cancer (CRC) is a global pressing healthcare priority. Dysregulation of the IL6/JAK2/STAT3 and p53/caspase downstreaming pathways are significantly involved in the progression of CRC, and mainly affecting apoptosis. Discovery of new anti-cancer agents is laborious, time consuming, and costly with obvious socioeconomic burden. In the present study, we are proposing new molecular insights on the anti-proliferative and apoptotic therapeutic effects of nitazoxanide (NTZ) on CRC. NTZ is FDA-approved thiazolide antiparasitic agent, which has excellent safety and pharmacokinetic profiles. The molecular docking study revealed that NTZ has better binding affinity and docking score against JAK2 and BCL2 proteins compared to 5-Fluorouracil, which is the standard drug for treatment of CRC. The current in vitro work on a human HCT116 cell line displayed that NTZ had lower IC50 value (11.20µM) than 5-flurouracil (23.78µM), and NTZ induced a statistically significant down-regulation of IL6/JAK2/STAT3. NTZ also modulated significantly the p53/caspases-dependent signaling pathways, leading to enhancement of apoptosis and an increase of DNA fragmentation. Moreover, NTZ regulated the Bcl-2 gene family and promoted the loss of mitochondrial function which was depicted by release of cytochrome c (Cyt c), and caspase activation in apoptotic HCT116 cells. Additionally, NTZ was able to reduce the expression of VEGF in CRC cell line, which needs future thorough molecular investigations. In conclusion, our findings provided a novel evidence that NTZ could be a dual potential IL6/JAK2/STAT3 signaling inhibitor and p53/caspases-dependent pathway activator in CRC cell line. These potentials support further exploratory molecular researches targeting the therapeutic roles of NTZ in CRC; individually and simultaneously with current approved chemotherapeutic regimens.

Association Between Functional Activity of Mitochondria and Actin Cytoskeleton Instability in Oocytes from Advanced Age Mice.

Mitochondrial dysfunction is strongly associated with the oocyte quality and aging, wherein the aged oocytes are related to the actin cytoskeleton integrity; however, whether this integrity is associated with mitochondrial dysfunction in oocytes from aged mice remains unclear. In the present study, we investigated the relationship between mitochondrial dysfunction and actin cytoskeleton instability in oocytes from the aged mice. We performed comparable analysis of mitochondrial motility between young, 1.5 μM cytochalasin B (CB)-treated young oocytes, and aged oocytes by confocal live imaging. Moreover, we analyzed the relationships between mitochondrial motility and maturation ratios, including ATP production ratio of the young, CB-treated young, and aged oocytes. Actin cytoskeleton instability in the aged oocytes and CB-treated young oocytes led to a significant decrease in the mitochondrial motility and low ATP productive ratios compared to those in the young group. Our data suggest that the actin cytoskeleton instability is presumably the primary cause for the loss of mitochondrial function in the aged murine oocytes.

Transcriptional responses of Candida glabrata biofilm cells to fluconazole are modulated by the carbon source

Candida glabrata is an important human fungal pathogen known to trigger serious infections in immune-compromised individuals. Its ability to form biofilms, which exhibit high tolerance to antifungal treatments, has been considered as an important virulence factor. However, the mechanisms involving antifungal resistance in biofilms and the impact of host niche environments on these processes are still poorly defined. In this study, we performed a whole-transcriptome analysis of C. glabrata biofilm cells exposed to different environmental conditions and constraints in order to identify the molecular pathways involved in fluconazole resistance and understand how acidic pH niches, associated with the presence of acetic acid, are able to modulate these responses. We show that fluconazole treatment induces gene expression reprogramming in a carbon source and pH-dependent manner. This is particularly relevant for a set of genes involved in DNA replication, ergosterol, and ubiquinone biosynthesis. We also provide additional evidence that the loss of mitochondrial function is associated with fluconazole resistance, independently of the growth condition. Lastly, we propose that C. glabrata Mge1, a cochaperone involved in iron metabolism and protein import into the mitochondria, is a key regulator of fluconazole susceptibility during carbon and pH adaptation by reducing the metabolic flux towards toxic sterol formation. These new findings suggest that different host microenvironments influence directly the physiology of C. glabrata, with implications on how this pathogen responds to antifungal treatment. Our analyses identify several pathways that can be targeted and will potentially prove to be useful for developing new antifungals to treat biofilm-based infections.

Mitochondrial hyperactivity as a potential therapeutic target in Parkinson’s disease

Mitochondrial dysfunction is thought to contribute to neurodegeneration in Parkinson’s disease (PD), yet the cellular events that lead to mitochondrial disruption remain unclear. Post-mortem studies of PD patient brains and the use of complex I inhibitors to model the disease previously suggested a reduction in mitochondrial activity as a causative factor in PD, but this may represent an endpoint in the disease process. In our recent studies, we identified a novel link between branched-chain amino acid metabolism and PD, and uncovered mitochondrial hyperactivity as a potential alternative mechanism of PD pathogenesis. Increased mitochondrial activity may occur in a subset of PD patients, or may be a more common early event that precedes the ultimate loss of mitochondrial function. Therefore, it may be that any imbalance in mitochondrial activity, either increased or decreased, could cause a loss of mitochondrial homeostasis that leads to disease. An effective therapeutic strategy may be to target specific imbalances in activity at selective stages of PD or in specific patients, with any efforts to reduce mitochondrial activity constituting a surprising new avenue for PD treatment.

Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons.

B-cell lymphoma-extra large (Bcl-xL) is an anti-apoptotic member of the Bcl2 family of proteins, which supports neurite outgrowth and neurotransmission by improving mitochondrial function. During excitotoxic stimulation, however, Bcl-xL undergoes post-translational cleavage to ∆N-Bcl-xL, and accumulation of ∆N-Bcl-xL causes mitochondrial dysfunction and neuronal death. In this study, we hypothesized that the generation of reactive oxygen species (ROS) during excitotoxicity leads to formation of ∆N-Bcl-xL. We further proposed that the application of an antioxidant with neuroprotective properties such as α-tocotrienol (TCT) will prevent ∆N-Bcl-xL-induced mitochondrial dysfunction via its antioxidant properties. Primary hippocampal neurons were treated with α-TCT, glutamate, or a combination of both. Glutamate challenge significantly increased cytosolic and mitochondrial ROS and ∆N-Bcl-xL levels. ∆N-Bcl-xL accumulation was accompanied by intracellular ATP depletion, loss of mitochondrial membrane potential, and cell death. α-TCT prevented loss of mitochondrial membrane potential in hippocampal neurons overexpressing ∆N-Bcl-xL, suggesting that ∆N-Bcl-xL caused the loss of mitochondrial function under excitotoxic conditions. Our data suggest that production of ROS is an important cause of ∆N-Bcl-xL formation and that preventing ROS production may be an effective strategy to prevent ∆N-Bcl-xL-mediated mitochondrial dysfunction and thus promote neuronal survival.

Ropinirole induces neuroprotection following reperfusion-promoted mitochondrial dysfunction after focal cerebral ischemia in Wistar rats

Stroke is characterized by an initial ischemia followed by a reperfusion that promotes cascade of damage referred to as primary injury. The loss of mitochondrial function after ischemia, which is characterized by oxidative stress and activation of apoptotic factors is considered to play a crucial role in the proliferation of secondary injury and subsequent brain neuronal cell death. Dopamine D2 receptor agonist, Ropinirole, has been found to promote neuroprotection in Parkinson´s disease and restless leg syndrome. The current study was designed to test its efficacy in preclinical model of stroke. Previously it has been demonstrated that Ropinirole mediates its neuroprotection via mitochondrial pathways. Assuming this, we investigated the effect of Ropinirole on mitochondrial dysfunction, we have shown the positive effect of Ropinirole administration on behavioral deficits and mitochondrial health in an ischemic stroke injury model of transient middle cerebral artery occlusion (tMCAO). Male Wistar rats underwent transient middle cerebral artery occlusion and then received the Ropinirole (10 mg and 20 mg/kg b.w.) at 6 h, 12 and 18 h post occlusion. Behavioral assessment for functional deficits included grip strength, motor coordination and gait analysis. Our findings revealed a significant improvement with Ropinirole treatment in tMCAO animals. Staining of isolated brain slices from Ropinirole-treated rats with 2, 3,5-triphenyltetrazolium chloride (TTC) showed a reduction in the infarct area in comparison to the vehicle group, indicating the presence of an increased number of viable mitochondria. Ropinirole treatment was also able to attenuate mitochondrial reactive oxygen species (ROS) production, as well as block the mitochondrial permeability transition pore (mPTP), in the tMCAO injury model. In addition, it was also able to ameliorate the altered mitochondrial membrane potential and respiration ratio in the ischemic animals, thereby suggesting that Ropinirole has a positive effect on mitochondrial bioenergetics. Ropinirole inhibited the translocation of cytochrome c from mitochondria to cytosol reduces the downstream apoptotic processes. In conclusion, these results demonstrate that Ropinirole treatment is beneficial in preserving the mitochondrial functions that are altered in cerebral ischemic injury and thus can help in defining better therapies.

Doxorubicin persistently rewires cardiac circadian homeostasis in mice.

Circadian rhythms disruption can be the cause of chronic diseases. External cues, including therapeutic drugs, have been shown to modulate peripheral-circadian clocks. Since anthracycline cardiotoxicity is associated with loss of mitochondrial function and metabolic remodeling, we investigated whether the energetic failure induced by sub-chronic doxorubicin (DOX) treatment in juvenile mice was associated with persistent disruption of circadian regulators. Juvenile C57BL/6J male mice were subjected to a sub-chronic DOX treatment (4 weekly injections of 5mg/kg DOX) and several cardiac parameters, as well as circadian-gene expression and acetylation patterns, were analyzed after 6weeks of recovery time. Complementary experiments were performed with Mouse Embryonic Fibroblasts (MEFs) and Human Embryonic Kidney 293 cells. DOX-treated juvenile mice showed cardiotoxicity markers and persistent alterations of transcriptional- and signaling cardiac circadian homeostasis. The results showed a delayed influence of DOX on gene expression, accompanied by changes in SIRT1-mediated cyclic deacetylation. The mechanism behind DOX interference with the circadian clock was further studied in vitro, in which were observed alterations of circadian-gene expression and increased BMAL1 SIRT1-mediated deacetylation. In conclusion, DOX treatment in juvenile mice resulted in disruption of oscillatory molecular mechanisms including gene expression and acetylation profiles.

Impairment of mitochondrial unfolded protein response contribute to resistance declination of H2 O2 -induced injury in senescent MRC-5 cell model.

Accumulation of oxidative proteins within mitochondria leads to loss of mitochondrial function, which may lead to age-related degenerative diseases. Mitochondrial antioxidant defense capacity reflects the expression of mitochondrial unfolded protein response (mtUPR)-related proteins. Senescent cells are considered to be less resistant to cellular stress stimuli than exponentially growing cells. In this study, we aimed to investigate the ability of mitochondrial stress response in senescent cells to cope with the accumulation of mitochondrial unfolded proteins induced by hydrogen peroxide (H2 O2 ) and to understand the relevant molecular mechanisms. We report here that senescence-associated β-galactosidase (SA-β-gal) and senescence marker protein-30 (SMP-30), commonly used replicative senescence biomarkers, changed remarkably between population doubling (PD) 25 (exponentially growing cells) and PD50 (senescent cells) of MRC-5 fibroblasts. Mitochondrial unfolded proteins were significantly accumulated in H2 O2 -treated senescent cells, whereas mtUPR-related molecular chaperones (heat shock protein Hsp60 and Hsp10) and proteases (caseinolytic Clp protease) were not concomitantly elevated in senescent cells. In addition, decreased expression of stromal interacting molecule 1-Orai1-mediated store-operated Ca2+ entry following an declined intracellular calcium level after 2 mM calcium treatment together with H2 O2 addition, implying impairment of calcium influx in senescent MRC-5 during H2 O2 -induced injury. These findings suggest that senescent fibroblasts expressed higher vulnerability to H2 O2 -induced injury involving the imbalance of calcium homeostasis and impaired mitochondrial nuclear communication. This may provide useful information for the future development of therapeutic agents to prevent the adverse effects of aging on cells and the potential for treatment of proteinopathies in the elderly.

Serine Protease HtrA2/Omi Deficiency Impairs Mitochondrial Homeostasis and Promotes Hepatic Fibrogenesis via Activation of Hepatic Stellate Cells.

The loss of mitochondrial function impairs intracellular energy production and potentially results in chronic liver disease. Increasing evidence suggests that mitochondrial dysfunction in hepatocytes contributes to the activation of hepatic stellate cells (HSCs), thereby resulting in hepatic fibrogenesis. High-temperature requirement protein A2 (HtrA2/Omi), a mitochondrial serine protease with various functions, is responsible for quality control in mitochondrial homeostasis. However, little information is available regarding its role in mitochondrial damage during the development of liver fibrosis. This study examined whether HtrA2/Omi regulates mitochondrial homeostasis in hepatocyte during the development of hepatic fibrogenesis. In this study, we demonstrated that HtrA2/Omi expression considerably decreased in liver tissues from the CCl4-induced liver fibrotic mice model and from patients with liver cirrhosis. Knockdown of HtrA2/Omi in hepatocytes induced the accumulation of damaged mitochondria and provoked mitochondrial reactive oxygen species (mtROS) stress. We further show that the damaged mtDNA isolated from HtrA2/Omi-deficient hepatocytes as a form of damage-associated molecular patterns can induce HSCs activation. Moreover, we found that motor neuron degeneration 2-mutant mice harboring the missense mutation Ser276Cys in the protease domain of HtrA2/Omi displayed altered mitochondrial morphology and function, which increased oxidative stress and promoted liver fibrosis. Conversely, the overexpression of HtrA2/Omi via hydrodynamics-based gene transfer led to the antifibrotic effects in CCl4-induced liver fibrosis mice model through decreasing collagen accumulation and enhancing anti-oxidative activity by modulating mitochondrial homeostasis in the liver. These results suggest that suppressing HtrA2/Omi expression promotes hepatic fibrogenesis via modulating mtROS generation, and these novel mechanistic insights involving the regulation of mitochondrial homeostasis by HtrA2/Omi may be of importance for developing new therapeutic strategies for hepatic fibrosis.

Dietary Polyphenols and Mitochondrial Function: Role in Health and Disease.

Mitochondria are cytoplasmic double-membraned organelles that are involved in a myriad of key cellular regulatory processes. The loss of mitochondrial function is related to the pathogenesis of several human diseases. Over the last decades, an increasing number of studies have shown that dietary polyphenols can regulate mitochondrial redox status, and in some cases, prevent or delay disease progression. This paper aims to review the role of four dietary polyphenols - resveratrol, curcumin, epigallocatechin-3-gallate nd quercetin - in molecular pathways regulated by mitochondria and their potential impact on human health. Cumulative evidence showed that the aforementioned polyphenols improve mitochondrial functions in different in vitro and in vivo experiments. The mechanisms underlying the polyphenols' beneficial effects include, among others, the attenuation of oxidative stress, the regulation of mitochondrial metabolism and biogenesis and the modulation of cell-death signaling cascades, among other mitochondrial-independent effects. The understanding of the chemicalbiological interactions of dietary polyphenols, namely with mitochondria, may have a huge impact on the treatment of mitochondrial dysfunction-related disorders.

Inhibition of Mitochondrial Complex I Impairs Release of α-Galactosidase by Jurkat Cells.

Fabry disease (FD) is caused by mutations in the GLA gene that encodes lysosomal α-galactosidase-A (α-gal-A). A number of pathogenic mechanisms have been proposed and these include loss of mitochondrial respiratory chain activity. For FD, gene therapy is beginning to be applied as a treatment. In view of the loss of mitochondrial function reported in FD, we have considered here the impact of loss of mitochondrial respiratory chain activity on the ability of a GLA lentiviral vector to increase cellular α-gal-A activity and participate in cross correction. Jurkat cells were used in this study and were exposed to increasing viral copies. Intracellular and extracellular enzyme activities were then determined; this in the presence or absence of the mitochondrial complex I inhibitor, rotenone. The ability of cells to take up released enzyme was also evaluated. Increasing transgene copies was associated with increasing intracellular α-gal-A activity but this was associated with an increase in Km. Release of enzyme and cellular uptake was also demonstrated. However, in the presence of rotenone, enzyme release was inhibited by 37%. Excessive enzyme generation may result in a protein with inferior kinetic properties and a background of compromised mitochondrial function may impair the cross correction process.

Brown and Beige Adipose Tissue and Aging.

Across aging, adipose tissue (AT) changes its quantity and distribution: AT becomes dysfunctional with an increase in production of inflammatory peptides, a decline of those with anti-inflammatory activity and infiltration of macrophages. Adipose organ dysfunction may lead to age-related metabolic alterations. Aging is characterized by an increase in adiposity and a decline in brown adipose tissue (BAT) depots and activity, and UCP1 expression. There are many possible links to age-associated involution of BAT, including the loss of mitochondrial function, impairment of the sympathetic nervous system, age-induced alteration of brown adipogenic stem/progenitor cell function and changes in endocrine signals. Aging is also associated with a reduction in beige adipocyte formation. Beige adipocytes are known to differentiate from a sub-population of progenitors resident in white adipose tissue (WAT); a defective ability of progenitor cells to proliferate and differentiate has been hypothesized with aging. The loss of beige adipocytes with age may be caused by changes in trophic factors in the adipose tissue microenvironment, which regulate progenitor cell proliferation and differentiation. This review focuses on possible mechanisms involved in the reduction of BAT and beige activity with aging, along with possible targets for age-related metabolic disease therapy.